WO2011146336A1 - Macrocyclic compounds as trk kinase inhibitors - Google Patents

Macrocyclic compounds as trk kinase inhibitors Download PDF

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Publication number
WO2011146336A1
WO2011146336A1 PCT/US2011/036452 US2011036452W WO2011146336A1 WO 2011146336 A1 WO2011146336 A1 WO 2011146336A1 US 2011036452 W US2011036452 W US 2011036452W WO 2011146336 A1 WO2011146336 A1 WO 2011146336A1
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Prior art keywords
alkyl
ring
formula
fluoro
compound according
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PCT/US2011/036452
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French (fr)
Inventor
Steven Wade Andrews
Kevin Ronald Condroski
Julia Haas
Yutong Jiang
Gabrielle R. Kolakowski
Jeongbeob Seo
Hong-Woon Yang
Qian Zhao
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Array Biopharma Inc.
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Priority to EP11728970.2A priority Critical patent/EP2571883B1/en
Priority to KR1020197024602A priority patent/KR102132405B1/en
Priority to KR1020127033226A priority patent/KR101852169B1/en
Application filed by Array Biopharma Inc. filed Critical Array Biopharma Inc.
Priority to EP17163978.4A priority patent/EP3205654B1/en
Priority to RU2012155278/04A priority patent/RU2594742C2/en
Priority to UAA201214588A priority patent/UA110701C2/en
Priority to KR1020187011138A priority patent/KR102015402B1/en
Priority to KR1020207019372A priority patent/KR20200085364A/en
Priority to US13/698,922 priority patent/US8933084B2/en
Priority to MX2014013626A priority patent/MX365251B/en
Priority to PL17163978T priority patent/PL3205654T3/en
Priority to MX2012013467A priority patent/MX2012013467A/en
Priority to CR20170098A priority patent/CR20170098A/en
Priority to ES11728970.2T priority patent/ES2534335T3/en
Priority to EP18208279.2A priority patent/EP3521291A1/en
Priority to NZ604708A priority patent/NZ604708A/en
Priority to CA2800079A priority patent/CA2800079C/en
Priority to BR112012029405-9A priority patent/BR112012029405B1/en
Priority to CN201180025013.9A priority patent/CN102971322B/en
Priority to SG2012084844A priority patent/SG185644A1/en
Priority to AU2011256380A priority patent/AU2011256380C1/en
Priority to MYPI2012700967A priority patent/MY191934A/en
Priority to JP2013511239A priority patent/JP5832527B2/en
Priority to BR122019024201-1A priority patent/BR122019024201B1/en
Publication of WO2011146336A1 publication Critical patent/WO2011146336A1/en
Priority to IL223094A priority patent/IL223094B/en
Priority to HK13108950.6A priority patent/HK1181756A1/en
Priority to US14/575,663 priority patent/US9493476B2/en
Priority to PH12015500190A priority patent/PH12015500190B1/en
Priority to AU2016203348A priority patent/AU2016203348C1/en
Priority to US15/350,888 priority patent/US9840519B2/en
Priority to US15/401,839 priority patent/US9718822B2/en
Priority to US15/401,952 priority patent/US9750744B2/en
Priority to US15/632,187 priority patent/US9902741B2/en
Priority to IL257104A priority patent/IL257104B/en
Priority to US15/900,019 priority patent/US10647730B2/en
Priority to AU2018208676A priority patent/AU2018208676B2/en
Priority to CY20191100365T priority patent/CY1121688T1/en
Priority to US16/818,125 priority patent/US20200291026A1/en
Priority to AU2020205339A priority patent/AU2020205339A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain macrocyclic compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • the current treatment regimes for pain conditions utilize several classes of compounds.
  • the opioids such as morphine
  • Nonsteroidal anti-inflammatory analgesics NSAIDs, such as COX-1 or COX-2 types
  • COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.
  • Trk's are high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT).
  • the Trk receptor family has three members: TrkA, TrkB and TrkC.
  • the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC.
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • Trk-3 which activates TrkC.
  • Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).
  • Inhibitors of the Trk/neurotrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain.
  • antagonistic NGF and TrkA antibodies such as RN-624 have been shown to be efficacious in inflammatory and neuropathic pain animal models (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.
  • NGF secreted by tumor cells and tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers.
  • Using various tumor models in both mice and rats it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine.
  • activation of the BDNF/TrkB pathway has been implicated in numerous studies as a modulator of various types of pain including inflammatory pain (Matayoshi, S., J. Physiol. 2005, 569:685-95), neuropathic pain (Thompson, S.W., Proc. Natl. Acad. Sci. USA 1999, 96:7714-18) and surgical pain (Li, C.-Q. et al, Molecular Pain, 2008, 4(28), 1-1 1).
  • Trk kinases are associated with many cancers including 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. 644-653), gastric carcinoma (Du, J.
  • inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of pre-clinical models of inflammatory diseases with NGF antibodies or non-selective small molecule inhibitors of Trk A, B and C.
  • inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma (Freund-Michel, V; Frossard, N., Pharmacology & Therapeutics (2008), 1 17(1), 52-76), interstitial cystitis (Hu Vivian, Y., et. al. The Journal of Urology
  • inflammatory bowel diseases 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. Archives of Dermatological Research
  • the neurotrophin/Trk pathway has also been implicated in the etiology of neurodegenerative diseases including multiple sclerosis, Parkinson's disease and Alzheimer's Disease (Sohrabji, F., Lewis, Danielle K., Frontiers in Neuroendocrinology (2006), 27(4), 404-414).
  • TrkA receptor is also thought to be critical to the disease process in the infection of the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts (de Melo- Jorge, M., et al, Cell Host & Microbe (2007), 1(4), 251-261).
  • Trk kinases [0010] Several classes of small molecule inhibitors of Trk kinases said to be useful for treating pain or cancer are known (Expert Opin. Ther. Patents (2009) 19(3)).
  • macrocyclic compounds are inhibitors of Trk kinases, in particular inhibitors of TrkA and/or TrkB and/or TrkC, and are useful for treating disorders and diseases such as cancer and pain, including chronic and acute pain.
  • Compounds which are inhibitors of TrkA and/or TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery and bone fracture.
  • compounds of the invention may be useful for treating inflammation, neurodegenerative diseases and certain infectious diseases.
  • present invention provides novel compounds having the general Formula I:
  • compositions comprising compounds of Formula I and a carrier, diluent or excipient.
  • a method for treating or preventing pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases in a mammal comprising administering to said mammal an effective amount of a compound of Formula I.
  • Formula I in the manufacture of a medicament for the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • Formula I in the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • Another aspect provides intermediates for preparing compounds of Formula I.
  • certain compounds of Formula I may be used as intermediates for the preparation of other compounds of Formula I.
  • Another aspect includes processes for preparing, methods of separation, and methods of purification of the compounds described herein.
  • One embodiment of this invention provides compounds of the general
  • ring A is selected from rings A-l, A-2 and A-3 having the structures:
  • X is N or CH
  • Y is H or F
  • R 1 is H, ( 1 -3 Qalkoxy or halogen
  • ring B is selected from rings B-l and B-2 having the structures:
  • W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
  • m 0, 1 or 2;
  • D is carbon
  • R 2 and R 2a are independently H, F, (1-3 Qalkyl or OH, provided that R 2 and
  • R 2a are not both OH
  • R 3 and R 3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl; [0037] or D is carbon or nitrogen, R 2 and R 3 are absent and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;
  • R 4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R 4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • 6C)alkyl hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, A ⁇ O)-, HOCH 2 C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (S0 2 )-, H0 2 CCH 2 - or (1-6C alkyl)NH(CO)-;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
  • Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
  • R 5 and R 6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • ring B is ring B-2 having the structure:
  • D is carbon, R 2 and R 2a are independently (1-3 Qalkyl, and R 3 and R 3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl, or
  • D is carbon or nitrogen, R 2 and R 3 are absent and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.
  • ring A is ring A- 1 having the structure
  • X is CH. In one embodiment, X is N. In one embodiment of Formula I, Y is F. In one embodiment, Y is H. In one embodiment of Formula I, R 1 is H. In one embodiment, R 1 is (l-3C)alkoxy. A particular example is methoxy. In one embodiment, R 1 is halogen. In one embodiment, R 1 is F.
  • ring A when represented by structure A- 1 include the structures:
  • ring A is ring A-2 having the structure
  • Y is H or F. In one embodiment, Y is F. In one embodiment, Y is H.
  • R 1 is H. In one embodiment, R 1 is (l-3C)alkoxy. A particular example is methoxy. In one embodiment, R 1 is halogen. In one embodiment, R 1 is F.
  • ring A when represented by ring A-2 are the structures:
  • ring A is ring A-3 having the structure
  • Y and R 1 is as defined for Formula I.
  • Y is F.
  • Y is H.
  • R 1 is H.
  • R 1 is (1- 3C)alkoxy. A particular example is methoxy.
  • R 1 is halogen.
  • R 1 is F.
  • ring A when represented by ring A-3 are the structures:
  • W is O.
  • W is NH
  • W is CH 2 .
  • D is carbon, R 2 and R 2a are independently H,
  • R 2 and R 2a are not both OH
  • R 3 and R 3a are independently H, (1-3 Qalkyl or hydroxy( 1-3 Qalkyl.
  • R 2 and R 2a are independently H, F, methyl or OH, provided that R 2 and R 2a are not both OH.
  • R 2 and R 2a are both H.
  • R 2 is H and R 2a is F.
  • R 2 and R 2a are both F.
  • R 2 is H and R 2a is OH.
  • R 2 is H and R 2a is methyl.
  • R 2 and R 2a are both methyl.
  • R 3 and R 3a are independently H, (l-3Qalkyl or hydroxy(l-3 Qalkyl.
  • R 3a is H. In one embodiment, R 3 is H. In one embodiment, both R 3 and R 3a are H.
  • R 3a is (l-3Qalkyl. Examples include methyl, ethyl, propyl and isopropyl. In one embodiment, R 3 is (l-3Qalkyl. Examples include methyl, ethyl, propyl and isopropyl.
  • R 3a is (1-3 Qalkyl and R 3 is H. In one embodiment, R 3a is methyl and R 3 is H.
  • both R 3a and R 3 are (l-3Qalkyl. In one embodiment, R 3a and R 3a are both methyl.
  • R 3 is hydroxy(l-3Qalkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl. In one embodiment, R 3 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl and R 3a is H. [0073] In one embodiment of Formula I, D is carbon or nitrogen, R 2 and R 3 are absent, and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.
  • R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms.
  • heteroaryl rings include pyridyl and pyrazolyl rings.
  • Specific examples of hete rings include the structures:
  • R 4a is H.
  • R 4a is (l-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
  • R 4a is fluoro(l-6C)alkyl. Examples include fluoromethyl and 2-fluoroethyl.
  • R 4a is difluoro(l-6C)alkyl.
  • Example include difluoromethyl and 2,2-difluoroethyl.
  • R 4a is trifluoro(l-6C)alkyl. Examples include trifluoromethyl and 2,2,2-trifluoroethyl.
  • R 4a is hydroxy(l-6C alkyl). Examples include hydroxymethyl, 2 -hydroxy ethyl, 2-hydroxypropyl and 3-hydroxypropyl.
  • R 4a is dihydroxy(2-6C alkyl).
  • An example includes 2,3- dihydroxypropyl.
  • R 4a is H or (l-6C)alkyl. In one embodiment, R 4a is H or
  • Z is *-NR 4b CH 2 -.
  • R 4b is H.
  • R 4b is selected from (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, and trifluoro(l-6C)alkyl.
  • R 4b is (l-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. In one embodiment, R 4b is methyl.
  • R 4b is fluoro(l-6C)alkyl. Examples include fluoromethyl and 2-fluoroethyl. [0089] In one embodiment, R 4b is difluoro(l-6C)alkyl. Example include difluoromethyl and 2,2-difluoroethyl.
  • R 4b is trifluoro(l-6C)alkyl. Examples include trifluoromethyl and 2,2,2-trifluoroethyl.
  • R 4b is selected from (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar ⁇ O)- and HOCH 2 C(0)-.
  • R 4b is (1-6C alkyl)C(O)-. Examples include CH 3 C(0)-,
  • R 4 is CH 3 C(0)-.
  • R 4b is (3-6C cycloalkyl)C(O)-.
  • examples include cyclopropylC(O)-, cyclobutylC(O)-, cyclopentylC(O)- and cyclohexylC(O)-.
  • R 4b is A ⁇ QO)-.
  • An example is phenylC(O)-.
  • R 4b is HOCH 2 C(0)-.
  • R 4b is selected from (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, and Ar 2 (S0 2 )-.
  • R 4b is (1-6C alkyl)sulfonyl. Examples include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • R 4b is (3-6C cycloalkyl)sulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl. In one embodiment, R 4 is methylsulfonyl.
  • R 4b is Ar 2 (S0 2 )-.
  • An example is phenylsulfonyl.
  • R 4b is H0 2 CCH 2 -.
  • R 4b is (1-6C alkyl)NH(CO)-. Examples include
  • R 4 is CH 3 NHC(0)-.
  • R 4b is selected from H, methyl, -C(0)CH 3 , methylsulfonyl, -C(0)CH 2 OH, -CH 2 COOH and -C(0)NHCH 2 CH 3 .
  • ring B is ring B-l :
  • R 5 and R 6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy( 1 -6C)alkyl.
  • R 5 and R 6 are independently H, F, OH, (l-6C)alkyl or hydroxy(l-6C)alkyl. In one embodiment, R 5 is H and R 6 is H, F, OH, (l-6C)alkyl or hydroxy( 1 -6C)alkyl.
  • R 5 and R 6 are independently H, F, OH, (l-3C)alkyl or hydroxy(l-3C)alkyl. In one embodiment, R 5 is hydrogen and R 6 is H, F, OH, (l-3C)alkyl or hydroxy(l-3C)alkyl.
  • R and R are independently H, F, OH, methyl, ethyl,
  • R 5 is hydrogen and R 6 is H, F, OH, methyl, ethyl, HOCH 2 - or HOCH 2 CH 2 -.
  • R 5 and R 6 are independently H, F, or methyl. In one embodiment, R 5 is H and R is H, F, or methyl.
  • R 5 is H and R 6 is F.
  • R is H and R is methyl.
  • R 5 and R 6 are both H.
  • R 5 and R 6 are both F.
  • R 5 and R 6 are both methyl.
  • ring B is ring B-l which is optionally substituted with one or two substituents independently selected from OH and F, provided that two OH substituents are not on the same ring carbon atom.
  • ring B when represented by ring B-l include the structures:
  • ring B is ring B-2 having the formula:
  • m is 0.
  • n is 1. [00120] In one embodiment, m is 2.
  • One embodiment of this invention provides compounds of the general
  • ring B is ring B-l :
  • ring A is selected from rings A-1, A-2 and A-3 having the structures:
  • X is N or CH
  • Y is H or F
  • R 1 is H, (l-3C)alkoxy or halogen
  • W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
  • m 0, 1 or 2;
  • R 2 and R 2a are independently H, F, (1-3 Qalkyl or OH, provided that R 2 and
  • R 2a are not both OH
  • R 3 and R 3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
  • R 2 and R 3 are absent and R 2a and R 3a together with the atoms to which they are attached form a bivalent 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms;
  • R 4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R 4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • 6C)alkyl hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar ⁇ O)-, HOCH 2 C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (S0 2 )-, H0 2 CCH 2 - or (1-6C alkyl)NH(CO)-;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
  • Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
  • R and R are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • One embodiment of this invention provides compounds of the general
  • ring A is selected from rings A-1, A-2 and A-3 having the structures:
  • X is N or CH
  • Y is H or F
  • R 1 is H, (l-3C)alkoxy or halogen
  • W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
  • m is 0, 1 or 2;
  • R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
  • R 3 is H, (1-3 Qalkyl or hydroxy(l-3 C)alkyl
  • R 4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R 4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • 6C)alkyl hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar ⁇ O)-, HOCH 2 C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (S0 2 )-, H0 2 CCH 2 - or (1-6C alkyl)NH(CO)-;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
  • Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
  • R 5 and R 6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • Formula IA includes compounds wherein:
  • ring A is ring A-1 represented by the structure
  • ring B is ring B-1 represented by the structure:
  • X is N or CH
  • Y is H or F
  • R 1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
  • W is O or H
  • m is 0, 1 or 2;
  • R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
  • R 3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
  • R 4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R 5 and R 6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • X is N. In one embodiment, X is CH.
  • Formula IA includes compounds wherein:
  • ring A is ring A-2 represented by the structure
  • ring B is ring B-1 represented by the structure:
  • Y is H or F
  • R 1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
  • m is 0, 1 or 2;
  • W is CH 2 ;
  • m 0, 1 or 2;
  • R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
  • R 3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
  • R 4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R and R are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • Formula IA includes compounds wherein:
  • ring A is ring A-3 represented by the structure
  • ring B is ring B-1 represented by the structure:
  • Y is H or F
  • R 1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
  • W is O
  • m is 0, 1 or 2;
  • R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
  • R 3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
  • R 4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R 5 and R 6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • Formula IA includes compounds wherein:
  • ring A is ring A-1 represented by the structure
  • ring B is ring B-1 represented by the structure:
  • X is N or CH
  • Y is H or F
  • R 1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
  • W is O
  • m is 0, 1 or 2;
  • R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
  • R 3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
  • Z is *-NR 4b CH 2 -, wherein the asterisk indicates the point of attachment to the carbon bearing R 3 ;
  • R 4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • 6C)alkyl (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, A ⁇ O)-, HOCH 2 C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (S0 2 )-, H0 2 CCH 2 - or (1-6C alkyl)NH(CO)-;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
  • Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
  • R 5 and R 6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
  • certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated as a mixture of isomers such as a racemic or diastereomeric mixture, or in an enantiomerically or diastereomerically pure form. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • (l-3C)alkyl and "(l-6C)alkyl” as used herein refer to saturated linear or branched-chain monovalent hydrocarbon radicals of one to three carbon atoms and one to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec -butyl, tert-butyl, 2 -methyl-2 -propyl, pentyl, and hexyl.
  • fluoro(l-6C)alkyl refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein one of the hydrogens is replaced by a fluorine atom.
  • difluoro(l-6C)alkyl refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein two of the hydrogens are replaced by fluorine atoms.
  • trifluoro(l-6C)alkyl refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein three of the hydrogens are replaced by fluorine atoms.
  • hydroxy(l-6Calkyl) refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms, wherein one of the hydrogens is replaced by a hydroxy (OH) group.
  • dihydroxy(l-6Calkyl) refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein two of the hydrogens are replaced by hydroxy (OH) groups, provided the hydroxy groups are not on the same carbon atom.
  • (1-6C alkyl)sulfonyl refers to a (1-6C alkyl)S0 2 - group, wherein the radical is on the sulfur atom and the (1-6C alkyl) portion is as defined above. Examples include methylsulfonyl (CH 3 SO 2 -) and ethylsulfonyl (CH 3 CH 2 SO 2 -).
  • (3-6C cycloalkyl)sulfonyl refers to a (3-6C cycloalkyl)S0 2 - group, wherein the radical is on the sulfur atom.
  • An example is cyclopropylsulfonyl.
  • (l-4C)alkoxy and "(l-6C)alkoxy”, as used herein refer to saturated linear or branched-chain monovalent alkoxy radicals of one to four carbon atoms or one to six carbon atoms, respectively, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy.
  • halogen includes fluoro, chloro, bromo and iodo.
  • the compounds of Formula I include salts thereof.
  • the salts are pharmaceutically acceptable salts.
  • the compounds of Formula I include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of
  • composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • Compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • the compounds according to the invention therefore also comprise compounds with one or more isotopes of one or more atom, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes.
  • Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the present invention further provides a process for the preparation of a compound of Formula I or a salt thereof as defined herein which comprises:
  • P 1 is H or a carboxyl protecting group, in the presence of a coupling reagent and a base; or
  • X is N
  • ring B, D, Z, Y, R 1 , R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula III
  • n 1, 2, 3 or 4 and L 1 is a leaving group or atom, in the presence of a base; or
  • L 2 is a leaving group or atom, in the presence of a base
  • W, D, R 2 , R 2 aa ,, RR 33 ,, RR 33aa aanndd mm are as defined for Formula I, cyclizing a corresponding compound having the formula VI
  • R 3 , and R 3a are as defined for Formula I, Z is *-NR 4b CH 2 -, and R 4b is (1-6C alkyl)C(O)-, (3- 6C cycloalkyl)C(O)-, Ar ⁇ O)-, HOCH 2 C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, or Ar 2 (S0 2 )-, coupling a corresponding compound having the formula VIII
  • R 3a and m are as defined for Formula I, Z is *-NR 4b CH 2 -, and R 4b is (1-6C alkyl)NH(CO)-, reacting a compound having the formula VIII
  • X is CH, and Y, R 1 , D, ring B, Z, R 2 , R 2a , R 3 and m are as defined for Formula I, cyclizing a corresponding compound having the formula X
  • n 1, 2, 3 or 4 and L 1 is a leaving group or atom, in the presence of a base;
  • ring B is ring B-1 having the structure:
  • D is carbon
  • R 2 and R 2a are independently H, F, (1-3 Qalkyl or OH (provided that R 2 and R 2a are not both OH)
  • R 3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl.
  • ring A, W, m, Z, R 5 and R 6 are as defined for Formula I.
  • the cyclization may be performed using conventional amide bond formation conditions, for example by treating the carboxylic acid with an activating agent, followed by addition of the amine in the presence of a base.
  • Suitable activating agents include EDCI, oxalyl chloride, thionyl chloride, HATU, and HOBt.
  • Suitable bases include amine bases, for example triethylamine, diisopropylethylamine, pyridine, or excess ammonia.
  • Suitable solvents include DCM, DCE, THF and DMF.
  • the leaving atoms L 1 and L 2 may be, for example a halogen atom such as Br, CI or I.
  • L 1 and L 2 can be a leaving group, for example an arylsulfonyloxy group or an alkylsulfonyloxy group, such as a mesylate or a tosylate group.
  • Suitable bases include alkali metal carbonates, such as sodium carbonate, potassium carbonate or cesium carbonate.
  • Convenient solvents include aprotic solvents such as ethers (for example tetrahydrofuran or p-dioxane), DMF, or acetone.
  • the reaction can be conveniently performed at elevated temperatures, for example 50-150 °C, for example at 85 °C.
  • suitable coupling reagents include HATU, HBTU,
  • Suitable bases include tertiary amine bases such as DIEA and triethylamine.
  • Convenient solvents include DMF, THF, DCM and DCE.
  • suitable reducing agents include Me 4 (OAc) 3 BH,
  • Suitable solvents include neutral solvents such as acetonitrile, THF and DCE.
  • the reaction can be conveniently performed at ambient temperature.
  • the triphenylphosphine reagent is used in the form of a polystyrene-bound PPh 3 resin (sold as PS-PPh 3 by Biotage Systems).
  • the reaction is conveniently performed at ambient temperature.
  • Suitable solvents include neutral solvents, for example DCM.
  • the leaving atom L 3 may be a halogen, for example
  • Suitable bases include tertiary amine bases such as diisopropylethylamine and triethylamine. The reaction is conveniently performed at ambient temperature.
  • suitable bases include tertiary amine bases such as
  • the fluorination reagent may be, for example, bis(2- methoxyethyl)amino-sulfur trifluoride (Deoxo-FluorTM) or diethylaminosulfur trifluoride (DAST).
  • Suitable solvents include dichloromethane, chloroform, dichloroethane, and toluene. The reaction is conveniently performed at ambient temperature.
  • base may be, for example, an alkali metal carbonate , such as for example sodium carbonate, potassium carbonate or cesium carbonate.
  • Convenient solvents include aprotic solvents such as ethers (for example tetrahydrofuran or p-dioxane) or toluene.
  • the reaction can be conveniently performed at a temperature between ambient temperature and reflux, for example at 85 °C.
  • Amine groups in compounds described in any of the above methods may be protected with any convenient amine protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991.
  • amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), and [2-(trimethylsilyl)ethoxy]methyl (SEM).
  • carboxyl groups may be protected with any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed.
  • carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl.
  • Alcohol groups may be protected with any convenient alcohol protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991.
  • alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.
  • Certain compounds which are inhibitors of TrkA and/or TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture.
  • compounds of Formula I are useful for treating pain, including chronic and acute pain, in a mammal.
  • Acute pain as defined by the International Association for the Study of Pain, results from disease, inflammation, or injury to tissues. This type of pain generally comes on suddenly, for example, after trauma or surgery, and may be accompanied by anxiety or stress. The cause can usually be diagnosed and treated, and the pain is confined to a given period of time and severity. In some rare instances, it can become chronic.
  • Pain is widely believed to represent disease itself. It can be made much worse by environmental and psychological factors. Chronic pain persists over a longer period than acute pain and is resistant to most medical treatments, generally over 3 months or more. It can and often does cause severe problems for patients.
  • Compounds of Formula I are also useful for treating cancer in a mammal.
  • Particular examples include neuroblastoma, ovarian, pancreatic, colorectal and prostate cancer.
  • Compounds of Formula I are also useful for treating inflammation in a mammal.
  • Compounds of Formula I are also useful for treating certain infectious diseases in a mammal, such as Trypanosoma cruzi infection.
  • Compounds of Formula I may also be used to treat neurodegenerative diseases in a mammal.
  • neurodegenerative disease include demyelination and dysmyelination. Additional examples of neurodegenerative diseases include multiple sclerosis, Parkinson's disease and Alzheimer's disease.
  • compounds of Formula I may also be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, anorexia, atopic dermatitis, and psoriasis in a mammal.
  • IC interstitial cystitis
  • PBS painful bladder syndrome
  • urinary incontinence asthma
  • anorexia atopic dermatitis
  • psoriasis in a mammal.
  • another embodiment of this invention provides a method of treating or preventing pain in a mammal, 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 pain.
  • the pain is chronic pain.
  • the pain is acute pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is pain associated with cancer.
  • the pain is pain associated with surgery.
  • the pain is pain associated with bone fracture.
  • the method comprises a method of treating said pain in a mammal.
  • the method comprises a method of preventing said pain in a mammal.
  • Another embodiment of this invention provides a method of treating or preventing inflammation in a mammal, 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 inflammation.
  • the method comprises a method of treating said inflammation in a mammal.
  • the method comprises a method of preventing said inflammation in a mammal.
  • Another embodiment of this invention provides a method of treating or preventing a neurodegenerative disease in a mammal, 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 neurodegenerative disease.
  • the neurodegenerative disease is demyelination.
  • the neurodegenerative disease is dysmyelination.
  • the neurodegenerative disease is multiple sclerosis.
  • the neurodegenerative disease is Parkinson's disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • Another embodiment of this invention provides a method of treating or preventing infectious diseases in a mammal, 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 infectious disease.
  • the infectious disease is Trypanosoma cruzi infection.
  • the method comprises a method of treating said neurodegenerative disease in a mammal.
  • the method comprises a method of preventing said neurodegenerative disease in a mammal.
  • Another embodiment of this invention provides a method of treating or preventing cancer in a mammal, 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 cancer.
  • the cancer is neuroblastoma. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the method comprises a method of treating said cancer in a mammal. In one embodiment, the method comprises a method of preventing said cancer in a mammal.
  • Compounds of Formula I may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments that work by the same or a different mechanism of action.
  • examples include anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine), and chemotherapeutic agents.
  • steroids e.g., dexamethasone, cortisone and fluticasone
  • analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen)
  • opioids such as morphine
  • chemotherapeutic agents chemotherapeutic agents.
  • compositions of the present invention may be, for example, surgery, radiotherapy, chemotherapy, signal transduction inhibitors and/or monoclonoal antibodies.
  • the compounds of Formula I may be administered in combination with one or more agents selected from mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferase inhibitors.
  • agents selected from mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-
  • 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 according to standard pharmaceutical practice known to one skilled in the art.
  • treat or “treatment” refer to therapeutic, prophylactic, palliative or preventative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • treatment means an alleviation, in whole or in part, of symptoms associated with a disorder or condition as described herein (e.g., multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture), or slowing, or halting of further progression or worsening of those symptoms.
  • the term "preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein (e.g., multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture), or a symptom thereof.
  • an effective amount refers to an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of a compound of Formula I that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the term "mammal” refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • Compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally.
  • Compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
  • the present invention further provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove.
  • the pharmaceutical composition includes the compound of Formula I together with a pharmaceutically acceptable diluent or carrier.
  • the present invention further provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pain in a mammal.
  • the pain is chronic pain.
  • the pain is acute pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is pain associated with cancer.
  • the pain is pain associated with surgery.
  • the pain is pain associated with bone fracture.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation in a mammal.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease in a mammal.
  • the neurodegenerative disease is demyelination.
  • the neurodegenerative disease is dysmyelination.
  • the neurodegenerative disease is multiple sclerosis.
  • the neurodegenerative disease is Parkinson's disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of infectious diseases in a mammal.
  • infectious disease is Trypanosoma cruzi infection.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a mammal.
  • the cancer is neuroblastoma.
  • the cancer is ovarian cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pain in a mammal.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammation in a mammal.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease in a mammal.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of infectious diseases in a mammal.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a mammal.
  • HATU (2-(7-Aza- IH-benzotriazole- 1 -yl)- 1 , 1 ,3,3 -tetramethyluronium hexafluorophosphate)
  • ELISA enzyme-linked immunosorbant assay
  • the assay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v/v) Triton X-100 and 5 mM MgCl 2 .
  • the reaction mixture was removed from the plate by washing with PBS containing 0.1% (v/v) Tween 20.
  • the phosphorylated reaction product was detected using 0.2 ⁇ g/mL of a phosphotyrosine specific monoclonal antibody (clone PY20) conjugated to horseradish peroxidase in conjunction with the TMB Peroxidase Substrate System (KPL).
  • KPL TMB Peroxidase Substrate System
  • Table 1 provides averaged IC5 0 values for compounds of the invention when tested in this assay.
  • the letter “A” designates an IC5 0 value between about 1 and 100 nM
  • the letter “B” designates an IC50 value >100 nM and ⁇ 3000 nM.
  • Table 1 provides averaged IC5 0 values for compounds of the invention when tested in this assay.
  • the letter “A” designates an IC5 0 value between about 1 and 100 nM
  • the letter “B” designates an IC 50 value >100 nM and ⁇ 3000 nM.
  • Compound may have been isolated along with the enantiomer and/or one or more diastereomers, which additional isomer(s) were believed to make up ⁇ 1.5% of the total amount isolated.
  • Step A Preparation of ( R)-ter t-butyl 2-(5-fluoro-2-methoxypyridin-3- vDpyrrolidine- 1 -carboxylate: A solution of tert-butyl pyrrolidine- 1-carboxylate (4.09 mL, 23.4 mmol) and (-)-sparteine (6.44 mL, 28.0 mmol) in MTBE (50 mL) was cooled to -78 °C and sec- vLi (20 mL, 28.0 mmol, 1.4 M in cyclohexane) was introduced drop-wise by cannula, keeping the internal temperature under -78 °C.
  • the resulting solution was stirred for 3 hours at -78 °C, followed by addition of a solution of ZnC3 ⁇ 4 (21.0 mL, 21.0 mmol, 1M in Et20) drop-wise with rapid stirring, keeping the internal temperature below -65 °C.
  • the resulting light suspension was stirred at -78 °C for 10 minutes and then warmed to ambient temperature.
  • the resulting mixture was sequentially charged with 3-bromo-5-fluoro-2- methoxypyridine (5.05 g, 24.5 mmol), Pd(OAc) 2 (0.262 g, 1.17 mmol) and ?-Bu 3 P-HBF 4 (0.407 g, 1.40 mmol) in one portion.
  • Step B Preparation of (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine:
  • reaction mixture was diluted with acetonitrile and analyzed by HPLC (YMC ODS-AQ 4.6 x 50 mm 3 ⁇ 120A column; mobile phase: 5-95% solvent B in A; solvent A: H 2 0/ 1% IPA/ 10 mM ammonium acetate, and solvent B: ACN/1% IP A/10 mM ammonium acetate; flow rate: 2 mL/min).
  • HPLC YMC ODS-AQ 4.6 x 50 mm 3 ⁇ 120A column; mobile phase: 5-95% solvent B in A; solvent A: H 2 0/ 1% IPA/ 10 mM ammonium acetate, and solvent B: ACN/1% IP A/10 mM ammonium acetate; flow rate: 2 mL/min).
  • HPLC YMC ODS-AQ 4.6 x 50 mm 3 ⁇ 120A column; mobile phase: 5-95% solvent B in A; solvent A: H 2 0/ 1% IPA/ 10 mM ammonium a
  • Step A Preparation of ethyl 5-hvdroxypyrazolori .5-a1pyrimidine-3- carboxylate: To a mixture of ethyl 3-amino-lH-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (is)-ethyl 3-ethoxyacrylate (35.8 ml, 242 mmol) in DMF (537 mL) was added cesium carbonate (78.7 g, 242 mmol), and the reaction was heated at 110 °C for 15 hours. After cooling to ambient temperature the reaction was acidified with acetic acid to pH 4.
  • Step B Preparation of ethyl 5-chloropyrazolo[ 1.5-alpyrimidine-3-carboxylate:
  • Ethyl 5-hydroxypyrazolo[ l,5-a]pyrimidine-3-carboxylate (22.7 g, 1 10 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove excess POCI3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer was extracted with DCM (2 x 200 mL).
  • Step C Preparation of (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin- l-yl)pyrazolo[ 1.5-alpyrimidine-3-carboxylate: A mixture of ethyl 5- chloropyrazolo[l ,5-a]pyrimidine-3-carboxylate (0.75 g, 3.32 mmol), (R)-5-fluoro-2- methoxy-3-(pyrrolidin-2-yl)pyridine (Preparation A, 0.984 g, 3.66 mmol), DIEA (2.32 mL, 13.3 mmol) and n-butanol (1.1 1 mL) was sealed in a pressure tube and heated at 90 °C for 48 hours.
  • Step D Preparation of (R)-5 -(2-(5 -fluoro-2-methoxypyridin-3 -vDpyrrolidin- 1 - yl)pyrazolor i .5-a1pyrimidine-3-carboxylic acid: To a suspension of (R)-ethyl 5-(2-(5-fluoro-
  • Step A Preparation of (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one: To a suspension of (R)-4-hydroxypyrrolidin-2-one (purchased from Asta Tech or Aldrich) (5.030 g, 48.26 mmol) in DMF (24 mL) at 0 °C was added TBDMS-C1 (7.637 g, 50.67 mmol) followed by imidazole (4.978 g, 72.39 mmol). The resulting mixture was warmed to ambient temperature and stirred for 1 hour, then poured into 100 mL of water with stirring.
  • Step B Preparation of ( R)-ter t-butyl 4-(tert-butyldimethylsilyloxy)-2- oxopyrrolidine-l-carboxylate: To a solution of (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin- 2-one (10.14 g, 47.08 mmol) in MeCN (16 mL) at 0 °C was added sequentially DMAP (3.221 g, 26.37 mmol), TEA (3.957 mL, 28.25 mmol), and Boc 2 0 (1 1.49 g, 52.65 mmol). The resulting mixture was warmed to ambient temperature and stirred for 48 hours.
  • Step C Preparation of (R)-tert-butyl 2-(ter?-butyldimethylsilyloxy)-4-(5- fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate: To a solution of (R)-tert-butyl 4-(tert- butyldimethylsilyloxy)-2-oxopyrrolidine-l-carboxylate (6.00 g, 19.0 mmol) in THF (36 mL) at 0 °C was added a 0.5 M solution of (5-fluoro-2-methoxyphenyl)magnesium bromide in THF (50.0 mL, 25.0 mmol).
  • Step D Preparation of (R)-tert-butyl 4-(tert-butyldimethylsiryloxy)-2-(5- fluoro-2-methoxyphenyl)pyrrolidine- 1 -carboxylate: To a solution of (R)-tert-butyl 2-(tert- butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate (4.810 g, 10.84 mmol) in CH 2 C1 2 (108 mL) at -60 °C was added TEA (4.534 mL, 32.53 mmol) followed by methanesulfonyl chloride (0.9231 mL, 11.93 mmol).
  • the resulting mixture was slowly warmed to -5 °C and poured into a mixture of ice and saturated aqueous NaHCCh (50 mL). The organic layer was separated and the aqueous layer was extracted with (3 ⁇ 4(3 ⁇ 4 (2 x 50 mL).
  • Step E Preparation of (R)-4-(ter/-butyldimethylsilyloxy)-2-(5-£luoro-2- methoxyphenvDpyrrolidine 2,2,2-trifluoroacetate: To a solution of (R)-tert-butyl A-(tert- butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-l-carboxylate (2.648 g, 6.222 mmol) in CH 2 CI 2 (26 mL) at 0 °C was added TFA (9.3 mL). The resulting mixture was warmed to ambient temperature and stirred for 2 hours.
  • Step A Preparation of (R)-ethyl 5-(4-(ter?-butyldimethylsilyloxy -2-(5-fluoro-
  • Step B Preparation of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4- hydroxypyrrolidin-l -yDpyrazoloT 1 ,5-a1pyrimidine-3-carboxylate: To a solution of (R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (as a mixture of the cis and trans isomers) (0.0487 g, 0.0946 mmol) in THF (1 mL) at 0 °C was added 1 M TBAF in THF (0.104 mL, 0.104 mmol).
  • Step C Preparation of (R)-ethyl 5-(2-(5-fluoro-2-hvdroxyphenyl)-4- hydroxypyrrolidin-l -yDpyrazoloT 1 ,5-a1pyrimidine-3-carboxylate: To a solution of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylate (as a mixture of cis and trans isomers; 0.0379 g, 0.0947 mmol) in CH2CI2 (1 mL) at 0 °C was added 1 M BBr 3 in CH 2 C1 2 (0.473 ml, 0.473 mmol).
  • Step A Preparation of (R)-ethyl 5-(2-(5-fluoro-2-oxo-1.2-dihydropyridin-3-
  • Step B Preparation of (R)-ethyl 5-(2-(l-(3-(1.3-dioxoisoindolin-2-yl)propyl)-
  • Step C Preparation of (R)-ethyl 5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-1.2- dihydropyridin-3 -vDpyrrolidin- 1 -yDpyrazoloT 1 ,5-a1pyrimidine-3 -carboxylate: To a solution of (R)-ethyl 5-(2-(l-(3-(l,3-dioxoisoindolin-2-yl)propyl)-5-fluoro-2-oxo-l,2-dihydropyridin- 3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.20 g, 0.36 mmol) in 1 : 1 MeOH/THF (12 mL) was added hydrazine-H 2 0 (0.18 g, 3.6 mmol).
  • Step D Preparation of (R)-5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-l ,2- dihydropyridin-3 -vDpyrrolidin- 1 -yDpyrazoloT 1.5-a1pyrimidine-3 -carboxylic acid: To a solution of (R)-ethyl 5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.11 g, 0.26 mmol) in 3 : 1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol), and the reaction mixture was heated at 70 °C for 20 hours. After cooling, the reaction mixture was treated with MeOH, acidified with IN HC1 (
  • Step E Preparation of (6R)-9-fluoro-2.11.15.19.20.23- hexaazapentacvclori5.5.2.1 7 ' 11 .0 2 ' 6 .0 20 ' 24 1pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25- dione: To a solution of (R)-5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.24 mmol) in 1 :2 DMF/DCM (9 mL) was added EDCI (0.14 g, 0.71 mmol) followed by HOBT (96 mg, 0.71 mmol) at ambient temperature.
  • Step B Preparation of (R)-ethyl 5-(2-(6-methoxypyridin-2-yl)pyrrolidin-l- yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: Prepared by to the same method as described in Preparation B, Step C, substituting (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine with (R)-2-methoxy-6-(pyrrolidin-2-yl)pyridine.
  • MS (apci) m/z 368.0 (M+H).
  • Step C Preparation of (R)-ethyl 5-(2-(6-oxo-1.6-dihvdropyridin-2- yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a mixture of (R)-ethyl 5-(2- (6-methoxypyridin-2-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.46 g, 1.25 mmol) and acetic acid (3.0 g, 50 mmol) was added HBr (3.1 g, 12.5 mmol, 33% in acetic acid).
  • Step D Preparation of (R)-ethyl S- -Ce-CS-d -dioxoisoindolin ⁇ - yl)propoxy)pyridin-2-yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate ⁇
  • Step E Preparation of (R)-ethyl 5-(2-(6-(3-aminopropoxy)pyridin-2- yl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxylate: To a solution of (R)-ethyl 5-(2- (6-(3-( 1 ,3 -dioxoisoindolin-2-yl)propoxy)pyridin-2-yl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxylate (0.1 1 g, 0.20 mmol) in 1 : 1 MeOH/THF (12 mL) was added hydrazine-H 2 0 (0.10 g, 2.0 mmol).
  • Step G Preparation of (6R)-12-oxa-2, 16,20,21 ,24,26-hexaazapentacyclo- ri6.5.2.1 7 ' 11 .0 2 ' 6 .0 21 ' 25 1hexacosa-l(24),7(26).8.10.18(25).19.22-heptaen-17-one: To a solution of (R)-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (70 mg, 0.18 mmol) in 1 :2 DMF/DCM (9 mL) was added EDCI (1 10 mg, 0.55 mmol) followed by HOBT (74 mg, 0.55 mmol) at ambient temperature.
  • Step A Preparation of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- l-yl)-N-(3-hvdroxypropyl)pyrazolori .5-a1pyrimidine-3-carboxamide: To a DMF (2 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) cooled to 0 °C was added 3-aminopropan-l-ol (0.0642 mL, 0.840 mmol) drop- wise, resulting in a clear yellowish solution.
  • Step B Preparation of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2- hvdroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)-N-(3- hydroxypropyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (20 mg, 0.0483 mmol) in HCl (4 ⁇ dioxane, 1.2 mL, 4.83 mmol) was heated at 85 °C overnight.
  • Step C Preparation of (6RV9-fluoro-13-oxa-2.1 1.17.21.22.25- hexaazapentacvclori7.5.2.0 2 ' 6 .0 7 ' 12 .0 22 ' 26 lhexacosa-l(25).7.9.1 1.19(26).20.23-heptaen-18- one: A DMF (1 mL) suspension of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin- 3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (5 mg, 0.012 mmol) and CS2CO 3 (4 mg, 0.06 mmol) was heated at 85 °C overnight.
  • reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 5 to 60% acetonitrile/water), to provide the title product as white solid (2 mg, 44 % yield).
  • MS (apci) m/z 383.3 (M+H).
  • Step A Preparation of N-(2.3-dihvdroxypropyl)-5-((R)-2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) in 1 : 1 DMF/DMSO (2 mL) was cooled to 0 °C, followed first by drop-wise addition of 3- aminopropane-l,2-diol (76.5 mg, 0.840 mmol) and then addition of DIEA (366 ⁇ , 2.10 mmol).
  • Step B Preparation of N-(3-chloro-2-hvdroxypropyl)-5-((R)-2-(5-fluoro-2- oxo-1 , 2-dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidine-3-carboxamide: A mixture of N-(2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (100 mg, 0.232 mmol) and HC1 (4 ⁇ , dioxane, 5.8 mL) was sealed in a pressure tube and heated at 85 °C overnight. After the clear solution was decanted, the crude product was obtained as a brownish oily residue, which was vacuum- dried and used directly in the next step without further purification.
  • Step C Preparation of (6R)-9-fluoro-15-hvdroxy-13-oxa-2.1 1.17.21.22.25- hexaazapentacvclori7.5.2.0 2 ' 6 .0 7 ' 12 .0 22 ' 26 lhexacosa-l( ' 25).7.9.1 1.19( ' 26).20.23-heptaen-18- one: A suspension of N-(3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (100 mg, 0.23 mmol) and CS2CO3 (375 mg, 1.15 mmol) in DMF (3 niL) was heated at 85 °C for 2 hours.
  • reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 5 to 50% acetonitrile/water), to provide the title product as a white solid.
  • MS (apci) m/z 399.2 (M+H).
  • Step A Preparation of N-C ⁇ -S-chloro ⁇ -hvdroxypropyn-S-CfRl ⁇ -CS-fluoro-
  • Step B Preparation of (6R.135)-9-fluoro-13-hvdroxy-2,l 1, 15.19.20,23- hexaazapentacvclori5.5.2.1 7 ' 11 .0 2 ' 6 .0 20 ' 24 1pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25- dione: A suspension of N-((5)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo-l,2- dihydropyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5-a]pyrimidine-3 -carboxamide hydrochloride (40 mg, 0.085 mmol) and Cs 2 C0 3 (138 mg, 0.42 mmol) in DMF (0.8 mL) was heated at 85 °C for 2 hours.
  • reaction mixture was filtered through GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 40% acetonitrile/water), to provide the title product as a white solid (4 mg, 12 % yield).
  • MS (apci) m/z 399.2 (M+H).
  • Step B Preparation of (6R.15R)-9-fluoro-15-hvdroxy-13-oxa-
  • Step A Preparation of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- l-yl)-N-(2-hvdroxyethyl)pyrazolorL5-a1pyrimidine-3-carboxamide: To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.28 mmol) and HATU (128 mg, 0.336 mmol) was added DIEA (0.146 mL, 0.840 mmol) at ambient temperature, followed by a solution of 2-aminoethanol (20.5 mg, 0.336 mmol) in minimal amount of DMF dropwise at 0 °C.
  • Step B Preparation of (R)-N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1.2- dihydropyridin-3 -yDpyrrolidin- 1 -yPpyrazolof 1.5 -a]pyrimidine-3 -carboxamide: To (R)-5-(2- (5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)-N-(2-hydroxyethyl)pyrazolo[l,5- a]pyrimidine-3 -carboxamide (77 mg, 0.192 mmol) in a pressure reaction tube was charged hydrogen chloride (4 ⁇ dioxane, 4.8 mL, 19.2 mmol) and the resulting white suspension was heated at 85 °C overnight. After cooling to ambient temperature, the reaction mixture was decanted to yield the crude product as brownish oily residue, which was dried in vacuo and directly used in the next step without further purification. MS
  • Step C Preparation of (6R)-9-fluoro- 13 -oxa-2,1 1.16.20,21,24- hexaazapentacvclori6.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 1pentacosa-l( ' 24).7.9.1 1.18( ' 25).19.22-heptaen-17- one: A suspension of (R)-N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (78 mg, 0.19 mmol) and Cs 2 C0 3 (314 mg, 0.96 mmol) in DMF (5 mL) was heated at 85 °C for 30 minutes.
  • Step B Preparation of (6R)-9-fluoro- 13 -oxa-2,1 1.18.22.23.26- hexaazapentacvclo-r 18.5.2.0 2 ' 6 0 7 ' 12 .0 23 ' 27 1heptacosa- 1 (26).7.9.1 1.20(27).21.24-heptaen- 19- one: Prepared according to the method described in Example 3, substituting (R)-N-(3- chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxamide with (R)-N-(4-chlorobutyl)-5-(2-(5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine
  • Step A Preparation of (RYtert-butyl 2-(2-chloro-5-ffuoropyridin-3- vDpyrrolidine- 1 -carboxylate: A solution of tert-butyl pyrrolidine- 1-carboxylate (1 mL 5.70 mmol) and (-)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to -78 °C under nitrogen, followed by addition of sec -butyl lithium (4.07 mL, 1.4M, 5.70 mmol) drop-wise over 15 minutes with a syringe, maintaining the temperature below -75 °C.
  • the pale yellowish solution was stirred at -78 °C for 3 hours before being treated with zinc chloride (3.80 mL, 1.0 M, 3.80 mmol) drop-wise over 15 minutes, maintaining the temperature below -73 °C.
  • the mixture was stirred at -78 °C for 30 minutes, then placed into an ambient temperature water bath and stirred for another hour. At this point a large amount of white precipitate was present.
  • Step C Preparation of (R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a solution of ethyl 5- hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol).
  • BOP Benzotriazol-1- yloxy
  • Step D Preparation of (RVethyl S- ⁇ - ⁇ - ⁇ -qert- butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolorL5- alpyrimidine-3-carboxylate: A mixture of Pd 2 dba 3 (7.05 mg, 0.00770 mmol), CS2CO 3 (125 mg, 0.385 mmol), rac-Binap (19.2 mg, 0.0308 mmol), (R)-ethyl 5-(2-(2-chloro-5- fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (50 mg, 0.128 mmol), and tert-butyl 2-aminoethylcarbamate (24.7 mg, 0.154 mmol) in degassed toluene (1 m
  • Step E Preparation of (R)-5-(2-(2-(2-(tert- butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[1.5- alpyrimidine-3-carboxylic acid: To a solution of (R)-ethyl 5-(2-(2-(2-(tert- butoxycarbonylamino)ethylamino)-5-fluoropyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxylate (38 mg, 0.074 mmol) in THF/MeOH/water (2:2: 1, 0.7 mL) was added LiOH-H 2 0 (9.3 mg, 0.22 mmol), followed by stirring at 50 °C for 18 hours.
  • Step F Preparation of (R)-5-(2-(2-(2-aminoethylamino)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxylic acid hydrochloride: A solution of (R)-5-(2-(2-(2-(/er/-butoxycarbonylamino)ethylamino)-5-fluoropyridin-3 -yl)pyrrolidin- 1 - yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (31 mg, 0.064 mmol) in HCl (4 N dioxane, 798 ⁇ ) and TFA (50% DCM, 2 mL) was stirred at ambient temperature for 1 hour before it was concentrated and dried under high vacuum to yield to give the desired product as off- white solid, which was used in the next step directly without further purification, assuming quantitative conversion. MS (ap
  • Step G Preparation of (6fl>9-fluoro-2.11.13.16.20.21.24- heptaazapentacvclo-r 16.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 lpentacosa- 1 (24).7.9.1 1.18(25).19.22-heptaen- 17- one: To a DMF (3 mL) solution of (R)-5-(2-(2-(2-aminoethylamino)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.065 mmol) was first added HATU (29 mg, 0.077 mmol), followed by five-minute stirring and then drop-wise addition of DIEA (56 ⁇ , 0.32 mmol).
  • Step A Preparation of (R)-ethyl 5-(2-(2-(3-(tert-butoxycarbonylamino) propylamino)-5-fluoropyridin-3-yl)pyrrolidin- 1 -yPpyrazolof 1.5-a "
  • Step B Preparation of (6R)-9-fluoro-2.11.13.17.21.22.25- heptaazapentacvclo-r 17.5.2.0 2 ' 6 .0 7 ' 12 .0 22 ' 26 1hexacosa- 1 (25).7.9.1 1.19(26).20.23-heptaen- 18- one: Prepared according to the method described in Example 12, Steps E-G, in three steps, from (R)-ethyl 5-(2-(2-(3-(tert-butoxycarbonylamino)propylamino)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate obtained above.
  • Step A Preparation of (R)-2-chloroethyl 5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (Preparation B, 0.1 g, 0.28 mmol) and HATU (0.128 g, 0.336 mmol) was added DIEA (0.146 ml, 0.840 mmol), followed by 2-chloroethanol (0.0270 g, 0.336 mmol).
  • Step C Preparation of (6RV9-fluoro- 13.16-dioxa-2.1 1.20.21.24- pentaazapentacvclori6.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 1-pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one: A mixture of (R)-2-chloroethyl 5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (54 mg, 0.133 mmol) and CS2CO 3 (217 mg, 0.665 mmol) in DMF (6 mL) was heated at 90 °C overnight.
  • Step A Preparation of (R)-N-(2-bromoethoxy)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide: To a mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.280 mmol) and HATU (128 mg, 0.336 mmol) in DMF (1 mL) was added DIEA (0.146 mL, 0.840 mmol), followed by 0-(2- bromoethyl)hydroxylamine hydrobromide (74.2 mg, 0.336 mmol) in one portion.
  • Step B Preparation of (RVN-f2-chloroethoxy ' )-5-f2-f5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori ,5-a1pyrimidine-3-carboxamide: A mixture of (R)-N-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo[ 1,5- a]pyrimidine-3-carboxamide (70 mg, 0.146 mmol) and HC1 (4 ⁇ dioxane, 3.65 mL, 14.6 mmol) was sealed in a pressure tube and heated at 90 °C for 3 hours. The reaction mixture was then cooled, diluted with MeOH, concentrated, and dried on high vacuum to obtain the desired product which was used in the next step directly without further purification, assuming quantitative conversion
  • Step C Preparation of (6R)-9-fluoro-13.16-dioxa-2,l 1.17.21,22,25-
  • Step A Preparation of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)-N-m
  • Step B Preparation of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-1.2- dihydropyridin-3 -yDpyrrolidin- 1 -yl)-N-methylpyrazolo[ 1.5-a]pyrimidine-3 -carboxamide: A mixture of HC1 (4 N dioxane, 4 mL, 16.0 mmol) and (R)-N-(3-chloropropyl)-5-(2-(5-fluoro- 2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)-N-methylpyrazolo[ 1 ,5-a]pyrimidine-3 -carboxamide (100 mg, 0.224 mmol) was sealed in a pressure tube and heated at 90 °C for 90 minutes. The reaction mixture was then diluted with acetonitrile and concentrated to yield the crude product, which was carried to the next step without further purification (
  • Step C Preparation of (6RV9-fluoro-l 7-methyl- 13 -oxa-2.1 1.17.21.22.25- hexaazapentacvclori7.5.2.0 2 ' 6 .0 7 ' 12 .0 22 ' 26 lhexacosa-l(25).7.9.1 1.19(26).20.23-heptaen-18- one: A mixture of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)-N-methylpyrazolo[l,5-a]pyrimidine-3-carboxamide (50 mg, 0.12 mmol) and Cs 2 C0 3 (188 mg, 0.58 mmol) in DMF (12 mL) was heated at 90 °C for 15 minutes to reach completion.
  • Step A Preparation of (5 f )-l-amino-3-chloropropan-2-ol hydrochloride: To a solution of benzaldehyde (4.50 g, 42.4 mmol) in EtOH (12 mL) was added aqueous ammonia (4.01 g, 65.9 mmol) in several portions. After stirring for 10 minutes, (5)-2- (chloromethyl)oxirane (3.81 g, 41.2 mmol) was added and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then heated at 35-40 °C with a heating mantle for 6 hours, followed by stirring at ambient temperature for 18 hours.
  • the reaction was concentrated to 5 mL and toluene (5 mL) was added.
  • the mixture was heated to 36 °C and a solution of concentrated HC1 (6.09 g, 61.8 mmol) and water (5.9 mL) were added slowly over 5 minutes to maintain an internal reaction temperature range of 36-41 °C.
  • the biphasic mixture was heated at 42-45 °C for 3 hours.
  • the organic phase was separated and washed with water (10 mL).
  • the aqueous phases were combined and ethanol (10 mL) was added.
  • the mixture was concentrated to 10 mL, and ethanol (6 x 10 mL) was added, concentrating after each addition.
  • Step B Preparation of N-(( ⁇ -3-chloro-2-hvdroxypropyl)-5-((R)-2-(5-fluoro-
  • Step C Preparation of (R)-N-(3-chloro-2-oxopropyl)-5-(2-(5-fluoro-2- methoxypyridin-3 -vDpyrrolidin- 1 -vDpyrazolo ⁇ 1.5 -alpyrimidine-3 -carboxamide: To a solution of N-((5)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (180 mg, 0.401 mmol) in DCM (3 mL) was added Dess-Martin periodinane (204 mg, 0.481 mmol).
  • Step D Preparation of (R)-N-(3-chloro-2.2-difluoropropyl)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxamide: To a solution of (R)-N-(3-chloro-2-oxopropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (114 mg, 0.255 mmol) in DCM (3 mL) was added Deoxofluor (0.103 mL, 0.561 mmol), and the reaction mixture was stirred at ambient temperature for 23 hours.
  • Step E Preparation of (R)-N-(3-chloro-2.2-difluoropropyl)-5-(2-(5-fluoro-2- oxo-1.2-dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: Prepared according to the method described in Example 18, substituting (R)-N-(3-chloro-2,2- difluoropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a] pyrimidine-3 -carboxamide for (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)-N-methylpyrazolo[l,5-a]pyrimidine-3
  • Step F Preparation of (6R)-9.15.15-trifluoro-13-oxa-2,l 1 ,17.21,22,25-
  • Step B Preparation of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride:
  • Step D Preparation of (R)-ethyl 5-(2-(2-(3-(1.3-dioxoisoindolin-2- yl)propoxy)-5-fluorophenyl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidine-3-carboxylate: A suspension of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3 -carboxylate (280 mg, 0.756 mmol), 2-(3-bromopropyl)isoindoline-l,3-dione (263 mg, 0.983 mmol) and K 2 C0 3 (104 mg, 0.756 mmol) in DMF (0.4 mL) was stirred at ambient temperature for 15 hours.
  • Step E Preparation of (R)-ethyl 5-(2-(2-(3-aminopropoxy)-5- fluorophenyDpyrrolidin- 1 -yPpyrazolof 1.5-a "
  • pyrimidine-3 -carboxylate (R)-ethyl 5-(2-(2-(3- ( 1 ,3 -dioxoisoindolin-2-yl)propoxy)-5-fluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1,5- a]pyrimidine-3 -carboxylate (200 mg, 0.359 mmol) and hydrazine monohydrate (1 15 mg, 3.59 mmol) were combined in MeOH (1 mL) and THF (1 mL) in a sealed vessel and heated at 60 °C for 20 minutes.
  • Step F Preparation of (6R)-9-fluoro-13-oxa-2.17.21.22.25-
  • Step A Preparation of (R)-4-fluoro-2-(l-(pyrazolorL5-a1pyrimidin-5- yl)pyrrolidin-2-yl)phenol: A mixture of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride (Example 20, Step B, 1.50 g, 6.89 mmol), DIEA (2.67 g, 20.7 mmol), 5-chloropyrazolo[l,5- ajpyrimidine (1.11 g, 7.24 mmol) and isopropanol (1 mL) was heated at 120 °C overnight.
  • Step B Preparation of ( ' R -5-( ' 2-( ' 5-fluoro-2-hvdroxyphenyl pyrrolidin-l - yl)pyrazolo[ 1.5-alpyrimidine-3-carbaldehyde: After POCI 3 (221 ⁇ ⁇ , 2.41 mmol) was added drop-wise to a DMF (4 mL) solution of (R)-4-fluoro-2-(l -(pyrazolo[ l,5-a]pyrimidin-5- yl)pyrrolidin-2-yl)phenol (600 mg, 2.01 mmol) at ambient temperature, the reaction was stirred for 5 minutes before NaOH (804 mg, 10.1 mmol) was introduced.
  • Step C Preparation of (R)-fert-butyl 2-(4-fluoro-2-(l-(3-formylpyrazolor i .5- alpyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate: A mixture of (R)-5-(2-(5-fluoro-2- hydroxyphenyl)pyrrolidin-l -yl)pyrazolo[ l ,5-a]pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol), tert-butyl 2-bromoethylcarbamate (13 1 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and DMF (1 mL) was combined in a sealed vessel and stirred at ambient temperature overnight and then at 60 °C for 3 hours.
  • Step D Preparation of (R)-5-(2-(2-(2-aminoethoxy)-5- fluorophenyl)pyrrolidin- l -yl)pyrazolo[1.5-alpyrimidine-3-carbaldehyde: An HC1 (4N dioxane, 80 ⁇ , 0.32 mmol) was added to a DCM (2 mL) solution of (R)-tert-butyl 2-(4- fluoro-2-(l-(3-formylpyrazolo[l ,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 0.422 mmol), and the reaction was purged with 2 and stirred at ambient temperature overnight.
  • Step E Preparation of (6R)-9-fluoro- 13 -oxa-2.16.20.21.24- pentaazapentacvclori 6.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 1pentacosa-l (24).7.9.1 1.18(25).19.22-heptaene.
  • Tetramethylammonium triacetoxyborohydride (46.7 mg, 0.629 mmol) was added to a DCM (50 mL) solution of (R)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-l - yl)pyrazolo[l,5-a]pyrimidine-3-carbaldehyde (155 mg, 0.420 mmol), and the reaction was stirred at ambient temperature overnight.
  • Step B Preparation of (RVfe/ -butyl 3-(4- ⁇ 0 ⁇ 0-2-(1-(3-)
  • Step C Preparation of (RyCS- ⁇ - ⁇ -G-aminopropoxyVS- fluorophenyl)pyrrolidin-l-yl)pyrazolori .5-a1pyrimidin-3-yl)methanol hydrochloride: (R)- tert-butyl 3 -(4-fluoro-2-( 1 -(3 -(hydroxymethyl)pyrazolo[ 1 ,5-a]pyrimidin-5-yl)pyrrolidine-2- yl)phenoxy)propylcarbamate (80 mg, 0.16 mmol) was dissolved in 2 mL of DCM and treated with HC1 (4 N in dioxane, 6.0 mg, 0.16 mmol).
  • Step A Preparation of (5'.£l-N-( ' 2-( ' ter?-butyldimethylsilyloxy)ethylidene)-2- methylpropane-2-sulfinamide: To a solution of (5)-2-methylpropane-2-sulfinimide (3.3 g, 27.2 mmol) in DCM (50 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (4.98 g, 28.6 mmol) followed by anhydrous copper sulfate (8.69 g, 54.5 mmol). The heterogeneous mixture was stirred at ambient temperature for 3 days and then filtered through Celite®.
  • Step B Preparation of (y)-N-( ' ( ' y)-2-( ' ter?-butyldimethylsilyloxy)- 1 -(5- ⁇ -2- methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide: To a solution of n-butyl lithium (10.8 mL, 17.3 mmol, 1.6 M in hexanes) in toluene (100 mL) at -78 °C was added a solution of 3-bromo-5-fluoro-2-methoxypyridine (3.27 g, 15.9 mmol) in toluene (5 mL) dropwise, maintaining the internal temperature below -70 °C.
  • Step C Preparation of (y)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride: To a solution of (5)-N-((5)-2-(tert-butyldimethylsilyloxy)-l-(5-fluoro-2- methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 3.46 mmol) in methanol (20 mL) was added 4 ⁇ HCl/dioxane (8.65 mL, 34.6 mmol).
  • Step D Preparation of (y)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2- one: To a solution of (5)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride (897 mg, 3.46 mmol) in KOH (10 mL, 24.2 mmol, 2.42 M in water) was added THF (10 mL). The mixture was cooled to 0 °C and treated with triphosgene (1.03 g, 3.46 mmol).
  • Step E Preparation of (SVethyl S- ⁇ -CS-fluoro ⁇ -methoxypyridin-S-yl) ⁇ - oxooxazolidin-3-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a solution of (5)-4-(5- fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (254 mg, 1.20 mmol) in DMF (10 mL) was added sodium hydride (58 mg, 1.44 mmol, 60% in mineral oil).
  • Step F Preparation of (5)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2- hydroxyethylamino)pyrazolo[1.5-alpyrimidine-3-carboxylic acid: To a solution of (5)-ethyl 5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylate (311 mg, 0.77 mmol) in a 1 : 1 : 1 mixture of MeOH:THF:H 2 0 (15 mL) was added lithium hydroxide monohydrate (97.6 mg, 2.32 mmol).
  • Step G Preparation of (5)-N-(3-chloropropyl)-5-(l-(5-fluoro-2- methoxypyridin-3-yl)-2-hvdroxyethylamino)pyrazolori .5-a1pyrimidine-3-carboxamide: To a suspension of (5)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (50 mg, 0.14 mmol) in DCM (2 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (83 mg, 0.43 mmol).
  • the heterogeneous mixture was stirred at ambient temperature for 10 minutes then treated with triethylamine (100 ⁇ , 0.72 mmol) followed by 3-chloro-propylamine hydrochloride (56 mg, 0.43 mmol). The mixture was stirred for 2 hours, then DMF (2 mL) was added and stirring was continued for 48 hours. The mixture was partitioned between saturated NH 4 C1 solution (20 mL) and EtOAc (20 mL) and the layers were separated.
  • Step H Preparation of (5 f )-N-(3-chloropropyl)-5-(4-(5-fluoro-2- methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolorL5-a1pyrimidine-3-carboxamide: To a solution of (5 * )-N-(3-chloropropyl)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2- hydroxyethylamino)pyrazolo[l,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) in ACN (2 mL) was added CDI (35 mg, 0.21 mmol).
  • Step I Preparation of ffl-N-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A suspension of (5 * )-N-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2- oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (37 mg, 0.08 mmol) in 4 ⁇ HCl/dioxane (4 mL) was stirred at 85 °C for 17 hours and then at ambient temperature for 48 hours.
  • Step J Preparation of (6 ⁇ -9-fluoro-4,13-dioxa-2, l 1.17.21,22,25- hexaazapentacvclori7.5.2.0 2 ' 6 .0 7 ' 12 .0 22 ' 26 1hexacosa-l(25).7(12).8.10.19(26).20.23-heptaene- 3.18-dione: To a solution of (5)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-l,2- dihydropyridin-3 -yl)-2-oxooxazolidin-3 -yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxamide (35 mg, 0.08 mmol) in DMF (3 mL) was added cesium carbonate (79 mg, 0.24 mmol).
  • Step A Preparation of 5-hvdroxypyrazolori ,5-a1pyrimidine-3-carboxylic acid:
  • Step B Preparation of 5-chloropyrazolo[1.5-alpyrimidine-3-carbonyl chloride: To a suspension of 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.18 g, 6.59 mmol) in DMF (10 mL) at 0 °C was added thionyl chloride (10 mL) dropwise over 5 minutes. The mixture was warmed to ambient temperature, then stirred at 60 °C for 16 hours. The cooled solution was purged with 2 for 20 minutes then diluted with 50% EtOAc/hexanes (100 mL) and stirred vigorously for 30 minutes.
  • Step C Preparation of 5-chloro-N-(2-chloroethyl)pyrazolo
  • Step D Preparation of ffl-N-(2-chloroethyl)-5-(4-(5-fluoro-2- methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: To a solution of (5)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (prepared according to Example 30; 50 mg, 0.236 mmol) in DMF (1 mL) was added sodium hydride (1 1 mg, 0.28 mmol, 60% in mineral oil).
  • Step E Preparation of (5)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A suspension of (5)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin- 3-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (80 mg, 0.18 mmol) in 5-6 ⁇ HC1/IPA (2.5 mL) was warmed to 90 °C in a sealed tube for 1.5 hours.
  • Step F Preparation of (6_?)-9-fluoro-4.13-dioxa-2.11.16.20.21.24- hexaazapentacvclori6.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 1pentacosa-l(24).7(12).8.10.18(25).19.22-heptaene- 3.17-dione: Prepared according to the method of Example 30, Step J, using (5)-N-(2- chloroethyl)-5-(4-(5-fluoro-2-oxo-l,2-dihydropyridin-3-yl)-2-oxooxazolidin-3- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide in place of (5)-N-(3-chloropropyl)-5-(4-(5- fluoro-2-oxo-l,2-dihydropyridin-3-yl)-2
  • Step A Preparation of (R)-ethyl 5-(2-(2-(3-((tert-butoxycarbonyl)amino)prop-
  • Step B Preparation of (R)-ethyl 5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxylate: To (R)-ethyl 5-(2-(2-(3-(tert- butoxycarbonylamino)prop- 1 -ynyl)-5 -fluoropyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [1,5- a]pyrimidine-3-carboxylate (160 mg, 0.315 mmol) in MeOH (10 mL) was added dihydroxypalladium (101 mg, 0.144 mmol).
  • Step C Preparation of (R)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxylic acid: To (R)-ethyl 5-(2-(2-(3- aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate hydrochloride (160 mg, 0.356 mmol) in THF/MeOH (2 mL/1 mL) was added lithium hydroxide (1.1 mL, 2.20 mmol).
  • Step D Preparation of (6R)-9-fluoro-2, l 1.16.20,21,24- hexaazapentacvclori6.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 1pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one: To (R)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (16 mg, 0.042 mmol) in DMF (5 mL) was added HATU (63 mg, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (22 mg, 0.17 mmol).
  • Step A Preparation of (R)-methyl 5-(2-(5-fluoro-2-hvdroxypyridin-3- yl)pyrrolidin-l-yl)pyrazolori .5-alpyrimidine-3-carboxylate: To a suspension of (R)-5-(2-(5- fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxylic acid (Preparation B; 5.01 g, 14.0 mmol) in MeOH (150 mL) was added dropwise TMSCHN 2 (8.41 mL, 16.8 mmol).
  • Step B Preparation of methyl 5-((R)-2-(l-(( ⁇ -3-(1.3-dioxoisoindolin-2-yl)-2- methylpropyl)-5-fluoro-2-oxo- 1.2-dihydropyridin-3-yl)pyrrolidin-l -yl)pyrazolori .5- alpyrimidine-3-carboxylate: To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3- yl)pyrrolidin- l-yl)pyrazolo[ l ,5-a]pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in DMF (5 mL) was added lithium hydride (22.5 mg, 2.83 mmol) and (R)-2-(3-bromo-2- methylpropyl)isoindoline- l,3-dione (prepared according to the procedure described in Euro.
  • Step C Preparation of methyl 5-((R)-2-(l-((R)-3-amino-2-methylpropyl)-5- fluoro-2-oxo- 1 ,2-dihydropyridin-3-yl)pyrrolidin-l -yDpyrazoloT 1 ,5-a1pyrimidine-3- carboxylate: To a solution of methyl 5-((R)-2-(l -((S)-3-(l,3-dioxoisoindolin-2-yl)-2- methylpropyl)-5-fluoro-2-oxo- l,2-dihydropyridin-3-yl)pyrrolidin-l -yl)pyrazolo[l ,5- a]pyrimidine-3-carboxylate (1 10 mg, 0.197 mmol) in MeOH/THF (3 mL/3 mL) was added hydrazine (31.6 mg, 0.985 mmol).
  • Step D Preparation of (6R.13R)-9-fluoro-13-methyl-2,l 1.15.19.20.23- hexaazapentacvclori5.5.2.1 7 ' 11 .0 2 ' 6 .0 20 ' 24 1pentacosa-l( ' 23).7.9.17( ' 24).18.21-hexaene-16.25- dione: To a solution of methyl 5-((R)-2-(l-((R)-3-amino-2-methylpropyl)-5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (65 mg, 0.15 mmol) in THF/MeOH (6 mL/2 mL) was added lithium hydroxide (455 ⁇ , 0.91 mmol).
  • Step A Preparation of (R)-methyl 5-(2-(5-fluoro-2-(trifluoromethyl- sulfonyloxy)pyridin-3 -vDpyrrolidin- 1 -vDpyrazolor 1.5-a1pyrimidine-3 -carboxylate: To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3 -carboxylate (Prepared according to Example 34, Step A; 2.31 g, 6.46 mmol) in DMF (20 mL) was added l, l,l-trifluoro-N-phenyl-N-(trifluoromethyl- sulfonyl)methanesulfonamide (2.54 g, 7.11 mmol) and triethylamine (0.785 g, 7.76 mmol).
  • Step B Preparation of (R)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3- methylbutyl)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxylate: To (R)-methyl 5-(2-(5-fluoro-2-(trifluoromethylsulfonyloxy)pyridin-3 -yl)pyrrolidin- 1 - yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (503 mg, 1.03 mmol) in DMF (2 mL) was added tert-butyl 2-methylbut-3-yn-2-ylcarbamate (377 mg, 2.06 mmol), copper(I) iodide (39.1 mg, 0.206 mmol), di-triphenylphosphine palladium(II) chloride (144 mg, 0.
  • Step C Preparation of (6R)-9-fluoro-15.15-dimethyl-2.1 1.16.20.21.24- hexaazapentacvclori6.5.2.0 2 ' 6 .0 7 ' 12 .0 21 ' 25 1pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one: To (R)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3-methylbutyl)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (166 mg, 0.315 mmol) in THF/MeOH (3 mL / 1 mL) was added lithium hydroxide (946 ⁇ , 1.89 mmol).
  • the reaction vessel was sealed and heated to 70 °C for 3 hours.
  • the reaction mixture was then dried under reduced pressure and HC1 (4 mL, 4M in dioxane) was added.
  • the reaction mixture was stirred for one hour, then the solvent was removed and the residue was dried under high vacuum for two hours.
  • DMF 8 mL
  • HOBT-H2O 96.5 mg, 0.630 mmol
  • EDCI 121 mg, 0.630 mmol
  • triethylamine 159 mg, 1.58 mmol.
  • Step A Preparation of l-(2-(/gr/-butyldiphenylsilyloxy)ethyl)-lH-pyrazol-5- amine: To a suspension of 2-(5-amino-lH-pyrazol-l-yl)ethanol (2.07 g, 16.0 mmol) and 1H- imidazole (5.43 g, 79.8 mmol) in DMF (10 mL) was added dropwise tert- butylchlorodiphenylsilane (4.96 mL, 19.1 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (40 mL). The organic layer was washed with IN HQ (10 mL), water (10 mL) and brine (10 mL), then concentrated to give crude desired product (5.62 g, 96.4 % yield), which was used in the next step without purification.
  • Step B Preparation of (R)-N-( 1 -(2-(tert-butyldiphenylsiryloxy)ethyl)- 1H- pyrazol-5-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori .5- alpyrimidine-3-carboxamide: To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (220 mg, 0.616 mmol) in DMF (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 ⁇ , 0.677 mmol) and triethylamine (81.0 mg, 0.800 mmol).
  • Step C Preparation of (6R)-9-fluoro-13-oxa-2, l 1.16.17.21.25.26.29- octaazahexacvclor21.5.2.0 2 ' 6 .0 7 ' 12 .0 16 ' 20 .0 26 ' 30 1triaconta-l( ' 29).7.9.1 1.17.19.23G0).24.27- nonaen-22-one: A suspension of (R)-N-(l-(2-(tert-butyldiphenylsilyloxy)ethyl)-lH-pyrazol- 5 -yl)-5 -(2-(5 -fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [ 1 ,5-a]pyrimidine-3 - carboxamide (201 mg, 0.285 mmol) in 4M HQ in dioxane (6 mL) was sealed and heated
  • Step A Preparation of 3 -((ter?-butyldiphenylsilyloxy)methyl)pyridin-2-amine:
  • Step B Preparation of (6R)-9-fluoro-13-oxa-2, l 1.19.21.25.26.29- heptaazahexacvclor21.5.2.0 2 ' ⁇ 0 7 ' 1 0 15 ' 20 .0 26 ' 30 1triaconta ( ' 29).7.9.11.15( ' 20).16.18.23G0).24. 27-decaen-22-one: To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-
  • Step A Preparation of 3-bromo-2.2-dimethylpropan-l-amine hydrobromide: A mixture of 2-(3-bromo-2,2-dimethylpropyl)isoindoline-l,3-dione (1.00 g, 3.38 mmol) in 48% aqueous HBr (10 mL) was refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and the solids formed were filtered off. The filtrate was concentrated under reduced pressure to give the crude material that was azeotroped with toluene (3x) followed by acetonitrile until solids formed.
  • Step B Preparation of (R)-N-(3-bromo-2.2-dimethylpropyl)-5-(2-(5-fluoro-2- hvdroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidine-3-carboxamide: To a solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (Preparation B; 150 mg, 0.420 mmol), EDCI (88.5 mg, 0.462 mmol), and HOBT-H 2 0 (70.7 mg, 0.462 mmol) in DMF (10 mL) was added 3-bromo-2,2- dimethylpropan-1 -amine hydrobromide (124 mg, 0.504 mmol) followed by triethylamine (55.2 mg, 0.546 m
  • Step C Preparation of (6R)-9-fluoro-13.13-dimethyl-2,l 1, 15.19.20,23- hexaazapentacvclori5.5.2.1 7 ' 11 .0 2 ' 6 .0 20 ' 24 1pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25- dione: To a solution of (R)-N-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2- hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (30 mg, 0.061 mmol) in THF (5 mL) was added drop-wise potassium 2-methylpropan-2-olate (153 ⁇ , 0.15 mmol).
  • Step A Preparation of N- ⁇ -B-chloro ⁇ -hydroxypropyn-S-C ⁇ -fS-fluoro- 2-hvdroxyphenyl -4-hvdroxypyrrolidin-l-yl pyrazolorL5-a1pyrimidine-3-carboxami
  • (R)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid Preparation D; 0.0339 g, 0.0946 mmol
  • HATU 0.0540 g, 0.142 mmol
  • Step B Preparation of (4R.6R.15S)-9-fluoro-4.15-dihvdroxy-13-oxa-
  • Example 42 by isolating the fractions having retention time about 26.2 minutes (21.1 mg, 24.5% yield) which may have been isolated along with enantiomer and/or one or more diastereomers.
  • the stereochemistry of the title compound was confirmed by X H-NMR nOe experiment.
  • LC/MS (ES+APCI) m/z 398.1 (M+H).
  • Example 43 by isolating fractions having a retention time of about 21.3 minutes (15.9 mg, 21.1% yield) which may have been isolated along with the enantiomer and/or one or more diastereomers.
  • Diastereomer 1 and Diastereomer 2 of (15»Sy4.4.9-trifluoro-15-hvdroxy-13-oxa-2.17.21.22.
  • Step A Preparation of (R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride: To solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2- methoxyphenyl)pyrrolidine-l-carboxylate (1.01 g, 2.37 mmol) in CH 2 C1 2 (10 mL) at 0 °C was added 4 M HC1 in dioxane (5.93 mL, 23.7 mmol). The resulting mixture was warmed to ambient temperature and stirred for 8 hours.
  • Step B Preparation of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4- hvdroxypyrrolidin-l -yl pyrazolorL5-a1pyrimidine-3-carboxylate: To a suspension of ethyl 5-hydroxypyrazolo[ l,5-a]pyrimidine-3-carboxylate (0.541 g, 2.61 mmol) and BOP reagent (1.57 g, 3.56 mmol) in DMF/CH 2 C1 2 (3 mL/3 mL) at 0 °C was added (R)-5-(5-fluoro-2- methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.588 g, 2.37 mmol) followed by DIEA (1.66 mL, 9.50 mmol).
  • Step C Preparation of ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4- oxopyrrolidin- l -yl)pyrazolori .5-a1pyrimidine-3-carboxylate: To a suspension of Dess-Martin periodinane (0.233 g, 0.549 mmol) in CH 2 C1 2 (2.2 mL) at 0 °C was added a solution of (R)- ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin- l -yl)pyrazolo[l ,5-a]pyrimidine- 3-carboxylate (0.200 g, 0.499 mmol) in CH 2 C1 2 (1.5 mL).
  • the resulting mixture was warmed to ambient temperature and stirred for 18 hours.
  • the reaction mixture was cooled to 0 °C and quenched with saturated aqueous aHC0 3 (5 mL) containing Na 2 S 2 C>3 (0.608 g, 3.85 mmol).
  • the resulting mixture was warmed to ambient temperature and stirred for 10 minutes.
  • Step D Preparation of ethyl 5-(4.4-difluoro-2-(5-fluoro-2- methoxyphenvDpyrrolidin- l-vDpyrazolor 1 ,5-a1pyrimidine-3-carboxylate: To a solution of ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-oxopyrrolidin- l -yl)pyrazolo[l ,5-a]pyrimidine-3- carboxylate (0.162 g, 0.407 mmol) in CH 2 C1 2 (3 mL) was added a solution of bis(2- methoxyethyl)aminosulfur trifluoride (0.134 mL, 0.691 mmol) followed by EtOH (0.00475 mL, 0.0813 mmol).
  • Step E Preparation of 5-(4.4-difluoro-2-(5-fluoro-2- hydroxyphenvDpyrrolidin- 1 -vDpyrazolo ⁇ 1 ,5 -alpyrimidine-3 -carboxylic acid: To a solution of ethyl 5-(4,4-difluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (0.126 g, 0.267 mmol) in CH2CI2 (1.3 mL) at 0 °C was added 1 M BBr 3 in CH2CI2 (1.50 mL, 1.50 mmol).
  • the resulting mixture was warmed to ambient temperature and stirred for 18 hours.
  • the reaction mixture was diluted with CH2CI2 (5 mL) and poured into a mixture of ice and saturated aqueous aHC03 (3 mL).
  • the aqueous layer was then acidified to about pH 3 with 1 N aqueous HC1.
  • the aqueous layer was extracted with CH2CI2 (3 x 10 mL).
  • Step F Preparation of N-((y)-3-chloro-2-hvdroxypropyl)-5-(4.4-difluoro-2-(5- fluoro-2-hvdroxyphenyl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxamide: To a mixture of 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin- l-yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxylic acid (0.047 g, 0.124 mmol) and HOBT (0.0252 g, 0.186 mmol) in DMF (1 mL) at ambient temperature was added EDCI (0.0357 g, 0.186 mmol).
  • Step G Preparation of Diastereomers 1 and 2 of (15S)-4.4.9-trifluoro-15- hvdroxy-13-oxa-2.17.21.22.25-pentaazapentacvclori7.5.2.0 2 ' 6 .0 7 ' 12 .0 22 ' 26 1hexacosa-l(25).7 (12).8.10.19(26).20.23-heptaen-18-one: A mixture of N-((5)-3-chloro-2-hydroxypropyl)-5- (4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide (0.060 g, 0.128 mmol) and Cs 2 C0 3 (0.208 g, 0.639 mmol) in DMF (6.4 mL) was heated at 85 °C for 30 minutes.

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Abstract

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Description

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS
[0001] The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain macrocyclic compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
[0002] The current treatment regimes for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative respiratory effects, as well as the potential for addiction. Nonsteroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) also have drawbacks including insufficient efficacy in treating severe pain and the potential for internal gastrointestinal bleeding. In addition, COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.
[0003] Trk's are high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).
[0004] Inhibitors of the Trk/neurotrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain. For example, antagonistic NGF and TrkA antibodies such as RN-624 have been shown to be efficacious in inflammatory and neuropathic pain animal models (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. (2005) Pain 1 16, 8-16; Delafoy, L. et al. (2003) Pain 105, 489^197; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15, 355-361; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442- 448) and neuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999) Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Pain 79, 265-274 Herzberg, U. et al. (1997) Neuroreport 8, 1613-1618; Theodosiou, M. et al. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci. 23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117- 120).
[0005] It has also been shown that NGF secreted by tumor cells and tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers. Using various tumor models in both mice and rats, it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine. In addition, activation of the BDNF/TrkB pathway has been implicated in numerous studies as a modulator of various types of pain including inflammatory pain (Matayoshi, S., J. Physiol. 2005, 569:685-95), neuropathic pain (Thompson, S.W., Proc. Natl. Acad. Sci. USA 1999, 96:7714-18) and surgical pain (Li, C.-Q. et al, Molecular Pain, 2008, 4(28), 1-1 1).
[0006] Recent literature has also shown that overexpression, activation, amplification and/or mutation of Trk kinases are associated with many cancers including 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. 644-653), gastric carcinoma (Du, J. et al, World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), lung carcinoma (Ricci A., et al, American Journal of Respiratory Cell and Molecular Biology 25 (4), pp. 439-446), breast cancer (Jin, W., et al, Carcinogenesis 2010, 31 (11), pp. 1939-1947), Glioblastoma (Wadhwa, S., et al, Journal of Biosciences 2003, 28 (2), pp. 181- 188), medulloblastoma (Gruber-Olipitz, M., et al, Journal ofProteome Research 2008, 7 (5), pp. 1932-1944), secratory breast cancer (Euthus, D.M., et al, Cancer Cell 2002, 2 (5), pp. 347-348), salivary gland cancer (Li, Y.-G., et al, Chinese Journal of Cancer Prevention and Treatment 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma (Greco, A., et al, Molecular and Cellular Endocrinology 2010, 321 (1), pp. 44-49) and adult myeloid leukemia (Eguchi, M., et al, Blood 1999, 93 (4), pp. 1355-1363). In preclinical models of cancer, non-selective small molecule inhibitors of Trk A, B and C were efficacious in both inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169: 107-114; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia, M.A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351).
[0007] In addition, inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of pre-clinical models of inflammatory diseases with NGF antibodies or non-selective small molecule inhibitors of Trk A, B and C. For example, inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma (Freund-Michel, V; Frossard, N., Pharmacology & Therapeutics (2008), 1 17(1), 52-76), interstitial cystitis (Hu Vivian, Y., et. al. The Journal of Urology
(2005) , 173(3), 1016-21), inflammatory bowel diseases 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. Archives of Dermatological Research
(2006) , 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S. P., et al, J. Investigative Dermatology (2004), 122(3), 812-819).
[0008] The neurotrophin/Trk pathway, particularly BDNF/TrkB, has also been implicated in the etiology of neurodegenerative diseases including multiple sclerosis, Parkinson's disease and Alzheimer's Disease (Sohrabji, F., Lewis, Danielle K., Frontiers in Neuroendocrinology (2006), 27(4), 404-414).
[0009] The TrkA receptor is also thought to be critical to the disease process in the infection of the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts (de Melo- Jorge, M., et al, Cell Host & Microbe (2007), 1(4), 251-261).
[0010] Several classes of small molecule inhibitors of Trk kinases said to be useful for treating pain or cancer are known (Expert Opin. Ther. Patents (2009) 19(3)).
[0011] There remains a need, however, for compounds and methods for the treatment of pain, in particular chronic pain, as well as for the treatment of cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
SUMMARY OF THE INVENTION
[0012] It has now been found that macrocyclic compounds are inhibitors of Trk kinases, in particular inhibitors of TrkA and/or TrkB and/or TrkC, and are useful for treating disorders and diseases such as cancer and pain, including chronic and acute pain. Compounds which are inhibitors of TrkA and/or TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery and bone fracture. In addition, compounds of the invention may be useful for treating inflammation, neurodegenerative diseases and certain infectious diseases.
[0013] Accordingly, in one aspect present invention provides novel compounds having the general Formula I:
Figure imgf000005_0001
I
[0014] and stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein.
[0015] In another aspect, the present invention provides novel compounds having the general Formula I:
Figure imgf000005_0002
IA
[0016] or pharmaceutically acceptable salts or solvates thereof, wherein ring A, W, m, R2, R2a, R3, Z, R5 and R6 are as defined herein.
[0017] In another aspect of the invention, there are provided pharmaceutical compositions comprising compounds of Formula I and a carrier, diluent or excipient.
[0018] In another aspect of the invention, there is provided a method for treating or preventing pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases in a mammal, comprising administering to said mammal an effective amount of a compound of Formula I.
[0019] In another aspect of the invention, there is provided a use of a compound of
Formula I in the manufacture of a medicament for the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
[0020] In another aspect of the invention, there is provided a use of a compound of
Formula I in the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
[0021] Another aspect provides intermediates for preparing compounds of Formula I.
In one embodiment, certain compounds of Formula I may be used as intermediates for the preparation of other compounds of Formula I.
[0022] Another aspect includes processes for preparing, methods of separation, and methods of purification of the compounds described herein. DETAILED DESCRIPTION OF THE INVENTION
[0023] One embodiment of this invention provides compounds of the general
Formula I containing a pyrazolo[l,5-a]pyrimidinyl ring and having the structure:
Figure imgf000006_0001
I
[0024] or pharmaceutically acceptable salts or solvates thereof, wherein:
[0025] ring A is selected from rings A-l, A-2 and A-3 having the structures:
Figure imgf000006_0002
[0026] wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[0027] X is N or CH;
[0028] Y is H or F;
[0029] R1 is H, ( 1 -3 Qalkoxy or halogen;
[0030] ring B is selected from rings B-l and B-2 having the structures:
Figure imgf000006_0003
3 3
B-1 B-2
[0031] wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[l,5- ajpyrimidine ring of Formula I;
[0032] W is O, NH or CH2, wherein when ring A is A-2, then W is CH2;
[0033] m is 0, 1 or 2;
[0034] D is carbon;
[0035] R2 and R2a are independently H, F, (1-3 Qalkyl or OH, provided that R2 and
R2a are not both OH;
[0036] R3 and R3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl; [0037] or D is carbon or nitrogen, R2 and R3 are absent and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;
[0038] Z is *-NR4aC(=0)-, *-ONHC(=0)-, *-NR4bCH2- or *-OC(=0)-, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R3;
[0039] R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl);
[0040] R4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, A^ O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar2(S02)-, H02CCH2- or (1-6C alkyl)NH(CO)-;
[0041] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
[0042] Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
[0043] R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl.
[0044] In one embodiment of Formula I, ring B is ring B-2 having the structure:
Figure imgf000007_0001
3
B-2
[0045] D is carbon, R2 and R2a are independently (1-3 Qalkyl, and R3 and R3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl, or
[0046] D is carbon or nitrogen, R2 and R3 are absent and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.
[0047] In one embodiment of Formula I, ring A is ring A- 1 having the structure
Figure imgf000007_0002
A-1 [0048] wherein X, Y and R1 are as defined for Formula I. In one embodiment of
Formula I, X is CH. In one embodiment, X is N. In one embodiment of Formula I, Y is F. In one embodiment, Y is H. In one embodiment of Formula I, R1 is H. In one embodiment, R1 is (l-3C)alkoxy. A particular example is methoxy. In one embodiment, R1 is halogen. In one embodiment, R1 is F.
[0049] Particular examples of ring A when represented by structure A- 1 include the structures:
Figure imgf000008_0001
[0050] In one embodiment, ring A is ring A-2 having the structure
Figure imgf000008_0002
A-2
[0051] wherein Y is H or F. In one embodiment, Y is F. In one embodiment, Y is H.
In one embodiment, R1 is H. In one embodiment, R1 is (l-3C)alkoxy. A particular example is methoxy. In one embodiment, R1 is halogen. In one embodiment, R1 is F.
[0052] Particular examples of ring A when represented by ring A-2 are the structures:
Figure imgf000008_0003
[0053] In one embodiment of Formula I, ring A is ring A-3 having the structure
1
Figure imgf000008_0004
A-3
[0054] wherein Y and R1 is as defined for Formula I. In one embodiment, Y is F. In one embodiment, Y is H. In one embodiment, R1 is H. In one embodiment, R1 is (1- 3C)alkoxy. A particular example is methoxy. In one embodiment, R1 is halogen. In one embodiment, R1 is F.
[0055] Particular examples of ring A when represented by ring A-3 are the structures:
Figure imgf000009_0001
[0056] In one embodiment of Formula I, W is O.
[0057] In one embodiment, W is NH.
[0058] In one embodiment, W is CH2.
[0059] In one embodiment of Formula I, D is carbon, R2 and R2a are independently H,
F, (1-3 Qalkyl or OH (provided that R2 and R2a are not both OH), and R3 and R3a are independently H, (1-3 Qalkyl or hydroxy( 1-3 Qalkyl.
[0060] In one embodiment, R2 and R2a are independently H, F, methyl or OH, provided that R2 and R2a are not both OH.
[0061] In one embodiment, R2 and R2a are both H.
[0062] In one embodiment, R2 is H and R2a is F.
[0063] In one embodiment, R2 and R2a are both F.
[0064] In one embodiment, R2 is H and R2a is OH.
[0065] In one embodiment, R2 is H and R2a is methyl.
[0066] In one embodiment, R2 and R2a are both methyl.
[0067] In one embodiment, R3 and R3a are independently H, (l-3Qalkyl or hydroxy(l-3 Qalkyl.
[0068] In one embodiment, R3a is H. In one embodiment, R3 is H. In one embodiment, both R3 and R3a are H.
[0069] In one embodiment, R3a is (l-3Qalkyl. Examples include methyl, ethyl, propyl and isopropyl. In one embodiment, R3 is (l-3Qalkyl. Examples include methyl, ethyl, propyl and isopropyl.
[0070] In one embodiment, R3a is (1-3 Qalkyl and R3 is H. In one embodiment, R3a is methyl and R3 is H.
[0071] In one embodiment, both R3a and R3 are (l-3Qalkyl. In one embodiment, R3a and R3a are both methyl.
[0072] In one embodiment, R3 is hydroxy(l-3Qalkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl. In one embodiment, R3 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl and R3a is H. [0073] In one embodiment of Formula I, D is carbon or nitrogen, R2 and R3 are absent, and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms. In one embodiment, R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms. Examples of heteroaryl rings include pyridyl and pyrazolyl rings. Specific examples of hete rings include the structures:
Figure imgf000010_0001
[0074] In one embodiment, Z is *-NR4aC(=0)-.
[0075] In one embodiment, R4a is H.
[0076] In one embodiment, R4a is (l-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
[0077] In one embodiment, R4a is fluoro(l-6C)alkyl. Examples include fluoromethyl and 2-fluoroethyl.
[0078] In one embodiment, R4a is difluoro(l-6C)alkyl. Example include difluoromethyl and 2,2-difluoroethyl.
[0079] In one embodiment, R4a is trifluoro(l-6C)alkyl. Examples include trifluoromethyl and 2,2,2-trifluoroethyl.
[0080] In one embodiment, R4a is hydroxy(l-6C alkyl). Examples include hydroxymethyl, 2 -hydroxy ethyl, 2-hydroxypropyl and 3-hydroxypropyl.
[0081] In one embodiment, R4a is dihydroxy(2-6C alkyl). An example includes 2,3- dihydroxypropyl.
[0082] In one embodiments, R4a is H or (l-6C)alkyl. In one embodiment, R4a is H or
Me.
[0083] An example of Z when represented by *-NR4aC(=0)- is *-ONHC(=0)-.
[0084] In one embodiment, Z is *-NR4bCH2-.
[0085] In one embodiment, R4b is H.
[0086] In one embodiment, R4b is selected from (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, and trifluoro(l-6C)alkyl.
[0087] In one embodiment, R4b is (l-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. In one embodiment, R4b is methyl.
[0088] In one embodiment, R4b is fluoro(l-6C)alkyl. Examples include fluoromethyl and 2-fluoroethyl. [0089] In one embodiment, R4b is difluoro(l-6C)alkyl. Example include difluoromethyl and 2,2-difluoroethyl.
[0090] In one embodiment, R4b is trifluoro(l-6C)alkyl. Examples include trifluoromethyl and 2,2,2-trifluoroethyl.
[0091] In one embodiment, R4b is selected from (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar^O)- and HOCH2C(0)-.
[0092] In one embodiment, R4b is (1-6C alkyl)C(O)-. Examples include CH3C(0)-,
CH3CH2C(0)-, CH3CH2CH2C(0)-, and (CH3)2CHC(0)-. In one embodiment, R4 is CH3C(0)-.
[0093] In one embodiment, R4b is (3-6C cycloalkyl)C(O)-. Examples include cyclopropylC(O)-, cyclobutylC(O)-, cyclopentylC(O)- and cyclohexylC(O)-.
[0094] In one embodiment, R4b is A^QO)-. An example is phenylC(O)-.
[0095] In one embodiment, R4b is HOCH2C(0)-.
[0096] In one embodiment, R4b is selected from (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, and Ar2(S02)-.
[0097] In one embodiment, R4b is (1-6C alkyl)sulfonyl. Examples include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
[0098] In one embodiment, R4b is (3-6C cycloalkyl)sulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl. In one embodiment, R4 is methylsulfonyl.
[0099] In one embodiment, R4b is Ar2(S02)-. An example is phenylsulfonyl.
[00100] In one embodiment, R4b is H02CCH2-.
[00101] In one embodiment, R4b is (1-6C alkyl)NH(CO)-. Examples include
CH3NHC(0)-, CH3CH2NHC(0)-, CH3CH2CH2NHC(0)-, and (CH3)2CHNHC(0)-. In one embodiment, R4 is CH3NHC(0)-.
[00102] In one embodiment, R4b is selected from H, methyl, -C(0)CH3, methylsulfonyl, -C(0)CH2OH, -CH2COOH and -C(0)NHCH2CH3.
[00103] In one embodiment, Z is *-OC(=0)-.
[00104] In one embodiment of Formula I, ring B is ring B-l :
Figure imgf000011_0001
3
B-1 [00105] where R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy( 1 -6C)alkyl.
[00106] In one embodiment, R5 and R6 are independently H, F, OH, (l-6C)alkyl or hydroxy(l-6C)alkyl. In one embodiment, R5 is H and R6 is H, F, OH, (l-6C)alkyl or hydroxy( 1 -6C)alkyl.
[00107] In one embodiment, R5 and R6 are independently H, F, OH, (l-3C)alkyl or hydroxy(l-3C)alkyl. In one embodiment, R5 is hydrogen and R6 is H, F, OH, (l-3C)alkyl or hydroxy(l-3C)alkyl.
[00108] In one embodiment, R and R are independently H, F, OH, methyl, ethyl,
HOCH2- or HOCH2CH2-. In one embodiment, R5 is hydrogen and R6 is H, F, OH, methyl, ethyl, HOCH2- or HOCH2CH2-.
[00109] In one embodiment, R5 and R6 are independently H, F, or methyl. In one embodiment, R5 is H and R is H, F, or methyl.
[00110] In one embodiment, R5 is H and R6 is F.
[00111] In one embodiment, R is H and R is methyl.
[00112] In one embodiment, R5 and R6 are both H.
[00113] In one embodiment, R5 and R6 are both F.
[00114] In one embodiment, R5 and R6 are both methyl.
[00115] In one embodiment, ring B is ring B-l which is optionally substituted with one or two substituents independently selected from OH and F, provided that two OH substituents are not on the same ring carbon atom.
[00116] Particular examples of ring B when represented by ring B-l include the structures:
Figure imgf000012_0001
[00117] odiment of Formula I, ring B is ring B-2 having the formula:
Figure imgf000012_0002
3
B-2
[00118] In one embodiment, m is 0.
[00119] In one embodiment, m is 1. [00120] In one embodiment, m is 2.
[00121] One embodiment of this invention provides compounds of the general
Formula I or pharmaceutically acceptable salts or solvates thereof, wherein:
[00122] ring B is ring B-l :
Figure imgf000013_0001
3
B-1
[00123] ring A is selected from rings A-1, A-2 and A-3 having the structures:
Figure imgf000013_0002
A-1 A-2 A-3
[00124] wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[00125] X is N or CH;
[00126] Y is H or F;
[00127] R1 is H, (l-3C)alkoxy or halogen;
[00128] W is O, NH or CH2, wherein when ring A is A-2, then W is CH2;
[00129] m is 0, 1 or 2;
[00130] D is carbon;
[00131] R2 and R2a are independently H, F, (1-3 Qalkyl or OH, provided that R2 and
R2a are not both OH;
[00132] R3 and R3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
[00133] or R2 and R3 are absent and R2a and R3a together with the atoms to which they are attached form a bivalent 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms;
[00134] Z is *-NR4aC(=0)-, *-ONHC(=0)-, *-NR4bCH2- or *-OC(=0)-, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R3;
[00135] R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl); [00136] R4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar^O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar2(S02)-, H02CCH2- or (1-6C alkyl)NH(CO)-;
[00137] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
[00138] Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
[00139] R and R are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl.
[00140] One embodiment of this invention provides compounds of the general
Formula IA
Figure imgf000014_0001
IA
[00141] or pharmaceutically acceptable salts or solvates thereof, wherein:
[00142] ring A is selected from rings A-1, A-2 and A-3 having the structures:
Figure imgf000014_0002
A-1 A-2 Α-3
[00143] wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[00144] X is N or CH;
[00145] Y is H or F;
[00146] R1 is H, (l-3C)alkoxy or halogen;
[00147] W is O, NH or CH2, wherein when ring A is A-2, then W is CH2;
[00148] m is 0, 1 or 2; [00149] R2 and R2a are independently H, F, or OH, provided that R2 and R2a are not both OH;
[00150] R3 is H, (1-3 Qalkyl or hydroxy(l-3 C)alkyl;
[00151] Z is *-NR4aC(=0)-, *-ONHC(=0)-, *-NR4bCH2- or *-OC(=0)-, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R3;
[00152] R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl);
[00153] R4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar^O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar2(S02)-, H02CCH2- or (1-6C alkyl)NH(CO)-;
[00154] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
[00155] Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
[00156] R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl.
[00157] In one embodiment, Formula IA includes compounds wherein:
[00158] ring A is ring A-1 represented by the structure
Figure imgf000015_0001
A-1
[00159] wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[00160] ring B is ring B-1 represented by the structure:
Figure imgf000015_0002
B-1 [00161] wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[l,5- ajpyrimidine ring of Formula I;
[00162] X is N or CH;
[00163] Y is H or F;
[00164] R1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
[00165] W is O or H;
[00166] m is 0, 1 or 2;
[00167] R2 and R2a are independently H, F, or OH, provided that R2 and R2a are not both OH;
[00168] R3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
[00169] Z is *-NR4aC(=0)-, *-ONHC(=0)-, or *-OC(=0)-, wherein the asterisk indicates the point of attachment to the carbon bearing R3;
[00170] R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(l-6C alkyl); and
[00171] R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl.
[00172] In one embodiment, X is N. In one embodiment, X is CH.
[00173] In one embodiment, Formula IA includes compounds wherein:
[00174] ring A is ring A-2 represented by the structure
Figure imgf000016_0001
A-2
[00175] wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[00176] ring B is ring B-1 represented by the structure:
Figure imgf000016_0002
3
B-1 [00177] wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[l,5- ajpyrimidine ring of Formula I;
[00178] Y is H or F;
[00179] R1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
[00180] m is 0, 1 or 2;
[00181] W is CH2;
[00182] m is 0, 1 or 2;
[00183] R2 and R2a are independently H, F, or OH, provided that R2 and R2a are not both OH;
[00184] R3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
[00185] Z is *-NR4aC(=0)-, wherein the asterisk indicates the point of attachment to the carbon bearing R3;
[00186] R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(l-6C alkyl); and
[00187] R and R are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl,
[00188] In one embodiment, Formula IA includes compounds wherein:
[00189] ring A is ring A-3 represented by the structure
Figure imgf000017_0001
A-3
[00190] wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[00191] ring B is ring B-1 represented by the structure:
Figure imgf000017_0002
3
B-1 [00192] wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[l,5- ajpyrimidine ring of Formula I;
[00193] Y is H or F;
[00194] R1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
[00195] W is O;
[00196] m is 0, 1 or 2;
[00197] R2 and R2a are independently H, F, or OH, provided that R2 and R2a are not both OH;
[00198] R3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
[00199] Z is *-OC(=0)- or *-NR aC(=0)-, wherein the asterisk indicates the point of attachment to the carbon bearing R3;
[00200] R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(l-6C alkyl); and
[00201] R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl,
[00202] In one embodiment, Formula IA includes compounds wherein:
[00203] ring A is ring A-1 represented by the structure
Figure imgf000018_0001
A-1
[00204] wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
[00205] ring B is ring B-1 represented by the structure:
Figure imgf000018_0002
B-1 [00206] wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[l,5- ajpyrimidine ring of Formula I;
[00207] X is N or CH;
[00208] Y is H or F;
[00209] R1 is H, (l-3C)alkyl, (l-3C)alkoxy or halogen;
[00210] W is O;
[00211] m is 0, 1 or 2;
[00212] R2 and R2a are independently H, F, or OH, provided that R2 and R2a are not both OH;
[00213] R3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
[00214] Z is *-NR4bCH2-, wherein the asterisk indicates the point of attachment to the carbon bearing R3;
[00215] R4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, A^ O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar2(S02)-, H02CCH2- or (1-6C alkyl)NH(CO)-;
[00216] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
[00217] Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
[00218] R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-
6C)alkyl.
[00219] It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated as a mixture of isomers such as a racemic or diastereomeric mixture, or in an enantiomerically or diastereomerically pure form. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
[00220] In one embodiment, compounds of the general Formula I wherein Ring B is ring B-l have the absolute configuration of Figure 1-a:
Figure imgf000020_0001
1-a
[00221] In one embodiment, compounds of the general Formula I wherein Ring B is ring B-l have the absolute configur
Figure imgf000020_0002
1-b
[00222] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
[00223] The terms "(l-3C)alkyl" and "(l-6C)alkyl" as used herein refer to saturated linear or branched-chain monovalent hydrocarbon radicals of one to three carbon atoms and one to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec -butyl, tert-butyl, 2 -methyl-2 -propyl, pentyl, and hexyl.
[00224] The term "fluoro(l-6C)alkyl" as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein one of the hydrogens is replaced by a fluorine atom.
[00225] The term "difluoro(l-6C)alkyl" as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein two of the hydrogens are replaced by fluorine atoms.
[00226] The term "trifluoro(l-6C)alkyl" as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein three of the hydrogens are replaced by fluorine atoms. [00227] The term "hydroxy(l-6Calkyl) as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms, wherein one of the hydrogens is replaced by a hydroxy (OH) group.
[00228] The term "dihydroxy(l-6Calkyl) as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein two of the hydrogens are replaced by hydroxy (OH) groups, provided the hydroxy groups are not on the same carbon atom.
[00229] The term "(1-6C alkyl)sulfonyl" as used herein refers to a (1-6C alkyl)S02- group, wherein the radical is on the sulfur atom and the (1-6C alkyl) portion is as defined above. Examples include methylsulfonyl (CH3SO2-) and ethylsulfonyl (CH3CH2SO2-).
[00230] The term "(3-6C cycloalkyl)sulfonyl" as used herein refers to a (3-6C cycloalkyl)S02- group, wherein the radical is on the sulfur atom. An example is cyclopropylsulfonyl.
[00231] The terms "(l-4C)alkoxy" and "(l-6C)alkoxy", as used herein refer to saturated linear or branched-chain monovalent alkoxy radicals of one to four carbon atoms or one to six carbon atoms, respectively, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy.
[00232] The term "halogen" includes fluoro, chloro, bromo and iodo.
[00233] It will also be appreciated that certain compounds of Formula I may be used as intermediates for the preparation of further compounds of Formula I.
[00234] The compounds of Formula I include salts thereof. In certain embodiments, the salts are pharmaceutically acceptable salts. In addition, the compounds of Formula I include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of
Formula I and/or for separating enantiomers of compounds of Formula I.
[00235] The term "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[00236] It will further be appreciated that the compounds of Formula I and their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
[00237] Compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ¾ 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood to refer to UC, 12C, 13C, 14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13N, 14N, 15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to 140, 150, 160, 170, 180 or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18F, 19F or mixtures thereof. The compounds according to the invention therefore also comprise compounds with one or more isotopes of one or more atom, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
[00238] The present invention further provides a process for the preparation of a compound of Formula I or a salt thereof as defined herein which comprises:
[00239] (a) for a compound of Formula I wherein Z is *-NHC(=0)-, and ring A, ring
B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula II
Figure imgf000022_0001
[00240] where P1 is H or a carboxyl protecting group, in the presence of a coupling reagent and a base; or
[00241] (b) for a compound of Formula I wherein W is O, ring A is formula A- 1 :
Figure imgf000022_0002
[00242] X is N, and ring B, D, Z, Y, R1, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula III
Figure imgf000023_0001
III
[00243] where n is 1, 2, 3 or 4 and L1 is a leaving group or atom, in the presence of a base; or
[00244] (c) for a compound of Formula I wherein W is CH2, ring A is formula A-2:
[00245] and ring B, Z, D, Y, R ,
Figure imgf000023_0002
Ria and m are as defined for Formula I, cyclizing a corresponding compound having the formula IV
Figure imgf000023_0003
IV
[00246] where L2 is a leaving group or atom, in the presence of a base; or
[00247] (d) for a compound of Formula I wherein Z is *-NHC(=0)-, and ring A, ring
B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula V
Figure imgf000023_0004
[00248] in the presence of a base and a coupling reagent; or [00249] (e) for a compound of Formula I wherein Z is *-NHCH2-, and ring A, ring B,
W, D, R2, R2 aa,, RR33,, RR33aa aanndd mm are as defined for Formula I, cyclizing a corresponding compound having the formula VI
Figure imgf000024_0001
VI
[00250] in the presence of a reducing agent; or
[00251] (f) for a compound of Formula I wherein Z is *-NHCH2-, and ring A, ring B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VII
Figure imgf000024_0002
VII
[00252] in the presence of triphenylphosphine; or
[00253] (g) for a compound of Formula I wherein ring A, ring B, W, D, m, R2, R2a,
R3, and R3a are as defined for Formula I, Z is *-NR4bCH2-, and R4b is (1-6C alkyl)C(O)-, (3- 6C cycloalkyl)C(O)-, Ar^O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, or Ar2(S02)-, coupling a corresponding compound having the formula VIII
Figure imgf000024_0003
VIII
[00254] with a reagent having the formula (1-6C alkyl)C(0)-L3, (3-6C cycloalkyl)C(0)-L3, Ar^O)-!,3, HOCH2C(0)-L3, (1-6C alkyl)(S02)-L3, (3-6C cycloalkyl)(S02)-L3, or Ar2(S02)-L3, respectively, where L3 is a leaving atom, in the presence of a base; or
[00255] (h) for a compound of Formula I wherein ring A, ring B, W, D, R2, R2a, R3,
R3a and m are as defined for Formula I, Z is *-NR4bCH2-, and R4b is (1-6C alkyl)NH(CO)-, reacting a compound having the formula VIII
Figure imgf000025_0001
VIII
[00256] with a reagent having the formula (1-6C alkyl)N=C=0 in the presence of a base; or
[00257] (i) for a compound of Formula I wherein R2 is F, R2a is H, and ring A, ring B,
Z, W, D, R3, R3a, and m are as defined for Formula I, reacting a corresponding compound having the formula IX
Figure imgf000025_0002
IX
[00258] with a fluorination reagent;
[00259] (j) for a compound of Formula I wherein W is O, ring A is formula A- 1,
Figure imgf000025_0003
A-1
[00260] X is CH, and Y, R1, D, ring B, Z, R2, R2a, R3 and m are as defined for Formula I, cyclizing a corresponding compound having the formula X
Figure imgf000026_0001
X
[00261] where n is 1, 2, 3 or 4 and L1 is a leaving group or atom, in the presence of a base; and
[00262] optionally removing any protecting groups and optionally preparing a salt thereof.
[00263] In one embodiment of the above-described methods (a)-(j), ring B is ring B-1 having the structure:
Figure imgf000026_0002
B-1
[00264] D is carbon, R2 and R2a are independently H, F, (1-3 Qalkyl or OH (provided that R2 and R2a are not both OH), R3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl., and ring A, W, m, Z, R5 and R6 are as defined for Formula I.
[00265] Referring to method (a), the cyclization may be performed using conventional amide bond formation conditions, for example by treating the carboxylic acid with an activating agent, followed by addition of the amine in the presence of a base. Suitable activating agents include EDCI, oxalyl chloride, thionyl chloride, HATU, and HOBt. Suitable bases include amine bases, for example triethylamine, diisopropylethylamine, pyridine, or excess ammonia. Suitable solvents include DCM, DCE, THF and DMF.
[00266] Referring to methods (b) and (c), the leaving atoms L1 and L2 may be, for example a halogen atom such as Br, CI or I. Alternatively, L1 and L2 can be a leaving group, for example an arylsulfonyloxy group or an alkylsulfonyloxy group, such as a mesylate or a tosylate group. Suitable bases include alkali metal carbonates, such as sodium carbonate, potassium carbonate or cesium carbonate. Convenient solvents include aprotic solvents such as ethers (for example tetrahydrofuran or p-dioxane), DMF, or acetone. The reaction can be conveniently performed at elevated temperatures, for example 50-150 °C, for example at 85 °C. [00267] Referring to method (d), suitable coupling reagents include HATU, HBTU,
TBTU, DCC, DIEC, and any other amide coupling reagents well known to persons skilled in the art. Suitable bases include tertiary amine bases such as DIEA and triethylamine. Convenient solvents include DMF, THF, DCM and DCE.
[00268] Referring to method (e), suitable reducing agents include Me4 (OAc)3BH,
Na(OAc)3BH and NaCNBH3. Suitable solvents include neutral solvents such as acetonitrile, THF and DCE. The reaction can be conveniently performed at ambient temperature.
[00269] Referring to method (f), in certain embodiments the triphenylphosphine reagent is used in the form of a polystyrene-bound PPh3 resin (sold as PS-PPh3 by Biotage Systems). The reaction is conveniently performed at ambient temperature. Suitable solvents include neutral solvents, for example DCM.
[00270] Referring to method (g), the leaving atom L3 may be a halogen, for example
CI or Br. Suitable bases include tertiary amine bases such as diisopropylethylamine and triethylamine. The reaction is conveniently performed at ambient temperature.
[00271] Referring to method (h), suitable bases include tertiary amine bases such as
DIEA and triethylamine. The reaction is conveniently performed at ambient temperature.
[00272] Referring to method (i), the fluorination reagent may be, for example, bis(2- methoxyethyl)amino-sulfur trifluoride (Deoxo-Fluor™) or diethylaminosulfur trifluoride (DAST). Suitable solvents include dichloromethane, chloroform, dichloroethane, and toluene. The reaction is conveniently performed at ambient temperature.
[00273] Referring to method (j), base may be, for example, an alkali metal carbonate , such as for example sodium carbonate, potassium carbonate or cesium carbonate. Convenient solvents include aprotic solvents such as ethers (for example tetrahydrofuran or p-dioxane) or toluene. The reaction can be conveniently performed at a temperature between ambient temperature and reflux, for example at 85 °C.
[00274] Amine groups in compounds described in any of the above methods may be protected with any convenient amine protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), and [2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groups may be protected with any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groups may be protected with any convenient alcohol protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.
[00275] The compounds of the formulas II, III, IV, V, VI, VII, VIII, IX and X are also believed to be novel and are provided as further aspects of the invention.
[00276] The ability of compounds of the invention to act as TrkA inhibitors may be demonstrated by the assays described in Examples A and B.
[00277] Certain compounds which are inhibitors of TrkA and/or TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture.
[00278] In one embodiment, compounds of Formula I are useful for treating pain, including chronic and acute pain, in a mammal.
[00279] Acute pain, as defined by the International Association for the Study of Pain, results from disease, inflammation, or injury to tissues. This type of pain generally comes on suddenly, for example, after trauma or surgery, and may be accompanied by anxiety or stress. The cause can usually be diagnosed and treated, and the pain is confined to a given period of time and severity. In some rare instances, it can become chronic.
[00280] Chronic pain, as defined by the International Association for the Study of
Pain, is widely believed to represent disease itself. It can be made much worse by environmental and psychological factors. Chronic pain persists over a longer period than acute pain and is resistant to most medical treatments, generally over 3 months or more. It can and often does cause severe problems for patients.
[00281] Compounds of Formula I are also useful for treating cancer in a mammal.
Particular examples include neuroblastoma, ovarian, pancreatic, colorectal and prostate cancer.
[00282] Compounds of Formula I are also useful for treating inflammation in a mammal.
[00283] Compounds of Formula I are also useful for treating certain infectious diseases in a mammal, such as Trypanosoma cruzi infection.
[00284] Compounds of Formula I may also be used to treat neurodegenerative diseases in a mammal. Examples of neurodegenerative disease include demyelination and dysmyelination. Additional examples of neurodegenerative diseases include multiple sclerosis, Parkinson's disease and Alzheimer's disease. [00285] In addition, compounds of Formula I may also be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, anorexia, atopic dermatitis, and psoriasis in a mammal.
[00286] Accordingly, another embodiment of this invention provides a method of treating or preventing pain in a mammal, 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 pain. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain. In one embodiment, the pain is neuropathic pain. In one embodiment, the pain is pain associated with cancer. In one embodiment, the pain is pain associated with surgery. In one embodiment, the pain is pain associated with bone fracture. In one embodiment, the method comprises a method of treating said pain in a mammal. In one embodiment, the method comprises a method of preventing said pain in a mammal.
[00287] Another embodiment of this invention provides a method of treating or preventing inflammation in a mammal, 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 inflammation. In one embodiment, the method comprises a method of treating said inflammation in a mammal. In one embodiment, the method comprises a method of preventing said inflammation in a mammal.
[00288] Another embodiment of this invention provides a method of treating or preventing a neurodegenerative disease in a mammal, 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 neurodegenerative disease. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is dysmyelination. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease. Another embodiment of this invention provides a method of treating or preventing infectious diseases in a mammal, 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 infectious disease. In one embodiment, the infectious disease is Trypanosoma cruzi infection. In one embodiment, the method comprises a method of treating said neurodegenerative disease in a mammal. In one embodiment, the method comprises a method of preventing said neurodegenerative disease in a mammal. [00289] Another embodiment of this invention provides a method of treating or preventing cancer in a mammal, 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 cancer. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the method comprises a method of treating said cancer in a mammal. In one embodiment, the method comprises a method of preventing said cancer in a mammal.
[00290] Compounds of Formula I may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments that work by the same or a different mechanism of action. Examples include anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine), and chemotherapeutic agents. These 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 according to standard pharmaceutical practice known to one skilled in the art.
[00291] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to compositions of the present invention may be, for example, surgery, radiotherapy, chemotherapy, signal transduction inhibitors and/or monoclonoal antibodies.
[00292] Accordingly, the compounds of Formula I may be administered in combination with one or more agents selected from mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferase inhibitors. These 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 according to standard pharmaceutical practice known to one skilled in the art. [00293] As used herein, terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
[00294] In one embodiment, the terms "treatment" or "treating" as used herein, mean an alleviation, in whole or in part, of symptoms associated with a disorder or condition as described herein (e.g., multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture), or slowing, or halting of further progression or worsening of those symptoms.
[00295] In one embodiment, the term "preventing" as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein (e.g., multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture), or a symptom thereof.
[00296] The terms "effective amount" and "therapeutically effective amount" refer to an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of Formula I that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
[00297] As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
[00298] Compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally. Compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
[00299] The present invention further provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove. In one embodiment, the pharmaceutical composition includes the compound of Formula I together with a pharmaceutically acceptable diluent or carrier.
[00300] The present invention further provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in therapy.
[00301] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pain in a mammal. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain. In one embodiment, the pain is neuropathic pain. In one embodiment, the pain is pain associated with cancer. In one embodiment, the pain is pain associated with surgery. In one embodiment, the pain is pain associated with bone fracture.
[00302] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation in a mammal.
[00303] According to a further aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease in a mammal. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is dysmyelination. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease.
[00304] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of infectious diseases in a mammal. In one embodiment, the infectious disease is Trypanosoma cruzi infection.
[00305] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a mammal. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is prostate cancer.
[00306] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pain in a mammal.
[00307] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammation in a mammal.
[00308] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease in a mammal.
[00309] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of infectious diseases in a mammal.
[00310] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a mammal.
Examples
[00311] The following examples illustrate the invention. In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, Alfa, Aesar, TCI, Maybridge, Asta Tech, or other suitable suppliers, and were used without further purification unless otherwise indicated. THF, DCM, toluene, DMF and dioxane were purchased from Aldrich in Sure/Seal™ bottles and used as received.
[00312] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried or dried under a stream of dry nitrogen.
[00313] Column chromatography was done on a Biotage system (Manufacturer: Dyax
Corporation) having a silica gel or C-18 reverse phase column, or on a silica SepPak cartridge (Waters), or using conventional flash column chromatography on silica gel, unless otherwise specified. 0314] Abbreviations used herein have the following meanings:
CAN acetonitrile
APCI Atmospheric Pressure Chemical Ionization
ΒΓΝΑΡ 2,2'-bis(diphenylphosphino)-l, l'-binaphthyl
Boc tert-butoxycarbonyl
Boc20 Di-tert-butyl dicarbonate
BOP (Benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
CDI carbonyl diimidazole
DCC N,N'-dicyclohexylcarbodiimide
DCE Dichloroethane
DCM Dichloromethane
DIEA Diisopropylethylamine
DIEC l-(3-dimethylaminopropyl)-3-ethylcarboiimide
DIPHOS l,2-Bis(Diphenylphosphino)ethane
DMF N,N-Dimethylformamide
DMSO dimethylsulfoxide
EDCI 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide)
HATU (2-(7-Aza- IH-benzotriazole- 1 -yl)- 1 , 1 ,3,3 -tetramethyluronium hexafluorophosphate)
HOBt Hydroxybenzotriazole
IPA Isopropyl alcohol
MTBE tert-butyl-methylether
Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium (0)
Pd2dba3 Tris(dibenzylideneacetone)dipalladium (0)
PS-PPhs polystyrene-bound PPh3 resin
TEA triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography Biological Assays
Example A
TrkA ELISA assay
[00315] An enzyme-linked immunosorbant assay (ELISA) was used to assess TrkA kinase activity in the presence of inhibitors. Immulon 4HBX 384-well microtiter plates (Thermo part #8755) were coated with a 0.025 mg/mL solution of poly (Glu, Ala, Tyr; 6:3 : 1; Sigma P3899). Various concentrations of test compound, 2.5 nM TrkA (Invitrogen Corp., histidine-tagged recombinant human TrkA, cytoplasmic domain), and 500 μΜ ATP were incubated for 25 minutes at ambient temperature in the coated plates while shaking. The assay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v/v) Triton X-100 and 5 mM MgCl2. The reaction mixture was removed from the plate by washing with PBS containing 0.1% (v/v) Tween 20. The phosphorylated reaction product was detected using 0.2 μg/mL of a phosphotyrosine specific monoclonal antibody (clone PY20) conjugated to horseradish peroxidase in conjunction with the TMB Peroxidase Substrate System (KPL). After the addition of 1M phosphoric acid, the chromogenic substrate color intensity was quantitated via absorbance at 450 nm. IC50 values were calculated using either a 4 or 5-parameter logistic curve fit.
[00316] Table 1 provides averaged IC50 values for compounds of the invention when tested in this assay. In Table 1, the letter "A" designates an IC50 value between about 1 and 100 nM, and the letter "B" designates an IC50 value >100 nM and <3000 nM.
Example B
TrkA Binding assay
[00317] The ability of a compound to bind to TrkA was measured by Invitrogen's
LanthaScreen™ Eu Kinase Binding Assay. In this assay, His-tagged recombinant human TrkA (cytoplasmic domain) from Invitrogen is incubated with Invitrogen's Alexa-Fluor® Tracer 236, biotinylated anti-His, and europium-labeled Streptavidin, compound (2% DMSO final) in buffer (25 mM MOPS, pH 7.5, 5 mM MgC12, 0.005% Triton X-100). After a 60- minute incubation at 22°C, the reaction was measured using the EnVision via TR-FRET dual wavelength detection, and the POC was calculated from the emission ratio. The compound dose response data was fit to a 4-parameter logistic model and IC50 was defined as the concentration of compound at 50 POC.
[00318] Table 1 provides averaged IC50 values for compounds of the invention when tested in this assay. In Table 1, the letter "A" designates an IC50 value between about 1 and 100 nM, and the letter "B" designates an IC50 value >100 nM and <3000 nM. Table 1
Example No. TrkA Elisa Enzyme Assay TrkA Binding Assay
ICso ICso
1 A A
2 A A
3 A A
4 A A
5 A A
6 A A
7 A A
8 A A
9 A A
10 A A
11 A A
12 A
13 A
14 A
15 B
16 A A
17 A
18 A A
19 A A
20 A A
21 B
22 A
23 A A
24 B
25 A
26 B B
27 A
28 A
29 A
30 A
31 B B
32 A
33 A
34 A
35 A
36 A
37 A
38 A
39 A
40 A Example No. TrkA Elisa Enzyme Assay TrkA Binding Assay
ICso ICso
41 A
41-B B 1
42 A
42-B B 1
43 A
43-B B 1
44 A
44-B A 1
45 A 1
Diastereomer
1
45 A 1
Diastereomer
2
1 Compound may have been isolated along with the enantiomer and/or one or more diastereomers, which additional isomer(s) were believed to make up < 1.5% of the total amount isolated.
Figure imgf000037_0001
(R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine
[00319] Step A: Preparation of ( R)-ter t-butyl 2-(5-fluoro-2-methoxypyridin-3- vDpyrrolidine- 1 -carboxylate: A solution of tert-butyl pyrrolidine- 1-carboxylate (4.09 mL, 23.4 mmol) and (-)-sparteine (6.44 mL, 28.0 mmol) in MTBE (50 mL) was cooled to -78 °C and sec- vLi (20 mL, 28.0 mmol, 1.4 M in cyclohexane) was introduced drop-wise by cannula, keeping the internal temperature under -78 °C. The resulting solution was stirred for 3 hours at -78 °C, followed by addition of a solution of ZnC¾ (21.0 mL, 21.0 mmol, 1M in Et20) drop-wise with rapid stirring, keeping the internal temperature below -65 °C. The resulting light suspension was stirred at -78 °C for 10 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 3-bromo-5-fluoro-2- methoxypyridine (5.05 g, 24.5 mmol), Pd(OAc)2 (0.262 g, 1.17 mmol) and ?-Bu3P-HBF4 (0.407 g, 1.40 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (1 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite® and washed with Et20. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5% EtOAc/hexanes to give product (R)-tert-butyl 2-(5-fluoro- 2-methoxypyridin-3-yl)pyrrolidine-l-carboxylate as yellow oil (4.34 g, 63% yield).
[00320] Step B: Preparation of (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine:
A DCM (12 mL) solution of TFA (1 1.3 mL, 146 mmol) was added to (R)-tert-butyl 2-(5- fluoro-2-methoxypyridin-3-yl)pyrrolidine-l-carboxylate (4.33 g, 14.6 mmol) and stirred at ambient temperature for 1 hour. The reaction was then concentrated, taken up in EtOAc, then washed with aHC03 and brine. The organic phase was dried (MgSC^), filtered, and concentrated, and the crude material was purified by silica column chromatography eluting with a 1-2% 7 N NH3-MeOH/DCM to afford (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2- yl)pyridine as a liquid (1.40 g, 49 % yield).
[00321] The enantiomeric excess (ee%) of (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2- vDpyridine was determined as follows: To a propan-2-ol solution of small amount of ((R)-5- fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine was added excess N-(2,4-dinitro-5- fluorophenyl)-L-alanine amide (FDAA, Marfey's reagent). The mixture was heated to reflux for approximately two minutes. After cooling to ambient temperature, the reaction mixture was diluted with acetonitrile and analyzed by HPLC (YMC ODS-AQ 4.6 x 50 mm 3 μιη 120A column; mobile phase: 5-95% solvent B in A; solvent A: H20/ 1% IPA/ 10 mM ammonium acetate, and solvent B: ACN/1% IP A/10 mM ammonium acetate; flow rate: 2 mL/min). The enantiomeric excess was determined from the peak areas of the two diastereomeric derivatives formed. The ee% of the product was determined to be > 93%.
Figure imgf000038_0001
(R)-5 -(2-(5-fluoro-2-methoxypyridin-3 -vDpyrrolidin- 1 -vDpyrazolo Γ 1 ,5 -alpyrimidine-3 - carboxylic acid
[00322] Step A: Preparation of ethyl 5-hvdroxypyrazolori .5-a1pyrimidine-3- carboxylate: To a mixture of ethyl 3-amino-lH-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (is)-ethyl 3-ethoxyacrylate (35.8 ml, 242 mmol) in DMF (537 mL) was added cesium carbonate (78.7 g, 242 mmol), and the reaction was heated at 110 °C for 15 hours. After cooling to ambient temperature the reaction was acidified with acetic acid to pH 4. The resulting precipitate was filtered, washed with water and EtOAc, to provide the product as a white solid. To recover additional product, the filtrate was concentrated, diluted with EtOAc (500 mL) and washed with I¾0 (5 x 200 mL). The resulting precipitate in the EtOAc layer was filtered and washed with water and EtOAc to obtain a second batch product. The two batches of product were combined and dried under reduced pressure to afford ethyl 5- hydroxypyrazolo[ l,5-a]pyrimidine-3-carboxylate as a white solid (33.3 g, 100 % yield). MS (apci) m/z = 206.2 (M-H).
[00323] Step B: Preparation of ethyl 5-chloropyrazolo[ 1.5-alpyrimidine-3-carboxylate:
Ethyl 5-hydroxypyrazolo[ l,5-a]pyrimidine-3-carboxylate (22.7 g, 1 10 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove excess POCI3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer was extracted with DCM (2 x 200 mL). The combined organic layers were dried (MgS04), filtered and concentrated to afford ethyl 5- chloropyrazolo[l ,5-a]pyrimidine-3-carboxylate as a pale-yellow solid (24.2 g, 97.6 % yield). MS (apci) m/z = 225.9 (M+H).
[00324] Step C: Preparation of (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin- l-yl)pyrazolo[ 1.5-alpyrimidine-3-carboxylate: A mixture of ethyl 5- chloropyrazolo[l ,5-a]pyrimidine-3-carboxylate (0.75 g, 3.32 mmol), (R)-5-fluoro-2- methoxy-3-(pyrrolidin-2-yl)pyridine (Preparation A, 0.984 g, 3.66 mmol), DIEA (2.32 mL, 13.3 mmol) and n-butanol (1.1 1 mL) was sealed in a pressure tube and heated at 90 °C for 48 hours. The reaction mixture was diluted with EtOAc and washed with water, brine and sat aHC03. The organic layer was dried (MgS04), filtered and concentrated to afford a dark orange oil. The crude material was purified by silica column chromatography eluting with 50-80% EtOAc/hexanes to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-
1 - yl)pyrazolo[l ,5-a]pyrimidine-3-carboxylate (0.72 g, 56.2 % yield) as a yellow foamy solid. MS (apci) m/z = 386.0 (M+H).
[00325] Step D: Preparation of (R)-5 -(2-(5 -fluoro-2-methoxypyridin-3 -vDpyrrolidin- 1 - yl)pyrazolor i .5-a1pyrimidine-3-carboxylic acid: To a suspension of (R)-ethyl 5-(2-(5-fluoro-
2- methoxypyridin-3-yl)pyrrolidin-l -yl)pyrazolo[l ,5-a]pyrimidine-3-carboxylate (0.72 g, 1.868 mmol) in MeOH (9.34 mL) was added LiOH (1 N, 3.74 mL, 3.74 mmol), and the reaction mixture was heated at 70 °C for 15 hours. After cooling, the reaction mixture was concentrated and the resulting residue diluted in water. After acidifying with citric acid, the aqueous layer was extracted with DCM. The combined organics were dried (MgS04), filtered and concentrated to afforded (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (0.67 g, 100 % yield) as a yellow solid. MS (apci) m/z = 357.9 (M+H).
Preparation C
Figure imgf000040_0001
(R)-4-((tert-butyldimethylsilyl)oxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin 2.2.2- trifluoroacetate
[00326] Steps A-D followed the procedure reported by H. Imamura, et al. in
Tetrahedron, 2000, 56, 7705.
[00327] Step A: Preparation of (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one: To a suspension of (R)-4-hydroxypyrrolidin-2-one (purchased from Asta Tech or Aldrich) (5.030 g, 48.26 mmol) in DMF (24 mL) at 0 °C was added TBDMS-C1 (7.637 g, 50.67 mmol) followed by imidazole (4.978 g, 72.39 mmol). The resulting mixture was warmed to ambient temperature and stirred for 1 hour, then poured into 100 mL of water with stirring. The resulting suspension was filtered and the solids were washed with water and dried under reduced pressure to afford (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one (10.14 g, 97.56 % yield) that was used directly without further purification.
[00328] Step B: Preparation of ( R)-ter t-butyl 4-(tert-butyldimethylsilyloxy)-2- oxopyrrolidine-l-carboxylate: To a solution of (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin- 2-one (10.14 g, 47.08 mmol) in MeCN (16 mL) at 0 °C was added sequentially DMAP (3.221 g, 26.37 mmol), TEA (3.957 mL, 28.25 mmol), and Boc20 (1 1.49 g, 52.65 mmol). The resulting mixture was warmed to ambient temperature and stirred for 48 hours. The reaction mixture was poured into water and extracted with EtOAc (100 mL). The organic layer was successively washed with 1 N aqueous HC1 (2 x 50 mL), 1 N aqueous NaOH (50 mL), and brine. The organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-l-carboxylate (13.62 g, 91.69 % yield). XH NMR (CDC13) δ 4.39 (m, 1H), 3.87 (m, 1H), 3.62 (m, 1H), 2.71 (m, 1H), 2.46 (m, 1H), 1.53 (s, 9H), 0.88 (s, 9H), 0.08 (d, 6H).
[00329] Step C: Preparation of (R)-tert-butyl 2-(ter?-butyldimethylsilyloxy)-4-(5- fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate: To a solution of (R)-tert-butyl 4-(tert- butyldimethylsilyloxy)-2-oxopyrrolidine-l-carboxylate (6.00 g, 19.0 mmol) in THF (36 mL) at 0 °C was added a 0.5 M solution of (5-fluoro-2-methoxyphenyl)magnesium bromide in THF (50.0 mL, 25.0 mmol). The resulting mixture was stirred at 0 °C for 30 minutes, then treated with MeOH (60 mL) and NaBH4 (0.966 g, 25.2 mmol). After stirring at 0 °C for an additional 30 minutes, the reaction mixture was poured into saturated aqueous NH4C1 (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-2% MeOH/DCM to afford (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)-4-(5-fluoro-2- methoxyphenyl)-4-hydroxybutylcarbamate (which was assumed to be a mixture of the syn and anti isomers), (4.81 g, 57.0 % yield). XH NMR (CDC13) δ 7.20 (m, 1H), 6.90 (m, 1H), 6.77 (m, 1H), 5.12 (m, 1H), 4.10 (m, 1H), 3.82 (m, 3H), 3.29 (m, 2H), 1.71-1.93 (m, 2H), 1.45 (s, 9H), 0.93 (d, 9H), 0.1 1-0.14 (m, 6H).
[00330] Step D: Preparation of (R)-tert-butyl 4-(tert-butyldimethylsiryloxy)-2-(5- fluoro-2-methoxyphenyl)pyrrolidine- 1 -carboxylate: To a solution of (R)-tert-butyl 2-(tert- butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate (4.810 g, 10.84 mmol) in CH2C12 (108 mL) at -60 °C was added TEA (4.534 mL, 32.53 mmol) followed by methanesulfonyl chloride (0.9231 mL, 11.93 mmol). The resulting mixture was slowly warmed to -5 °C and poured into a mixture of ice and saturated aqueous NaHCCh (50 mL). The organic layer was separated and the aqueous layer was extracted with (¾(¾ (2 x 50 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica column chromatography, eluting with 2-10% MeOH/DCM to afford (R)-tert-butyl 4-(tert- butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine- 1 -carboxylate (assumed to be a mixture of cis and trans isomers; 2.648 g, 57.38 % yield). LC/MS (ES+APCI) m/z = 326.1 (M+H-Boc).
[00331] Step E: Preparation of (R)-4-(ter/-butyldimethylsilyloxy)-2-(5-£luoro-2- methoxyphenvDpyrrolidine 2,2,2-trifluoroacetate: To a solution of (R)-tert-butyl A-(tert- butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-l-carboxylate (2.648 g, 6.222 mmol) in CH2CI2 (26 mL) at 0 °C was added TFA (9.3 mL). The resulting mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was azeotroped with toluene-CH2Cl2 (2x) and dried under reduced pressure to provide (R)-4-(tert- butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (assumed to be a mixture of cis and trans isomers; 2.92 g, 106.8 % yield), which was used directly without further purification. LC/MS (ES+APCI) m/z = 326.3 (M+H).
Preparation D
Figure imgf000042_0001
(R)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxy^^
carboxylic acid
[00332] Step A: Preparation of (R)-ethyl 5-(4-(ter?-butyldimethylsilyloxy -2-(5-fluoro-
2-methoxyphenyl pyrrolidin-l-yl pyrazolorL5-a1pyrimidine-3-carboxylate: To a suspension of ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (0.100 g, 0.483 mmol) and BOP reagent (0.320 g, 0.724 mmol) in DMF (1 mL) at 0 °C was added a solution of (R)-4-(tert- butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (Preparation C; 0.167 g, 0.483 mmol) in (¾(¾ (1 mL) and N,N-diisopropylethylamine (0.420 mL, 2.41 mmol) sequentially. The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCC and brine. The brine phase was back-extracted with EtOAc (3x). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica column chromatography, eluting with 0-50% EtOAc/Hexanes to afford (R)-ethyl 5-(4-(tert- butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers) (0.0487 g, 19.6 % yield). LC/MS (ES+APCI) m/z = 515.2 (M+H).
[00333] Step B: Preparation of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4- hydroxypyrrolidin-l -yDpyrazoloT 1 ,5-a1pyrimidine-3-carboxylate: To a solution of (R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (as a mixture of the cis and trans isomers) (0.0487 g, 0.0946 mmol) in THF (1 mL) at 0 °C was added 1 M TBAF in THF (0.104 mL, 0.104 mmol). The reaction mixture was warmed to ambient temperature and stirred for 2.5 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to afford the crude (R)-ethyl 5-(2-(5-fluoro-2- methoxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers; 37.9 mg, 100 % yield). LC/MS (ES+APCI) m/z = 401.1 (M+H).
[00334] Step C: Preparation of (R)-ethyl 5-(2-(5-fluoro-2-hvdroxyphenyl)-4- hydroxypyrrolidin-l -yDpyrazoloT 1 ,5-a1pyrimidine-3-carboxylate: To a solution of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylate (as a mixture of cis and trans isomers; 0.0379 g, 0.0947 mmol) in CH2CI2 (1 mL) at 0 °C was added 1 M BBr3 in CH2C12 (0.473 ml, 0.473 mmol). The resulting mixture was warmed to ambient temperature for 25 hours, then diluted with CH2CI2 (10 mL) and poured into a mixture of ice and saturated aqueous aHC03 (15 mL). The organic layer was separated and the aqueous layer acidified with IN aqueous HC1 until pH = 5-6. The aqueous layer was extracted with CH2CI2 (3x) and the combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give a mixture of (R)-5-(2-(5- fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin- 1 -yl)pyrazolo[ 1 ,5-a]pyrimidine-3 -carboxylic acid (as a mixture of cis and trans isomers) and (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)-4- hydroxypyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers). The mixture was dissolved in MeOH-THF (0.25 mL/0.75 mL) and treated with 1 N aqueous LiOH (0.474 mL, 0.474 mmol). The resulting mixture was heated at 50 °C for 1 hour, then cooled to ambient temperature and acidified to pH 3 to 4 with 1 N aqueous HC1. The mixture was extracted with EtOAc (3 x 15 mL) and the combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give crude (R)- 5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (as a mixture of cis and trans isomers; 33.9 mg, 100 % yield). LC/MS (ES+APCI) m/z = 357.1 (M-H).
Figure imgf000043_0001
1 (23).7.9.17(24).18.21 -hexaene- 16.25-dione
[00335] Step A: Preparation of (R)-ethyl 5-(2-(5-fluoro-2-oxo-1.2-dihydropyridin-3-
1 vDpyrrolidin- 1 -yDpyrazoloT 1 ,5-a1pyrimidine-3-carboxylate: To a mixture of (R)-ethyl 5-(2- (5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (Preparation B, Step C; 0.92 g, 2.39 mmol) and Acetic acid (5.73 g, 95.5 mmol) was added HBr (4.4 rnL, 23.9 mmol, 33% in acetic acid). The reaction mixture was heated at 90 °C for 2 hours. After cooling, the reaction mixture was treated with EtOAc, washed with water, saturated NaHCCh and brine, then dried (MgS04), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 3% MeOH/DCM to yield the desired product (0.605 g, 68 % yield). MS (apci) m/z = 372.0 (M+H).
[00336] Step B: Preparation of (R)-ethyl 5-(2-(l-(3-(1.3-dioxoisoindolin-2-yl)propyl)-
5-fluoro-2-oxo- 1.2-dihydropyridin-3-yl)pyrrolidin- l-yl)pyrazolo[ 1.5-a]pyrimidine-3- carboxylate: To a DMF (5 mL) suspension of (R)-ethyl 5-(2-(5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.20 g, 0.54 mmol) was added LiH (6.8 mg, 0.81 mmol) at 0 °C, followed first by 20-minute stirring, then addition of a DMF (1 mL) solution of 2-(3-bromopropyl)isoindoline-l,3-dione (0.29 g, 1.1 mmol). The reaction was warmed to ambient temperature and stirred for 17 hours. After cooling to 0 °C the reaction was quenched with ice-water (30 mL) and the aqueous was extracted with EtOAc (3 x 50 mL). The combined organic layers were backwashed with water and brine, dried (MgS04), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH DCM to yield the desired product (0.2 g, 66 % yield). MS (apci) m/z = 559.0 (M+H).
[00337] Step C: Preparation of (R)-ethyl 5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-1.2- dihydropyridin-3 -vDpyrrolidin- 1 -yDpyrazoloT 1 ,5-a1pyrimidine-3 -carboxylate: To a solution of (R)-ethyl 5-(2-(l-(3-(l,3-dioxoisoindolin-2-yl)propyl)-5-fluoro-2-oxo-l,2-dihydropyridin- 3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.20 g, 0.36 mmol) in 1 : 1 MeOH/THF (12 mL) was added hydrazine-H20 (0.18 g, 3.6 mmol). The reaction mixture was heated at 50 °C for 24 hours. After cooling, the reaction mixture was poured into water and extracted with DCM (3 x 20 mL). The combined organics were dried (MgS04), filtered, and concentrated to afford the desired product (0.11 g, 72 % yield). MS (apci) m/z = 429.0 (M+H).
[00338] Step D: Preparation of (R)-5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-l ,2- dihydropyridin-3 -vDpyrrolidin- 1 -yDpyrazoloT 1.5-a1pyrimidine-3 -carboxylic acid: To a solution of (R)-ethyl 5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.11 g, 0.26 mmol) in 3 : 1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol), and the reaction mixture was heated at 70 °C for 20 hours. After cooling, the reaction mixture was treated with MeOH, acidified with IN HC1 (1.5 mL), and concentrated to afford the desired product (O. lg, 100 % yield). MS (apci) m/z = 401.1 (M+H).
[00339] Step E: Preparation of (6R)-9-fluoro-2.11.15.19.20.23- hexaazapentacvclori5.5.2.17'11.02'6.020'241pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25- dione: To a solution of (R)-5-(2-(l-(3-aminopropyl)-5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.24 mmol) in 1 :2 DMF/DCM (9 mL) was added EDCI (0.14 g, 0.71 mmol) followed by HOBT (96 mg, 0.71 mmol) at ambient temperature. After stirring for 10 minutes, TEA (0.099 mL, 0.71 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was treated with EtOAc, washed with saturated NH4C1, saturated aHC03, and brine, then dried (MgS04), filtered, concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH/DCM to yield the title product (35 mg, 39 % yield). MS (apci) m/z = 383.2 (M+H).
Example 2
Figure imgf000045_0001
(6R)-12-oxa-2.16.20.21.24.26-hexaazapentacvclor 16.5.2.17,11.02'6 021'251hexacosa- 1 (24).7(26).8.10.18(25).19.22-heptaen- 17-one
[00340] Step A: Preparation of (R)-2-methoxy-6-(pyrrolidin-2-yl)pyridine: Prepared according to the method described in Preparation A, substituting 3-bromo-5-fluoro-2- methoxypyridine with 2-bromo-6-methoxypyridine in Step A. MS (apci) m/z = 179.1 (M+H).
[00341] Step B: Preparation of (R)-ethyl 5-(2-(6-methoxypyridin-2-yl)pyrrolidin-l- yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: Prepared by to the same method as described in Preparation B, Step C, substituting (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine with (R)-2-methoxy-6-(pyrrolidin-2-yl)pyridine. MS (apci) m/z = 368.0 (M+H).
[00342] Step C: Preparation of (R)-ethyl 5-(2-(6-oxo-1.6-dihvdropyridin-2- yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a mixture of (R)-ethyl 5-(2- (6-methoxypyridin-2-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.46 g, 1.25 mmol) and acetic acid (3.0 g, 50 mmol) was added HBr (3.1 g, 12.5 mmol, 33% in acetic acid). The reaction mixture was heated at 90 °C for 2 hours. After cooling, the reaction was diluted with EtOAc, washed with water, saturated aHC03, and brine, then dried (MgS04), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH/DCM to yield the desired product (0.3 g, 67 % yield). MS (apci) m/z = 354.1 (M+H).
[00343] Step D: Preparation of (R)-ethyl S- -Ce-CS-d -dioxoisoindolin^- yl)propoxy)pyridin-2-yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate^ To a suspension of (R)-ethyl 5-(2-(6-oxo-l,6-dihydropyridin-2-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (0.091 g, 0.26 mmol) in DMF (2 mL) was added LiH (3.2 mg, 0.39 mmol) at 0 °C. After stirring for 20 minutes, a solution of 2-(3- bromopropyl)isoindoline-l,3-dione (0.14 g, 0.52 mmol) in DMF (1 mL) was added, and the reaction was warmed up to ambient temperature and stirred for 17 hours. After cooling to 0 °C, the reaction was quenched with ice-water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water and brine, dried (MgS04), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 1.5% MeOH/DCM to yield the desired product (0.1 17 g, 84 % yield). MS (apci) m/z = 541.1 (M+H).
[00344] Step E: Preparation of (R)-ethyl 5-(2-(6-(3-aminopropoxy)pyridin-2- yl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxylate: To a solution of (R)-ethyl 5-(2- (6-(3-( 1 ,3 -dioxoisoindolin-2-yl)propoxy)pyridin-2-yl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxylate (0.1 1 g, 0.20 mmol) in 1 : 1 MeOH/THF (12 mL) was added hydrazine-H20 (0.10 g, 2.0 mmol). The reaction mixture was heated at 50 °C for 24 hours. After cooling, the reaction mixture was poured into water then extracted with DCM (3 x 20 mL). The combined organics were dried (MgS04), filtered, and concentrated to afford the desired product (70 mg, 84 % yield). MS (apci) m/z = 441.1 (M+H).
[00345] Step F: Preparation of (R)-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin- l-yl)pyrazolorL5-a1pyrimidine-3-carboxylic acid: To a solution of (R)-ethyl 5-(2-(6-(3- aminopropoxy)pyridin-2-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (70 mg, 0.17 mmol) in 3 : 1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol) and the reaction mixture was heated at 70 °C for 20 hours. After cooling, the reaction mixture was diluted with MeOH, acidified with 1 N HC1 (1.5 mL), and concentrated to afford the desired product (65 mg, 100 % yield). MS (apci) m/z = 383.1 (M+H).
[00346] Step G: Preparation of (6R)-12-oxa-2, 16,20,21 ,24,26-hexaazapentacyclo- ri6.5.2.17'11.02'6.021'251hexacosa-l(24),7(26).8.10.18(25).19.22-heptaen-17-one: To a solution of (R)-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (70 mg, 0.18 mmol) in 1 :2 DMF/DCM (9 mL) was added EDCI (1 10 mg, 0.55 mmol) followed by HOBT (74 mg, 0.55 mmol) at ambient temperature. After stirring for 10 minutes, TEA (0.077 mL, 0.55 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was diluted with EtOAc, washed with saturated NH4C1, saturated NaHCCh, and brine, then dried (MgS04), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH/DCM to yield the title product (30 mg, 45 % yield). MS (apci) m/z = 365.2 (M+H).
Figure imgf000047_0001
(6R)-9-fluoro- 13 -oxa-2.1 1.17.21.22.25-hexaazapentacvclor 17.5.2.02'6 07'12.022'26lhexacosa-
1 (25V7.9.11.19(26).20.23 -heptaen- 18-one
[00347] Step A: Preparation of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- l-yl)-N-(3-hvdroxypropyl)pyrazolori .5-a1pyrimidine-3-carboxamide: To a DMF (2 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) cooled to 0 °C was added 3-aminopropan-l-ol (0.0642 mL, 0.840 mmol) drop- wise, resulting in a clear yellowish solution. After dropwise addition of DIEA (0.366 mL, 2.10 mmol), ice bath was removed and reaction was stirred at ambient temperature for 1 hour. The reaction was directly purified on reverse phase column chromatography (Biotage SP4 system, C-18 25+M column, 0 to 54% Acetonitrile/water), to provide the product as white solid (200 mg, 69 % yield). MS (apci) m/z = 415.1 (M+H).
[00348] Step B: Preparation of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2- hvdroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)-N-(3- hydroxypropyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (20 mg, 0.0483 mmol) in HCl (4 Ν dioxane, 1.2 mL, 4.83 mmol) was heated at 85 °C overnight. The reaction mixture was concentrated, triturated with ether, and filtered, to provide the crude product as a beige solid, which was directly used in the next step without further purification (22 mg, 106 % yield). MS (apci) m/z = 419.1 (M+H).
[00349] Step C: Preparation of (6RV9-fluoro-13-oxa-2.1 1.17.21.22.25- hexaazapentacvclori7.5.2.02'6.07'12.022'26lhexacosa-l(25).7.9.1 1.19(26).20.23-heptaen-18- one: A DMF (1 mL) suspension of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin- 3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (5 mg, 0.012 mmol) and CS2CO3 (4 mg, 0.06 mmol) was heated at 85 °C overnight. The reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 5 to 60% acetonitrile/water), to provide the title product as white solid (2 mg, 44 % yield). MS (apci) m/z = 383.3 (M+H).
Figure imgf000048_0001
(6RV9-fluoro- 15-hvdroxy- 13 -oxa-2.1 1.17.21.22.25- hexaazapentacvclor 17.5.2.02'6.07'12.022'261hexacosa- 1 (25 V7.9.1 1.19(26).20.23 -heptaen- 18-one
[00350] Step A: Preparation of N-(2.3-dihvdroxypropyl)-5-((R)-2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) in 1 : 1 DMF/DMSO (2 mL) was cooled to 0 °C, followed first by drop-wise addition of 3- aminopropane-l,2-diol (76.5 mg, 0.840 mmol) and then addition of DIEA (366 μί, 2.10 mmol). The reaction was warmed up to ambient temperature, stirred for 20 minutes, and then directly purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M cartridge, 5 to 50% acetonitrile/water), to provide the product as a white solid (295 mg, 98 % yield). MS (apci) m/z = 431.1 (M+H).
[00351] Step B: Preparation of N-(3-chloro-2-hvdroxypropyl)-5-((R)-2-(5-fluoro-2- oxo-1 , 2-dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidine-3-carboxamide: A mixture of N-(2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (100 mg, 0.232 mmol) and HC1 (4 Ν, dioxane, 5.8 mL) was sealed in a pressure tube and heated at 85 °C overnight. After the clear solution was decanted, the crude product was obtained as a brownish oily residue, which was vacuum- dried and used directly in the next step without further purification. MS (apci) m/z = 435.0 (M+H).
[00352] Step C: Preparation of (6R)-9-fluoro-15-hvdroxy-13-oxa-2.1 1.17.21.22.25- hexaazapentacvclori7.5.2.02'6.07'12.022'26lhexacosa-l('25).7.9.1 1.19('26).20.23-heptaen-18- one: A suspension of N-(3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (100 mg, 0.23 mmol) and CS2CO3 (375 mg, 1.15 mmol) in DMF (3 niL) was heated at 85 °C for 2 hours. The reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 5 to 50% acetonitrile/water), to provide the title product as a white solid. MS (apci) m/z = 399.2 (M+H).
Figure imgf000049_0001
(6RJ3»Sy9-fluoro-13-hvdroxy-2, 1 1, 15, 19,20,23 -hexaazapentacyclo- ri5.5.2.17'11.02'6 020'241pentacosa-l(23).7.9.17(24), 18.21-hexaene-16.25-dione
[00353] Step A: Preparation of N-C^-S-chloro^-hvdroxypropyn-S-CfRl^-CS-fluoro-
2-oxo-l , 2-dihvdropyridin-3-yl pyrrolidin-l-yl pyrazolorL5-a1pyrimidine-3-carboxamide hydrochloride: Prepared according to the method described in Example 3, Steps A-B, substituting 3-aminopropan-l-ol in Step A with (5)-3-aminopropane-l,2-diol. MS (apci) m/z = 435.0 (M+H).
[00354] Step B: Preparation of (6R.135)-9-fluoro-13-hvdroxy-2,l 1, 15.19.20,23- hexaazapentacvclori5.5.2.17'11.02'6.020'241pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25- dione: A suspension of N-((5)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo-l,2- dihydropyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5-a]pyrimidine-3 -carboxamide hydrochloride (40 mg, 0.085 mmol) and Cs2C03 (138 mg, 0.42 mmol) in DMF (0.8 mL) was heated at 85 °C for 2 hours. The reaction mixture was filtered through GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 40% acetonitrile/water), to provide the title product as a white solid (4 mg, 12 % yield). MS (apci) m/z = 399.2 (M+H).
Figure imgf000049_0002
(6R)-9-fluoro- 15-hydroxy- 13-oxa-2.1 1.17.21.22.25-hexaazapentacyclo- Γ 17.5.2.02'6.07'12.022'261hexacosa- 1 (25).7.9.11.19(26).20,23 -heptaen- 18-one [00355] Prepared according to the method described in Example 5 and isolated as a by- produce in Step B. The enantiomeric integrity of the chiral center where the HO group resides was found to have unexpectedly eroded (R/S ratio was about 10:7) in the isolated final product (6R)-9-fluoro- 15 -hydroxy- 13 -oxa-2, 1 1, 17,21,22,25-hexaazapentacyclo- [17.5.2.02'6.07'12.022'26]hexacosa-l(25),7,9,l l,19(26),20,23-heptaen-18-one, which was obtained as a white solid (5 mg, 15 % yield) by reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 50% acetonitrile/water). MS (apci) m/z = 399.2 (M+H).
Figure imgf000050_0001
(6R, 15R)-9-fluoro- 15 -hydroxy- 13-oxa-2, 11 , 17,21 ,22,25-hexaazapentacvclo- Γ 17.5.2.02'6.07'12.022'261hexacosa- 1 (25V7.9.11.19(26).20.23 -heptaen- 18-one
[00356] Step A: Preparation of N-((R) -chloro-2-hvd-Oxypropyl)-5-(fR)-2-(5-fluo-O- 2-oxo- l,2-dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori ,5-a1pyrimidine-3-carboxamide: Prepared according to the method described in Example 3, Steps A-B, substituting 3- aminopropan-l-ol in Step A with (R)-3-aminopropane-l,2-diol. MS (apci) m/z = 435.0 (M+H).
[00357] Step B: Preparation of (6R.15R)-9-fluoro-15-hvdroxy-13-oxa-
2.1 1.17.21.22.25-hexaazapentacvclori7.5.2.02'6.07'12.022'261hexacosa-
1 (25V7.9.1 1.19(26).20.23-heptaen- 18-one: A suspension of N-((R)-3-chloro-2- hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo- 1 ,2-dihydropyridin-3 -yl)pyrrolidin- 1 - yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (30 mg, 0.069 mmol) and CS2CO3 (112 mg, 0.34 mmol) in DMF (0.7 mL) was heated at 85 °C for 1 hour. The reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 50% acetonitrile/water), to provide the title product as a white solid (10 mg, 36 % yield). Unlike Example 6, no erosion of the enantiomeric integrity of the chiral center where HO group resides was observed for this final product. MS (apci) m/z = 399.2 (M+H).
Example 8
Figure imgf000051_0001
(6R, 13R)-9-ffuoro- 13-hydroxy-2, 11 , 15, 19, 20,23 -hexaazapentacyclo- ri5.5 . l7,1^02^0∞,Mlpentacosa-l(23\7.9J7(24\ 18.21-hexaene-16.25-dione
[00358] Obtained as a by-product of Example 7, Step B and isolated as a white solid
(1.2 mg, 4 % yield) by reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 44% acetonitrile/water) of the crude material of Example 7, Step B. MS (apci) m/z = 399.2 (M+H).
Figure imgf000051_0002
(6R)-9-fluoro-13-oxa-2.11.16.20.21.24-hexaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-
1 (24).7.9.11.18(25).19.22-heptaen-l 7-one
[00359] Step A: Preparation of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- l-yl)-N-(2-hvdroxyethyl)pyrazolorL5-a1pyrimidine-3-carboxamide: To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.28 mmol) and HATU (128 mg, 0.336 mmol) was added DIEA (0.146 mL, 0.840 mmol) at ambient temperature, followed by a solution of 2-aminoethanol (20.5 mg, 0.336 mmol) in minimal amount of DMF dropwise at 0 °C. The reaction was warmed up to ambient temperature and stirred for 30 minutes, then directly purified by reverse-phase column chromatography (0 to 70% acetonitrile/water) to yield the product as white solid (95 mg, 85 % yield). MS (apci pos) m/z = 401.1 (M+H).
[00360] Step B: Preparation of (R)-N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1.2- dihydropyridin-3 -yDpyrrolidin- 1 -yPpyrazolof 1.5 -a]pyrimidine-3 -carboxamide: To (R)-5-(2- (5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)-N-(2-hydroxyethyl)pyrazolo[l,5- a]pyrimidine-3 -carboxamide (77 mg, 0.192 mmol) in a pressure reaction tube was charged hydrogen chloride (4 Ν dioxane, 4.8 mL, 19.2 mmol) and the resulting white suspension was heated at 85 °C overnight. After cooling to ambient temperature, the reaction mixture was decanted to yield the crude product as brownish oily residue, which was dried in vacuo and directly used in the next step without further purification. MS (apci) m/z = 405.0 (M+H).
[00361] Step C: Preparation of (6R)-9-fluoro- 13 -oxa-2,1 1.16.20,21,24- hexaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-l('24).7.9.1 1.18('25).19.22-heptaen-17- one: A suspension of (R)-N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (78 mg, 0.19 mmol) and Cs2C03 (314 mg, 0.96 mmol) in DMF (5 mL) was heated at 85 °C for 30 minutes. After filtering through a GF/F paper the reaction was diluted with water (40 mL) and NH4C1 (saturated, 5 mL), then extracted with EtOAc (3 x 40 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 73% acetonitrile/water), to provide the title product as a white solid (17 mg, 24 % yield). MS (apci) m/z = 369.2 (M+H).
Figure imgf000052_0001
(6R)-9-fluoro-13-oxa-2.11.18.22.23.26-hexaazapentacvclori 8.5.2.02'6.07'12.023'271heptacosa-
1 (26) .9.1120(27) 1 ,24-heptaen- 19-one
[00362] Step A: Preparation of (R)-N-(4-chlorobutyl)-5-(2-(5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori .5-a1pyrimidine-3-carboxamide: Prepared according to the method described in Example 3, Steps A-B, substituting 3-aminopropan-l-ol in Step A with 4-aminobutan-l-ol. MS (apci) m/z = 433.0 (M+H).
[00363] Step B: Preparation of (6R)-9-fluoro- 13 -oxa-2,1 1.18.22.23.26- hexaazapentacvclo-r 18.5.2.02'6 07'12.023'271heptacosa- 1 (26).7.9.1 1.20(27).21.24-heptaen- 19- one: Prepared according to the method described in Example 3, substituting (R)-N-(3- chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxamide with (R)-N-(4-chlorobutyl)-5-(2-(5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide in Step C. The crude product was purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 0 to 80% acetonitrile/water), to provide the title product as a white solid (32 mg, 44%). MS (apci pos) m/z =397.2 (M+H).
Figure imgf000053_0001
('6R)-9-fluoro-2.1 1.16.20.21.24-hexaazapentacvclori6.5.2.17'11.02'6.021'251hexacosa- l(24\7.9.18(25U9.22-hexaene-17.26-dione
[00364] Obtained as a by-product in Example 10, Step B and isolated a white solid (4 mg, 6%) upon purification of the crude material of Example 10, Step B by reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 0 to 50% acetonitrile/water). MS (apci) m/z = 397.2 (M+H).
Figure imgf000053_0002
(6RV9-fluoro-2.1 1.13.16.20.21.24-heptaazapentacvclor 16.5.2.02'6 07'12.021'25lpentacosa- 1 (24Ί.7.9.11.18(25).19.22-heptaen-l 7-one
[00365] Step A: Preparation of (RYtert-butyl 2-(2-chloro-5-ffuoropyridin-3- vDpyrrolidine- 1 -carboxylate: A solution of tert-butyl pyrrolidine- 1-carboxylate (1 mL 5.70 mmol) and (-)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to -78 °C under nitrogen, followed by addition of sec -butyl lithium (4.07 mL, 1.4M, 5.70 mmol) drop-wise over 15 minutes with a syringe, maintaining the temperature below -75 °C. The pale yellowish solution was stirred at -78 °C for 3 hours before being treated with zinc chloride (3.80 mL, 1.0 M, 3.80 mmol) drop-wise over 15 minutes, maintaining the temperature below -73 °C. The mixture was stirred at -78 °C for 30 minutes, then placed into an ambient temperature water bath and stirred for another hour. At this point a large amount of white precipitate was present. The mixture was treated with 3-bromo-2-chloro-5- fluoropyridine (1.00 g, 4.75 mmol) in MTBE (5 mL), followed by addition of palladium acetate (53 mg, 0.24 mmol) and tri-?-butylphosphine tetrafluoroborate (83 mg, 0.28 mmol). The mixture was allowed to stir at ambient temperature overnight to reach completion. The mixture was treated with NH4OH (1 mL), stirred for 30 minutes and filtered through GF/F paper, washing with MTBE. The filtrate was washed with 10% citric acid (30 mL) and the aqueous layer was back-washed with MTBE (2 x 30 mL). The combined organic phases were washed with brine (20 mL), dried (MgS04), and concentrated to afford the crude product as dark yellowish oil. This crude material was purified on a silica 50 g Biotage SNAP cartridge eluting with 10% EtOAc in hexanes to afford the desired product as colorless oil (0.5 g, 35 % yield). MS (apci) m/z = 201.1 (M+H-Boc).
[00366] Step B: Preparation of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride: To a dioxane (5 mL) solution of (R)-tert-butyl 2-(2-chloro-5-fluoropyridin- 3-yl)pyrrolidine-l-carboxylate (500 mg, 1.66 mmol) was added HC1 (4 N dioxane, 20 mL), followed by stirring at ambient temperature overnight. The mixture was concentrated and treated with Et20, then vacuum-dried, to provide the product as a white solid (0.36 g, 80 % yield). MS (apci) m/z = 201.1 (M+H). The enantiomeric excess (ee%) of the product was determined to be >92% according to the method described in Preparation A.
[00367] Step C: Preparation of (R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a solution of ethyl 5- hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHC03 (20 mL), water (20 mL) and brine (3 x 20 mL), then dried (Na2S04) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68 % yield). MS (apci) m/z = 390.0 (M+H).
[00368] Step D: Preparation of (RVethyl S-^-^-^-qert- butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolorL5- alpyrimidine-3-carboxylate: A mixture of Pd2dba3 (7.05 mg, 0.00770 mmol), CS2CO3 (125 mg, 0.385 mmol), rac-Binap (19.2 mg, 0.0308 mmol), (R)-ethyl 5-(2-(2-chloro-5- fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (50 mg, 0.128 mmol), and tert-butyl 2-aminoethylcarbamate (24.7 mg, 0.154 mmol) in degassed toluene (1 mL) was first purged with nitrogen, then sealed and subjected to microwave irradiation (120 °C) for 16 hours. After cooled to ambient temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (2 x 5 mL). The organic was dried (Na2S04) and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system CI 8 12+M cartridge, 5 to 70% acetonitrile/water) to yield the desired product as white foamy solid (38 mg, 58 % yield). MS (apci) m/z = 514.1 (M+H).
[00369] Step E: Preparation of (R)-5-(2-(2-(2-(tert- butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[1.5- alpyrimidine-3-carboxylic acid: To a solution of (R)-ethyl 5-(2-(2-(2-(tert- butoxycarbonylamino)ethylamino)-5-fluoropyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxylate (38 mg, 0.074 mmol) in THF/MeOH/water (2:2: 1, 0.7 mL) was added LiOH-H20 (9.3 mg, 0.22 mmol), followed by stirring at 50 °C for 18 hours. After removal of solvent, the reaction residue was taken up in water (0.5 mL), and acidified with 1 N HCl (0.22 mL) to pH 3. The reaction mixture was extracted with EtOAc (3 x 2 mL), dried (Na2S04), filtered and concentrated to give the desired product, which was used in the next step directly without further purification, assuming quantitative conversion. MS (apci) m/z = 486.0 (M+H).
[00370] Step F: Preparation of (R)-5-(2-(2-(2-aminoethylamino)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxylic acid hydrochloride: A solution of (R)-5-(2-(2-(2-(/er/-butoxycarbonylamino)ethylamino)-5-fluoropyridin-3 -yl)pyrrolidin- 1 - yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (31 mg, 0.064 mmol) in HCl (4 N dioxane, 798 μί) and TFA (50% DCM, 2 mL) was stirred at ambient temperature for 1 hour before it was concentrated and dried under high vacuum to yield to give the desired product as off- white solid, which was used in the next step directly without further purification, assuming quantitative conversion. MS (apci) m/z = 386.1 (M+H).
[00371] Step G: Preparation of (6fl>9-fluoro-2.11.13.16.20.21.24- heptaazapentacvclo-r 16.5.2.02'6.07'12.021'25lpentacosa- 1 (24).7.9.1 1.18(25).19.22-heptaen- 17- one: To a DMF (3 mL) solution of (R)-5-(2-(2-(2-aminoethylamino)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.065 mmol) was first added HATU (29 mg, 0.077 mmol), followed by five-minute stirring and then drop-wise addition of DIEA (56 μί, 0.32 mmol). After stirring at ambient temperature overnight, the reaction was directly purified by reverse phase column chromatography (Biotage SP4 system CI 8 25+M cartridge, acetonitrile/water 5 to 45%), to yield the title product as off- white solid (7 mg, 30 % yield). MS (apci) m/z = 368.2 (M+H). Example 13
Figure imgf000056_0001
(6R)-9-fluoro-2.11.13.17.21.22.25-heptaazapentacvclor 17.5.2.02'6.07'12.022'261hexacosa- 1 (25 V7.9.11.19(26).20,23 -heptaen- 18-one
[00372] Step A: Preparation of (R)-ethyl 5-(2-(2-(3-(tert-butoxycarbonylamino) propylamino)-5-fluoropyridin-3-yl)pyrrolidin- 1 -yPpyrazolof 1.5-a"|pyrimidine-3-carboxylate: Prepared according to the method described in Example 12, Steps D, substituting tert-butyl 2-aminoethylcarbamate with tert-butyl 3-aminopropylcarbamate. MS (apci) m/z = 528.1 (M+H).
[00373] Step B: Preparation of (6R)-9-fluoro-2.11.13.17.21.22.25- heptaazapentacvclo-r 17.5.2.02'6.07'12.022'261hexacosa- 1 (25).7.9.1 1.19(26).20.23-heptaen- 18- one: Prepared according to the method described in Example 12, Steps E-G, in three steps, from (R)-ethyl 5-(2-(2-(3-(tert-butoxycarbonylamino)propylamino)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate obtained above. The crude product was purified by reverse phase column chromatography (Biotage SP4 system C-18 25+M cartridge, 5 to 50% acetonitrile/water), to provide the title product as white solid (6 mg, 44 % yield). MS (apci pos) m/z =382.2 (M+H).
Example 14
Figure imgf000056_0002
(6R)-9-fluoro-13.16-dioxa-2.1 1.20.21.24-pentaazapentacvclori6.5.2.02'6.07'12.021'251- pentacosa- 1 (24).7.9.1 1.18(25).19.22-heptaen- 17-one
[00374] Step A: Preparation of (R)-2-chloroethyl 5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (Preparation B, 0.1 g, 0.28 mmol) and HATU (0.128 g, 0.336 mmol) was added DIEA (0.146 ml, 0.840 mmol), followed by 2-chloroethanol (0.0270 g, 0.336 mmol). After stirring at ambient temperature for 30 minutes, the reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, 5 to 65% acetonitrile/water) to obtain the intermediate (R)-3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl 5-(2- (5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate as white solid (94.7 mg, 71 % yield). This isolated intermediate was dissolved in excess chloroethanol (1 mL), followed by addition of drops of DIEA at ambient temperature and stirred overnight to reach completion. The reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, acetonitrile/water 5 to 73) to obtain the titled product as white foamy solid (56 mg, 48 % yield). MS (apci) m/z = 419.9 (Μ+Η).
[00375] Step B: Preparation of (R)-2-chloroethyl 5-(2-(5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)pyrrolidin- 1 -yDpyrazolol" 1 ,5-a1pyrimidine-3-carboxylate: A mixture of (R)-2-chloroethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (56 mg, 0.13 mmol) in HQ (4 N dioxane, 2.5 mL, 10 mmol) was sealed in a pressure reaction tube and heated at 100 °C for 45 minutes. The reaction mixture was cooled and concentrated to yield the product as yellowish oil, which was used directly in the next step without further purification, assuming quantitative yield. MS (apci) m/z = 406.0 (M+H).
[00376] Step C: Preparation of (6RV9-fluoro- 13.16-dioxa-2.1 1.20.21.24- pentaazapentacvclori6.5.2.02'6.07'12.021'251-pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one: A mixture of (R)-2-chloroethyl 5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (54 mg, 0.133 mmol) and CS2CO3 (217 mg, 0.665 mmol) in DMF (6 mL) was heated at 90 °C overnight. The reaction was filtered (GF/F paper) and directly purified by reverse phase column chromatography (Biotage SP4 system CI 8 25+M, 5 to 60% acetonitrile/water) to yield a mixture of desired product and impurities. This mixture was treated with a second column chromatography on Biotage SNAP KP-Sil 10 g, eluting with 10% hexanes/EtOAc to give the pure title product as a white solid (11 mg, 22 % yield). MS (apci pos) m/z =370.2 (M+H).
Figure imgf000058_0001
('6RV9-fluoro-14-oxa-2.1 1.18.19.22-pentaazapentacvclori4.5.2.17'11.02'6.019'231tetracosa- l(22),7.9.16(23).17.20-hexaene-15.24-dione
[00377] Obtained as a by-product of Example 14, Step C, and isolated as a white solid
(5 mg, 9 % yield) by reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 5 to 60% acetonitrile/water) of the crude material of Example 14, Step C. MS (apci) m/z = 370.2 (M+H).
Figure imgf000058_0002
(6R)-9-ffuoro- 13, 16-dioxa-2, 1 1, 17,21 ,22,25-hexaazapentacvclo Γ 17.5.2.02'6.07'12.022'261hexacosa- 1(25^.7.9.11.19(26).20.23 -heptaen- 18-one
[00378] Step A: Preparation of (R)-N-(2-bromoethoxy)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide: To a mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.280 mmol) and HATU (128 mg, 0.336 mmol) in DMF (1 mL) was added DIEA (0.146 mL, 0.840 mmol), followed by 0-(2- bromoethyl)hydroxylamine hydrobromide (74.2 mg, 0.336 mmol) in one portion. After stirring at ambient temperature overnight, the reaction mixture was directly purified by reverse phase column chromatography (Biotage SP4 system C-18 25+M, 5 to 67% acetonitrile/water) to yield the desired product as off-white solid (91 mg, 68 % yield). MS (apci) m/z = 479.0 (M+H).
[00379] Step B: Preparation of (RVN-f2-chloroethoxy')-5-f2-f5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori ,5-a1pyrimidine-3-carboxamide: A mixture of (R)-N-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo[ 1,5- a]pyrimidine-3-carboxamide (70 mg, 0.146 mmol) and HC1 (4 Ν dioxane, 3.65 mL, 14.6 mmol) was sealed in a pressure tube and heated at 90 °C for 3 hours. The reaction mixture was then cooled, diluted with MeOH, concentrated, and dried on high vacuum to obtain the desired product which was used in the next step directly without further purification, assuming quantitative conversion.
[00380] Step C: Preparation of (6R)-9-fluoro-13.16-dioxa-2,l 1.17.21,22,25-
Figure imgf000059_0001
one: A mixture of (R)-N-(2-chloroethoxy)-5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) and Cs2C03 (232 mg, 0.71 mmol) in DMF (1.4 mL) was heated at 90 °C for 20 minutes to reach completion. The reaction mixture was filtered (GF/F paper) and diluted with water (10 mL), then extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with brine and dried ( a2S04). The crude material was purified on reverse phase column chromatography (Biotage SP4 system CI 8 12+M, acetonitrile/water 5 to 55%) to yield a mixture of the desired final product and impurities. This mixture was again purified by preparative TLC (10% MeOH/DCM) to yield the pure title product as white solid (1 mg, 1 % yield). MS (apci) m/z = 385.1 (M+H).
Figure imgf000059_0002
1 (23).7.9.17(24).18.21 -hexaene- 16.25-dione
[00381] A solution of (6R, 135)-9-fluoro-13-hydroxy-2,l 1, 15, 19,20,23 - hexaazapentacyclo-[15.5.2.17'u.02'6.020'24]pentacosa-l(23),7,9, 17(24),18,21-hexaene-16,25- dione (Example 5; 10 mg, 0.0251 mmol) in a mixture solvent of DCM (0.3 mL) and 3 drops of DMSO was treated with bis(2-methoxyethyl)amino-sulfur trifluoride (7.87 μί, 0.0427 mmol) at 0 °C, followed by addition of a DCM (0.1 mL) solution of ethanol (0.231 mg, 0.00502 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into saturated NaHC(¾ and extracted with DCM, then dried ( a2S04), filtered, and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system CI 8 12+M cartridge, acetonitrile/water 5 to 50%) to give the title product as beige solid (1.3 mg, 12 % yield). MS (apci) m/z = 401.2 (M+H).
Figure imgf000060_0001
(6RV 9-fluoro- 17-methyl- 13 -oxa-2.1 1.17.21.22.25- hexaazapentacvclor 17.5.2.02'6.07'12.022'261hexacosa- 1 (25 V7.9.1 1.19(26).20.23 -heptaen- 18-one
[00382] Step A: Preparation of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)-N-m
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation B, 200 mg, 0.56 mmol) and 3-chloro-N- methylpropan- 1 -amine hydrochloride (177 mg, 1.23 mmol) in DMF (4 mL) was added N- methylmorpholine (0.25 mL, 2.30 mmol), followed by HATU (234 mg, 0.616 mmol). The reaction was stirred at ambient temperature for 18 hours, then diluted with FLO (10 mL), and extracted EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgS04), filtered, and concentrated. The crude product was purified by reverse- phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the desired product as a white foamy solid (129 mg, 52 % yield). MS (apci) m/z = 447.0 (M+H).
[00383] Step B: Preparation of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-1.2- dihydropyridin-3 -yDpyrrolidin- 1 -yl)-N-methylpyrazolo[ 1.5-a]pyrimidine-3 -carboxamide: A mixture of HC1 (4 N dioxane, 4 mL, 16.0 mmol) and (R)-N-(3-chloropropyl)-5-(2-(5-fluoro- 2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)-N-methylpyrazolo[ 1 ,5-a]pyrimidine-3 -carboxamide (100 mg, 0.224 mmol) was sealed in a pressure tube and heated at 90 °C for 90 minutes. The reaction mixture was then diluted with acetonitrile and concentrated to yield the crude product, which was carried to the next step without further purification (145mg, 150 % yield). MS (apci) m/z = 433.0 (M+H).
[00384] Step C: Preparation of (6RV9-fluoro-l 7-methyl- 13 -oxa-2.1 1.17.21.22.25- hexaazapentacvclori7.5.2.02'6.07'12.022'26lhexacosa-l(25).7.9.1 1.19(26).20.23-heptaen-18- one: A mixture of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)pyrrolidin-l-yl)-N-methylpyrazolo[l,5-a]pyrimidine-3-carboxamide (50 mg, 0.12 mmol) and Cs2C03 (188 mg, 0.58 mmol) in DMF (12 mL) was heated at 90 °C for 15 minutes to reach completion. The reaction mixture was filtered, rinsed with DMF, and concentrated. The crude material was purified directly by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the title product as pale yellow powder (17 mg, 36 % yield). MS (apci) m/z = 397.3 (M+H).
Figure imgf000061_0001
(6R)-9.15.15-trifluoro- 13-oxa-2, 11.17.21.22.25- hexaazapentacvclor 17.5.2.02'6.07'12.022'261hexacosa- 1 (25 V7.9.1 1.19(26).20.23 -heptaen- 18-one
[00385] Step A: Preparation of (5f)-l-amino-3-chloropropan-2-ol hydrochloride: To a solution of benzaldehyde (4.50 g, 42.4 mmol) in EtOH (12 mL) was added aqueous ammonia (4.01 g, 65.9 mmol) in several portions. After stirring for 10 minutes, (5)-2- (chloromethyl)oxirane (3.81 g, 41.2 mmol) was added and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then heated at 35-40 °C with a heating mantle for 6 hours, followed by stirring at ambient temperature for 18 hours. The reaction was concentrated to 5 mL and toluene (5 mL) was added. The mixture was heated to 36 °C and a solution of concentrated HC1 (6.09 g, 61.8 mmol) and water (5.9 mL) were added slowly over 5 minutes to maintain an internal reaction temperature range of 36-41 °C. The biphasic mixture was heated at 42-45 °C for 3 hours. The organic phase was separated and washed with water (10 mL). The aqueous phases were combined and ethanol (10 mL) was added. The mixture was concentrated to 10 mL, and ethanol (6 x 10 mL) was added, concentrating after each addition. After the last concentration step, the slurry was warmed to reflux, cooled to ambient temperature, and then placed at -20 °C for 18 hours. The product was collected by vacuum filtration, washed with cold ethanol, and vacuum-dried, to provide the product as white crystalline solid (3.58 g, 60 % yield). XH NMR (d6-DMSO) δ 8.14 (s, 3H), 5.91 (s, 1H), 3.93 (m, 1H), 3.59 (m, 2H), 2.89 (m, 1H), 2.69 (m, 1H).
[00386] Step B: Preparation of N-((^-3-chloro-2-hvdroxypropyl)-5-((R)-2-(5-fluoro-
2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxamide: Prepared according to the method described in Example 18, substituting (5)-l-amino-3-chloropropan- 2-ol hydrochloride (98.1 mg, 0.672 mmol) for 3-chloro-N-methylpropan-l-amine hydrochloride in Step A. MS (apci) m/z = 448.9 (M+H).
[00387] Step C: Preparation of (R)-N-(3-chloro-2-oxopropyl)-5-(2-(5-fluoro-2- methoxypyridin-3 -vDpyrrolidin- 1 -vDpyrazolo Γ 1.5 -alpyrimidine-3 -carboxamide: To a solution of N-((5)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (180 mg, 0.401 mmol) in DCM (3 mL) was added Dess-Martin periodinane (204 mg, 0.481 mmol). The reaction was stirred at ambient temperature for 3 hours, then purified directly by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the desired product as a white foamy solid (1 14 mg, 64 % yield). MS (apci) m/z = 447.0 (M+H).
[00388] Step D: Preparation of (R)-N-(3-chloro-2.2-difluoropropyl)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[1.5-alpyrimidine-3-carboxamide: To a solution of (R)-N-(3-chloro-2-oxopropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (114 mg, 0.255 mmol) in DCM (3 mL) was added Deoxofluor (0.103 mL, 0.561 mmol), and the reaction mixture was stirred at ambient temperature for 23 hours. The reaction was quenched with saturated aHC03 (5 mL), diluted with DCM (5 mL), and stirred for 30 minutes. After phase separation, the aqueous phase was extracted with DCM (10 mL). The combined organic phases were concentrated and purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the desired product as white solid (59 mg, 49 % yield). MS (apci) m/z = 469.0 (M+H).
[00389] Step E: Preparation of (R)-N-(3-chloro-2.2-difluoropropyl)-5-(2-(5-fluoro-2- oxo-1.2-dihvdropyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: Prepared according to the method described in Example 18, substituting (R)-N-(3-chloro-2,2- difluoropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a] pyrimidine-3 -carboxamide for (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)-N-methylpyrazolo[l,5-a]pyrimidine-3-carboxamide in Step B. MS (apci) m/z = 455.0 (M+H).
[00390] Step F: Preparation of (6R)-9.15.15-trifluoro-13-oxa-2,l 1 ,17.21,22,25-
Figure imgf000062_0001
one: Prepared according to the same method as described in Example 18, substituting (R)-N- (3-chloro-2,2-difluoropropyl)-5-(2-(5-fluoro-2-oxo-l,2-dihydropyridin-3-yl)pyrrolidin-l- yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxamide for (R)-N-(3 -chloropropyl)-5 -(2-(5 -fluoro-2- oxo- 1 ,2-dihydropyridin-3 -yl)pyrrolidin- 1 -yl)-N-methylpyrazolo[ 1 ,5 -a]pyrimidine-3 - carboxamide in Step C, and heating at 1 10 °C for 5 hours, to provide the title product as a pale pink solid (6 mg, 1 1 % yield). MS (apci) m/z = 419.3 (M+H).
Figure imgf000063_0001
(6^-9-£1ηοΓθ-13-οχ -2.17.21.22.25-Ρ6ηί ζ ρ6ηί ονο1οΠ 7.5.2.02'6 07'12.022'2611ΐ6χ οο8 - 1 (25).7.9.11.19(26).20.23 -heptaen- 18-one
[00391] Step A: Preparation of (R)-te -butyl 2-(5-fluoro-2- hydroxyphenyDpyrrolidine- 1 -carboxylate. This compound was prepared according to the method described in Preparation A, substituting 3-bromo-5-fluoro-2-methoxypyridine with 2- bromo-4-fluorophenyl acetate in Step A (3.2 g, 40 % yield). MS (apci) m/z = 182.1 (M+H - Boc).
[00392] Step B: Preparation of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride:
To a solution of (R)-tert-butyl 2-(5-fluoro-2-hydroxyphenyl)pyrrolidine-l-carboxylate (3.2 g, 1 1.4 mmol) in DCM (20 mL) was added HC1 (4 N dioxane, 5.69 mL, 22.7 mmol), and the mixture was stirred at ambient temperature for 15 hours. The reaction was concentrated, and the resulting precipitate was taken up in DCM (15 mL) and filtered to afford (R)-4-fluoro-2- (pyrrolidin-2-yl)phenol hydrochloride (1.85 g, 90 % yield) as a beige solid. MS (apci) m/z = 182.1 (M+H).
[00393] Step C: Preparation of (R)-ethyl 5-(2-(5-fluoro-2-hvdroxyphenyl)pyrrolidin-l- yDpyrazoloT 1 ,5-a1pyrimidine-3-carboxylate: Prepared according to the method described in Preparation B, substituting (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride for (R)-5- fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine in Step C. The crude material was purified by reverse-phase column chromatography (0-65% acetonitrile/H20) to yield the pure product (686 mg, 80 % yield). MS (apci) m/z = 371.0 (M+H).
[00394] Step D: Preparation of (R)-ethyl 5-(2-(2-(3-(1.3-dioxoisoindolin-2- yl)propoxy)-5-fluorophenyl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidine-3-carboxylate: A suspension of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3 -carboxylate (280 mg, 0.756 mmol), 2-(3-bromopropyl)isoindoline-l,3-dione (263 mg, 0.983 mmol) and K2C03 (104 mg, 0.756 mmol) in DMF (0.4 mL) was stirred at ambient temperature for 15 hours. The reaction was directly purified by reverse-phase column chromatography (5-80% acetonitrile/H20) to afford (R)-ethyl 5-(2-(2-(3-(l,3- dioxoisoindolin-2-yl)propoxy)-5-fluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5-a]pyrimidine-3 - carboxylate (202 mg, 48 % yield) as clear oil. MS (apci) m/z = 558.0 (M+H). [00395] Step E: Preparation of (R)-ethyl 5-(2-(2-(3-aminopropoxy)-5- fluorophenyDpyrrolidin- 1 -yPpyrazolof 1.5-a"|pyrimidine-3 -carboxylate: (R)-ethyl 5-(2-(2-(3- ( 1 ,3 -dioxoisoindolin-2-yl)propoxy)-5-fluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1,5- a]pyrimidine-3 -carboxylate (200 mg, 0.359 mmol) and hydrazine monohydrate (1 15 mg, 3.59 mmol) were combined in MeOH (1 mL) and THF (1 mL) in a sealed vessel and heated at 60 °C for 20 minutes. After cooling to ambient temperature, the reaction was concentrated, followed by addition of NaOH (1 N, 2 mL). The mixture was extracted with DCM, and the combined organic extracts were dried ( a2S04), filtered and concentrated to afford (R)-ethyl 5 -(2-(2-(3 -aminopropoxy)-5 -fluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5 -a]pyrimidine-3 - carboxylate (1 10 mg, 72 % yield). MS (apci) m/z = 428.2 (M+H).
[00396] Step F: Preparation of (6R)-9-fluoro-13-oxa-2.17.21.22.25-
Figure imgf000064_0001
one. (R)-ethyl 5 -(2-(2-(3 -aminopropoxy)-5 -fluorophenyl)pyrrolidin- 1 -yl)pyrazolo [1,5- a]pyrimidine-3 -carboxylate (10 mg, 0.023 mmol) and DIEA (8.1 μί, 0.047 mmol) were combined in dry EtOH (0.1 mL) in a sealed vessel and heated at 200 °C overnight. The reaction was concentrated and purified by reverse-phase column chromatography (0-70% acetonitrile/H20) to afford the title compound (4.5 mg, 50 % yield). MS (apci) m/z = 382.2 (M+H).
Figure imgf000064_0002
('6RV9-fluoro-13-oxa-2.16.20.21.24-pentaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-
1 (24),7,9.1 1.18(25).19.22-heptaene
[00397] Step A: Preparation of (R)-4-fluoro-2-(l-(pyrazolorL5-a1pyrimidin-5- yl)pyrrolidin-2-yl)phenol: A mixture of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride (Example 20, Step B, 1.50 g, 6.89 mmol), DIEA (2.67 g, 20.7 mmol), 5-chloropyrazolo[l,5- ajpyrimidine (1.11 g, 7.24 mmol) and isopropanol (1 mL) was heated at 120 °C overnight. The reaction was poured into ether (50 mL) and extracted with NaOH (IN aqueous, 3 x 25 mL). The combined aqueous extracts were brought to pH 4 with concentrated HC1 and extracted with DCM. The combined DCM extracts were filtered through phase separator paper and concentrated to provide (R)-4-fluoro-2-(l-(pyrazolo[l,5-a]pyrimidin-5- yl)pyrrolidin-2-yl)phenol (1.82 g, 89 % yield) as beige solid. MS (apci) m/z = 299.4 (M+H). [00398] Step B: Preparation of ('R -5-('2-('5-fluoro-2-hvdroxyphenyl pyrrolidin-l - yl)pyrazolo[ 1.5-alpyrimidine-3-carbaldehyde: After POCI3 (221 μΐ^, 2.41 mmol) was added drop-wise to a DMF (4 mL) solution of (R)-4-fluoro-2-(l -(pyrazolo[ l,5-a]pyrimidin-5- yl)pyrrolidin-2-yl)phenol (600 mg, 2.01 mmol) at ambient temperature, the reaction was stirred for 5 minutes before NaOH (804 mg, 10.1 mmol) was introduced. The reaction was stirred for another 10 minutes before HC1 (4 N dioxane, 3 mL) was added, followed by DCM (50 mL). After filtering through Celite®, the reaction was concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/ELO to provide (R)- 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l -yl)pyrazolo[ l,5-a]pyrimidine-3-carbaldehyde (524 mg, 80 % yield) as beige solid. MS (apci) m/z = 327.2 (M+H).
[00399] Step C: Preparation of (R)-fert-butyl 2-(4-fluoro-2-(l-(3-formylpyrazolor i .5- alpyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate: A mixture of (R)-5-(2-(5-fluoro-2- hydroxyphenyl)pyrrolidin-l -yl)pyrazolo[ l ,5-a]pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol), tert-butyl 2-bromoethylcarbamate (13 1 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and DMF (1 mL) was combined in a sealed vessel and stirred at ambient temperature overnight and then at 60 °C for 3 hours. After diluting with DCM (20 mL), the reaction was filtered through Celite®, concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/FLO to provide (R)-tert-butyl 2-(4-fluoro-2- (l-(3-formylpyrazolo[ l ,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 86.6 % yield) as yellowish solid. MS (apci) m/z = 370.4 (M+H - Boc).
[00400] Step D: Preparation of (R)-5-(2-(2-(2-aminoethoxy)-5- fluorophenyl)pyrrolidin- l -yl)pyrazolo[1.5-alpyrimidine-3-carbaldehyde: An HC1 (4N dioxane, 80 μΐ, 0.32 mmol) was added to a DCM (2 mL) solution of (R)-tert-butyl 2-(4- fluoro-2-(l-(3-formylpyrazolo[l ,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 0.422 mmol), and the reaction was purged with 2 and stirred at ambient temperature overnight. After removal of solvent, NaOH (5 mL x IN) was introduced and the reaction mixture was extracted with several portions of DCM in a phase separator tube. The combined organic extracts were concentrated to provide (R)-5-(2-(2-(2-aminoethoxy)-5- fluorophenyl)pyrrolidin- l -yl)pyrazolo[l ,5-a]pyrimidine-3-carbaldehyde (155 mg, 99.5 % yield), which was used immediately in the next step. MS (apci) m/z = 352.3 (M+H - H20).
[00401] Step E: Preparation of (6R)-9-fluoro- 13 -oxa-2.16.20.21.24- pentaazapentacvclori 6.5.2.02'6.07'12.021'251pentacosa-l (24).7.9.1 1.18(25).19.22-heptaene. Tetramethylammonium triacetoxyborohydride (46.7 mg, 0.629 mmol) was added to a DCM (50 mL) solution of (R)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-l - yl)pyrazolo[l,5-a]pyrimidine-3-carbaldehyde (155 mg, 0.420 mmol), and the reaction was stirred at ambient temperature overnight. The reaction mixture was then diluted with brine and extracted with several portions of DCM in a phase separator tube, and the combined organic extracts were concentrated and purified by reverse-phase column chromatography, eluting with 0-90% acetonitrile-H20, to obtain the title product (32 mg, 21.6 % yield). MS (apci) m/z = 354.2 (M+H).
Figure imgf000066_0001
1 -IY6RV 9-fluoro- 13-oxa-2.16.20.21.24-pentaazapentacvclor 16.5.2.02^07'12.021'25lpentacosa- l(24).7.9.11.18(25).19.22-heptaen-16-yl1ethan-l-one
[00402] Acetyl chloride (1.7 mg, 0.021 mmol) was added to a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2, 16,20,21,24-pentaazapentacyclo-[16.5.2.02'6.07'12.021'25]pentacosa- 1 (24),7,9, 1 1,18(25), 19,22-heptaene (Example 21, 5.0 mg, 0.014 mmol), followed by DIEA (7.4 μΐ^, 0.042 mmol). After stirring at ambient temperature overnight, the reaction was concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H20 to provide the title product (3.9 mg, 70 % yield). MS (apci) m/z = 396.2 (M+H).
Figure imgf000066_0002
1 -r(6R)-9-fluoro- 13-oxa-2.16.20.21.24-pentaazapentacvclor 16.5.2.02'6.07'12.021'251pentacosa-
1 (24).7.9.1 1.18(25).19.22-heptaen- 16-yl1-2-hvdroxyethan- 1 -one
[00403] To a DCM (0.5 mL) solution of (6R)-9-fluoro- 13 -oxa-2, 16,20,21,24- pentaazapentacyclo-[ 16.5.2.02'6.07'12.021'25]pentacosa- 1 (24),7,9, 1 1, 18(25), 19,22-heptaene (Example 21, 6 mg, 0.017 mmol) was added 2-chloro-2-oxoethyl acetate (3.5 mg, 0.025 mmol), followed by DIEA (8.9 μί, 0.051 mmol). The reaction was stirred at ambient temperature overnight, then concentrated, and MeOH (0.2 mL) was added followed by sodium hydroxide (6.8 mg, 0.085 mmol). After stirring at ambient temperature for 5 hours, the reaction was diluted with brine and extracted with several portions of DCM in a phase separator tube. The combined organic extracts were concentrated and purified by reverse- phase column chromatography, eluting with 0-70% acetonitrile/H^O, to provide the title product (3.6 mg, 52 % yield). MS (apci) m/z = 412.5 (M+H).
Figure imgf000067_0001
(6R)-9-fluoro-13-oxa-2.17.21.22.25-pentaazapentacvclori7.5.2.02'6 07'12.022'261hexacosa-
1(25^.7.9.1 1.19(26).20,23-heptaene
[00404] Step A: Preparation of (R)-fert-butyl 3-(4-fluoro-2-(l-(3-formylpyrazolori.5- a1pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)propylcarbamate: Prepared according to the method described in Example 21, substituting tert-butyl 2-bromoethylcarbamate with tert- butyl 3-bromopropylcarbamate in Step C to afford the desired product (119 mg, 84.5 % yield). MS (apci) m/z = 384.2 (M+H - Boc).
[00405] Step B: Preparation of (RVfe/ -butyl 3-(4-ίηΐ0Γ0-2-(1-(3-
(hvdroxymethyl)pyrazolori .5-a1pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)propylcarbamate: A solution of (R)-tert-butyl 3-(4-fluoro-2-(l-(3-formylpyrazolo[l,5-a]pyrimidin-5- yl)pyrrolidin-2-yl)phenoxy)propylcarbamate (85.0 mg, 0.176 mmol) in MeOH (2 mL) was first cooled to 0 °C, then NaBH4 (4.04 mg, 0.176 mmol) was introduced, and the reaction was stirred at 0 °C for 1 hour. The reaction was diluted with brine and extracted with DCM in a phase separator cartridge. The combined organic extracts were concentrated to provide (R)- tert-butyl 3-(4-fluoro-2-(l-(3-(hydroxymethyl)pyrazolo[l,5-a]pyrimidin-5-yl)pyrrolidin-2- yl)phenoxy)propylcarbamate (86 mg, 101 % yield) as beige solid. MS (apci) m z = 468.1 (M+H - H20).
[00406] Step C: Preparation of (RyCS-^-^-G-aminopropoxyVS- fluorophenyl)pyrrolidin-l-yl)pyrazolori .5-a1pyrimidin-3-yl)methanol hydrochloride: (R)- tert-butyl 3 -(4-fluoro-2-( 1 -(3 -(hydroxymethyl)pyrazolo[ 1 ,5-a]pyrimidin-5-yl)pyrrolidine-2- yl)phenoxy)propylcarbamate (80 mg, 0.16 mmol) was dissolved in 2 mL of DCM and treated with HC1 (4 N in dioxane, 6.0 mg, 0.16 mmol). The reaction was purged with N2, capped, and stirred at ambient temperature for 18 hours, then concentrated to provide (R)-(5-(2-(2-(3- aminopropoxy)-5-fluorophenyl)pyrrolidine- 1 -yl)pyrazole[ 1 ,5-a]pyrimidin-3 -yl)methanol hydrochloride (70 mg, 101 % yield) as a beige solid. MS (apci) m/z = 368.5 (M+H-H20). [00407] Step D: Preparation of (6R)-9-fluoro-13-oxa-2.17.21.22.25-
Figure imgf000068_0001
mixture of (R)-(5-(2-(2-(3-aminopropoxy)-5-fluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5- a]pyrimidin-3-yl)methanol (50 mg, 0.130 mmol), PS-PPI13 (0.259 mmol) and perchloromethane (200 mg, 1.30 mmol) in DCM (5 mL) was shaken at ambient temperature overnight. The reaction was filtered, concentrated and purified by reverse-phase column chromatography eluting with 0-60% acetonitrile/H20 to yield the title product (27.4 mg, 57.5 % yield). MS (apci) m/z = 368.1 (M+H).
Figure imgf000068_0002
(6RV 9-fluoro- 16-methanesulfonyl- 13 -oxa-2.16.20.21.24- pentaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-l(24).7.9.11.18(25).19.22-heptaene
[00408] To a DCM (0.5 mL) solution of (6R)-9-fluoro- 13 -oxa-2, 16,20,21,24- pentaazapentacyclo-[ 16.5.2.02'6.07'12.021'25]pentacosa- 1 (24),7,9, 1 1, 18(25), 19,22-heptaene (Example 21, 5 mg, 0.0141 mmol) was added DIEA (2.46 μί, 0.0141 mmol), followed by methanesulfonyl chloride (1.10 μί, 0.0141 mmol). The reaction was stirred at ambient temperature for 1 hour before MeOH (0.1 mL) was added. The reaction was concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/ELO to provide the title product (3.1 mg, 50.8 % yield). MS (apci) m/z = 432.3 (M+H).
Figure imgf000068_0003
2-r(6R)-9-fluoro-13-oxa-2.16.20.21.24-pentaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-
1 (24Ί.7.9.1 1.18(25).19.22-heptaen- 16-yllacetic acid
[00409] An IPA (0.1 mL) solution of (6R)-9-fluoro- 13 -oxa-2, 16,20,21,24- pentaazapentacyclo-[ 16.5.2.02'6.07'12.021'25]pentacosa- 1 (24),7,9, 1 1, 18(25), 19,22-heptaene (Example 21, 5 mg, 0.014 mmol), 2-bromoacetic acid (2.9 mg, 0.021 mmol) and NaOH (1 N, 42 μΕ, 0.042 mmol) was heated at 60 °C in a sealed vessel overnight, then at 120 °C for 24 hours. After cooling, the reaction mixture was directly purified by reverse-phase column chromatography eluting with 0-50% acetonitrile/EbO to afford the title product (3.1 mg, 53 % yield). MS (apci) m/z = 412.2 (M+H).
Figure imgf000069_0001
(6RV 9-fluoro- 17-methanesulfonyl- 13 -oxa-2, 17,21 ,22,25- pentaazapentacvclori7.5.2.02'6.07'12.022'261hexacosa-l(25).7.9.11.19(26).20.23-heptaene
[00410] Methanesulfonyl chloride (1.69 μΐ, 0.0218 mmol) was added to a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2, 17,21,22,25-pentaazapentacyclo
[17.5.2.02'6.07'12.022'26]hexacosa-l(25),7,9, l l,19(26),20,23-heptaene (Example 24, 4.0 mg, 0.0109 mmol), followed by DIEA (9.48 μΐ,, 0.0544 mmol). The reaction was stirred at ambient temperature overnight, concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H^O to afford the title compound (2.9 mg, 59.8 % yield). MS (apci) m/z = 446.3 (M+H).
Figure imgf000069_0002
(6R)-N-ethyl-9-fluoro- 13-oxa-2.17.21.22.25-pentaazapentacyclo 17.5.2.02'6.07'12.022'261hexacosa-l(25).7.9.11.19(26).20,23-heptaene-17-carboxamide
[00411] To a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2, 17,21,22,25- pentaazapentacyclo[17.5.2.02'6.07'12.022'26]hexacosa-l(25),7,9, l l, 19(26),20,23-heptaene (Example 24, 4 mg, 0.011 mmol) was added isocyanatoethane (1.5 mg, 0.022 mmol) followed by DIEA (1.9 μί, 0.011 mmol). The reaction was stirred at ambient temperature overnight, then concentrated and purified by reverse-phase column chromatography, eluting with 0-80% acetonitrile/H20, to afford the title compound (3.5 mg, 73 % yield). MS (apci) m/z = 439.1 (M+H).
Figure imgf000070_0001
(6R)-N-ethyl-9-fluoro-13-oxa-2, 16,20,21 ,24-pentaazapentacvclo- Γ 16.5.2.02'6 07'12.021'25lpentacosa- 1 (24).7.9.1 1.18(25), 19.22-heptaene- 16-carboxamide
[00412] To a DCM (0.5 mL) solution of (6R)-9-fluoro- 13 -oxa-2,16,20,21, 24- pentaazapentacyclo[16.5.2.02'6.07'12.021'25]pentacosa-l(24),7,9, l l,18(25), 19,22-heptaene (Example 21, 5.5 mg, 0.016 mmol) was added isocyanatoethane (1.5 mg, 0.022 mmol), followed by DIEA (1.9 μί, 0.011 mmol). After stirring at ambient temperature overnight the reaction was concentrated and purified by reverse-phase column chromatography, eluting with 0-80% acetonitrile/H20 to afford the title compound (3.3 mg, 50 % yield). MS (apci) m/z = 425.4 (M+H).
Figure imgf000070_0002
(65)-9-ίΐυοΓθ-4, 13 -dioxa-2, 1 1, 17,21 ,22,25-hexaazapentacvclo ri7.5.2.02'6.07'12.022'261hexacosa-l(25).7(12),8.10.19(26).20,23-heptaene-3.18-dione
[00413] Step A: Preparation of (5'.£l-N-('2-('ter?-butyldimethylsilyloxy)ethylidene)-2- methylpropane-2-sulfinamide: To a solution of (5)-2-methylpropane-2-sulfinimide (3.3 g, 27.2 mmol) in DCM (50 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (4.98 g, 28.6 mmol) followed by anhydrous copper sulfate (8.69 g, 54.5 mmol). The heterogeneous mixture was stirred at ambient temperature for 3 days and then filtered through Celite®. The filtrate concentrated and the residue was purified by flash column chromatography, eluting with 10% EtOAc/hexanes, to afford (5',JE)-N-(2-(ter?-butyldimethylsilyloxy)ethylidene)-2- methylpropane-2-sulfinamide (5.54 g, 73 % yield) as a colorless oil. XH NMR (CDC13) δ 7.96 (m, 1H), 4.44 (d, 1H, J = 2.7 Hz), 1.1 1 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H).
[00414] Step B: Preparation of (y)-N-('('y)-2-('ter?-butyldimethylsilyloxy)- 1 -(5-ΙΓΙΙΟΓΟ-2- methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide: To a solution of n-butyl lithium (10.8 mL, 17.3 mmol, 1.6 M in hexanes) in toluene (100 mL) at -78 °C was added a solution of 3-bromo-5-fluoro-2-methoxypyridine (3.27 g, 15.9 mmol) in toluene (5 mL) dropwise, maintaining the internal temperature below -70 °C. The mixture was stirred at -78 °C for 1 hour, then treated with a solution of (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2- methylpropane-2-sulfinamide (4.0 g, 14.4 mmol) in toluene (10 mL) dropwise, maintaining the internal temperature below -65 °C. After stirring at -78 °C for 3 hours the mixture was treated with brine (100 mL) and EtOAc (100 mL) and stirred at ambient temperature for 20 minutes. Saturated aHC03 solution (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic phases were washed with brine (50 mL), dried over a2S04, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 10% EtOAc/hexanes to 20% EtOAc/hexanes, to afford (5)-N-((S)-2-(tert-butyldimethylsilyloxy)-l-(5-fluoro-2- methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 24% yield) mixed with a less polar impurity as a colorless oil. MS (apci) m/z = 405.0 (M+H).
[00415] Step C: Preparation of (y)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride: To a solution of (5)-N-((5)-2-(tert-butyldimethylsilyloxy)-l-(5-fluoro-2- methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 3.46 mmol) in methanol (20 mL) was added 4Ν HCl/dioxane (8.65 mL, 34.6 mmol). The solution was stirred at ambient temperature for 16 hours, then concentrated and dried under vacuum to afford («S)-2- amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride as a yellow oil which was used without purification, assuming 100 % yield. MS (apci) m/z = 186.9 (M+H).
[00416] Step D: Preparation of (y)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2- one: To a solution of (5)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride (897 mg, 3.46 mmol) in KOH (10 mL, 24.2 mmol, 2.42 M in water) was added THF (10 mL). The mixture was cooled to 0 °C and treated with triphosgene (1.03 g, 3.46 mmol). The mixture was allowed to warm to ambient temperature with stirring over 16 hours then partitioned between EtOAc (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated. The residue was triturated with Et20, filtered and dried under reduced pressure to afford (5)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (254 mg, 35 % yield) as a white powder. ¾ NMR (CDC13) δ 7.98 (m, 1H), 7.44 (m, 1H), 5.61 (Br S, 1H), 5.13 (m, 1H), 4.83 (m, 1H), 4.16 (m, 1H), 3.96 (s, 3H). [00417] Step E: Preparation of (SVethyl S-^-CS-fluoro^-methoxypyridin-S-yl)^- oxooxazolidin-3-yl)pyrazolo[1.5-alpyrimidine-3-carboxylate: To a solution of (5)-4-(5- fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (254 mg, 1.20 mmol) in DMF (10 mL) was added sodium hydride (58 mg, 1.44 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 20 minutes then treated with ethyl 5-chloropyrazolo[l,5- a]pyrimidine-3-carboxylate (270 mg, 1.20 mmol) in one portion. The mixture was stirred for 48 hours then treated with saturated NH4C1 solution (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with water (5 x 10 mL) and brine (10 mL) then dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 20% EtOAc/hexanes to 66% EtOAc/hexanes, to afford (5)-ethyl 5 -(4-(5 -fluoro-2-methoxypyridin-3 -yl)-2-oxooxazolidin-3 -yl)pyrazolo[ 1,5- a]pyrimidine-3-carboxylate (31 1 mg, 65 % yield) as a white foam. MS (apci) m/z = 401.9 (M+H).
[00418] Step F: Preparation of (5)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2- hydroxyethylamino)pyrazolo[1.5-alpyrimidine-3-carboxylic acid: To a solution of (5)-ethyl 5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylate (311 mg, 0.77 mmol) in a 1 : 1 : 1 mixture of MeOH:THF:H20 (15 mL) was added lithium hydroxide monohydrate (97.6 mg, 2.32 mmol). The mixture was stirred at ambient temperature for 16 hours and then at 50 °C for 19 hours, then concentrated to 1/3 volume, diluted with water (30 mL) and acidified to pH 4-5 with IN HC1. The resulting precipitate was collected by filtration, washed with water and Et20 then dried under reduced pressure to afford (5)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (121 mg, 45 % yield) as a white powder. MS (apci) m/z = 347.9 (M+H).
[00419] Step G: Preparation of (5)-N-(3-chloropropyl)-5-(l-(5-fluoro-2- methoxypyridin-3-yl)-2-hvdroxyethylamino)pyrazolori .5-a1pyrimidine-3-carboxamide: To a suspension of (5)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (50 mg, 0.14 mmol) in DCM (2 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (83 mg, 0.43 mmol). The heterogeneous mixture was stirred at ambient temperature for 10 minutes then treated with triethylamine (100 μί, 0.72 mmol) followed by 3-chloro-propylamine hydrochloride (56 mg, 0.43 mmol). The mixture was stirred for 2 hours, then DMF (2 mL) was added and stirring was continued for 48 hours. The mixture was partitioned between saturated NH4C1 solution (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with water (5 x 10 mL) and brine (10 mL), then dried over Na2S04, filtered and concentrated to afford (5)-N-(3-chloropropyl)-5-(l-(5-fluoro- 2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[l,5-a]pyrimidine-3-carboxamide (60 mg, 99 % yield) as a pale yellow foam which was used without further purification. MS (apci) m/z = 423.0 (M+H).
[00420] Step H: Preparation of (5f)-N-(3-chloropropyl)-5-(4-(5-fluoro-2- methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolorL5-a1pyrimidine-3-carboxamide: To a solution of (5*)-N-(3-chloropropyl)-5-(l-(5-fluoro-2-methoxypyridin-3-yl)-2- hydroxyethylamino)pyrazolo[l,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) in ACN (2 mL) was added CDI (35 mg, 0.21 mmol). The solution was stirred at ambient temperature for 16 hours then partitioned between saturated NH4C1 solution (20 mL) and EtOAc (10 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography eluting with 1% MeOH/DCM to afford (5")-N-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2- oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (37 mg, 58 % yield) as a white solid. MS (apci) m/z = 449.0 (M+H).
[00421] Step I: Preparation of ffl-N-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A suspension of (5*)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2- oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (37 mg, 0.08 mmol) in 4Ν HCl/dioxane (4 mL) was stirred at 85 °C for 17 hours and then at ambient temperature for 48 hours. The resulting solution was concentrated to 1/2 volume, transferred to a sealed tube, treated with 4Ν HCl/dioxane (2 mL) and stirred at 100 °C for 2 hours. The heterogeneous mixture was concentrated, dried under reduced pressure and used directly in the next step, assuming 100 % yield. MS (apci) m/z = 435.1 (M+H).
[00422] Step J: Preparation of (6^-9-fluoro-4,13-dioxa-2, l 1.17.21,22,25- hexaazapentacvclori7.5.2.02'6.07'12.022'261hexacosa-l(25).7(12).8.10.19(26).20.23-heptaene- 3.18-dione: To a solution of (5)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-l,2- dihydropyridin-3 -yl)-2-oxooxazolidin-3 -yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxamide (35 mg, 0.08 mmol) in DMF (3 mL) was added cesium carbonate (79 mg, 0.24 mmol). The mixture was stirred at 65 °C for 30 minutes then at ambient temperature for 48 hours. The mixture was treated with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with water (5 x 10 mL) and brine (10 mL), then dried over a2S04, filtered and concentrated. The residue was purified via flash column chromatography eluting with 2% MeOH/DCM to afford the title compound (13 mg, 41% yield) as an amorphous white solid. MS (apci) m/z = 399.2 (M+H).
Figure imgf000074_0001
(65)-9-fluoro-4.13 -dioxa-2.1 1.16.20.21.24-hexaazapentacvclo ri6.5.2.02'6.07'12.021'251pentacosa-l(24).7(12).8.10.18(25).19.22-heptaene-3.17-dione
[00423] Step A: Preparation of 5-hvdroxypyrazolori ,5-a1pyrimidine-3-carboxylic acid:
To a solution of ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (Preparation B, Step A; 2.0 g, 9.65 mmol) in a 2: 1 mixture of THF:MeOH, (40 mL) was added lithium hydroxide monohydrate (29 mL, 29.0 mmol, 1.0 M in water). The solution was stirred at reflux for 16 hours then cooled and concentrated. The residue was dissolved in water (100 mL) and acidified with 6M HC1. The resulting white precipitate was collected by filtration and washed with water and Et20, then dried under reduced pressure to afford 5- hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.18 g, 68% yield) as a white solid. XH NMR (d6-DMSO) δ 8.50 (d, 2H, J = 7.7 Hz), 8.02 (s, 2H), 6.07 (d, 2H, J = 8.2 Hz).
[00424] Step B: Preparation of 5-chloropyrazolo[1.5-alpyrimidine-3-carbonyl chloride: To a suspension of 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.18 g, 6.59 mmol) in DMF (10 mL) at 0 °C was added thionyl chloride (10 mL) dropwise over 5 minutes. The mixture was warmed to ambient temperature, then stirred at 60 °C for 16 hours. The cooled solution was purged with 2 for 20 minutes then diluted with 50% EtOAc/hexanes (100 mL) and stirred vigorously for 30 minutes. The organic phase was decanted, treated with a2C03 and activated carbon, stirred for 5 minutes then filtered through Celite® and concentrated. The residue was dissolved in toluene (100 mL), treated with activated carbon and filtered through Celite® again. The filtrate was concentrated and dried under reduced pressure to afford 5-chloropyrazolo[l,5-a]pyrimidine-3-carbonyl chloride (800 mg, 56% yield) as a cream-colored solid. XH NMR (CDC13) δ 8.70 (m, 1H), 8.66 (s, 1H), 7.16 (m, 1H).
[00425] Step C: Preparation of 5-chloro-N-(2-chloroethyl)pyrazolo|T ,5-alpyrimidine-
3-carboxamide: To a suspension of 5-chloropyrazolo[l,5-a]pyrimidine-3-carbonyl chloride (284 mg, 1.31 mmol) in DCM (10 mL) was added DIEA (1.14 mL, 6.57 mmol). The solution was cooled to 0 °C, then treated with 2-chloroethylamine hydrochloride (183 mg, 1.58 mmol) and stirred for 1 hour. The mixture was partitioned between water (30 mL) and DCM (30 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated to afford 5-chloro-N-(2-chloroethyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide (290 mg, 85 % yield) as a beige solid. MS (apci) m/z = 258.9 (M+H).
[00426] Step D: Preparation of ffl-N-(2-chloroethyl)-5-(4-(5-fluoro-2- methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: To a solution of (5)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (prepared according to Example 30; 50 mg, 0.236 mmol) in DMF (1 mL) was added sodium hydride (1 1 mg, 0.28 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 20 minutes, then treated with 5-chloro-N-(2-chloroethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (61 mg, 0.236 mmol). The mixture was stirred at 16 hours, and then treated with saturated NH4C1 solution (10 mL) and water (20 mL). The resulting precipitate was collected by filtration, washed with water and Et20, then dried under reduced pressure to afford (5)-N-(2- chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[l,5- a]pyrimidine-3-carboxamide (83 mg, 81 % yield) as a beige solid. MS (apci) m/z = 434.9 (M+H).
[00427] Step E: Preparation of (5)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-1.2- dihvdropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolori.5-a1pyrimidine-3-carboxamide: A suspension of (5)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin- 3-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (80 mg, 0.18 mmol) in 5-6Ν HC1/IPA (2.5 mL) was warmed to 90 °C in a sealed tube for 1.5 hours. The cooled mixture was filtered and the filtrate was concentrated. The residue was concentrated twice from Et20 and dried under reduced pressure to afford (5)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-l,2-dihydropyridin-3- yl)-2-oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (63 mg, 82 % yield) as a beige solid. MS (apci) m/z = 421.0 (M+H).
[00428] Step F: Preparation of (6_?)-9-fluoro-4.13-dioxa-2.11.16.20.21.24- hexaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-l(24).7(12).8.10.18(25).19.22-heptaene- 3.17-dione: Prepared according to the method of Example 30, Step J, using (5)-N-(2- chloroethyl)-5-(4-(5-fluoro-2-oxo-l,2-dihydropyridin-3-yl)-2-oxooxazolidin-3- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide in place of (5)-N-(3-chloropropyl)-5-(4-(5- fluoro-2-oxo-l,2-dihydropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide to afford the title compound (14 mg, 24 % yield) as a white solid. MS (apci) m/z = 385.1 (M+H).
Figure imgf000076_0001
1 (24).7.9.11.18(25).19.22-heptaen-l 7-one
[00429] Step A: Preparation of (R)-ethyl 5-(2-(2-(3-((tert-butoxycarbonyl)amino)prop-
1 -yn- 1 -yl)-5-fluoropyridin-3-yl)pyrrolidin- 1-vDpyrazolor 1 ,5-a1pyrimidine-3-carboxylate: (R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylate (Example 12, Step C; 153 mg, 0.392 mmol) in DMF (2 mL) was added tert-butyl prop-2-ynylcarbamate (122 mg, 0.785 mmol), copper(I) iodide (1 1 mg, 0.0578 mmol), triphenylphosphine (82.4 mg, 0.314 mmol), di-triphenylphosphine palladium(II) chloride (116 mg, 0.165 mmol), and diisopropylamine (99.3 mg, 0.981 mmol). The reaction mixture was sealed and heated to 95 °C for 8 hours, then cooled to ambient temperature and concentrated under reduced pressure The residue was purified by silica column chromatography, eluting with 33% EtOAc/Hexanes to afford the final product mixed with Ph3P (160 mg, 80.2 % yield). MS (apci) m/z = 508.9 (M+H).
[00430] Step B: Preparation of (R)-ethyl 5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxylate: To (R)-ethyl 5-(2-(2-(3-(tert- butoxycarbonylamino)prop- 1 -ynyl)-5 -fluoropyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [1,5- a]pyrimidine-3-carboxylate (160 mg, 0.315 mmol) in MeOH (10 mL) was added dihydroxypalladium (101 mg, 0.144 mmol). The reaction mixture was stirred under a hydrogen balloon for 6 hours, then filtered through a pad of Celite® and washed with MeOH (30 mL). The filtrate was concentrated and the resultant residue was treated with 4 M HC1 in dioxane (3 mL). After stirring for 30 minutes, the solution was concentrated to afford the product as an HC1 salt (140 mg, 108 % yield). MS (apci) m/z = 413.0 (M+H).
[00431] Step C: Preparation of (R)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxylic acid: To (R)-ethyl 5-(2-(2-(3- aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate hydrochloride (160 mg, 0.356 mmol) in THF/MeOH (2 mL/1 mL) was added lithium hydroxide (1.1 mL, 2.20 mmol). The reaction mixture was heated to 70 °C for 5 hours, then concentrated under reduced pressure. Water (10 rnL) was added and the mixture washed with Et20 (2 x 5 mL), then neutralized with HC1 (1M) to pH = 4. The aqueous solution was extracted with DCM (2 x 10 mL). The organic extract was dried with a2S04, filtered and concentrated under reduced pressure to give the crude desired product (16.0 mg, 11.7 % yield). MS (apci) m/z = 385.0 (M+H).
[00432] Step D: Preparation of (6R)-9-fluoro-2, l 1.16.20,21,24- hexaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one: To (R)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (16 mg, 0.042 mmol) in DMF (5 mL) was added HATU (63 mg, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (22 mg, 0.17 mmol). The reaction mixture was stirred for 3 hours and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using 100% EtOAc to afford the title compound (6.0 mg, 39 % yield). MS (apci) m/z = 367.3 (M+H).
Figure imgf000077_0001
(6R)-9-fluoro- 15-methyl-2.11.16.20.21.24- hexaazapentacvclori6.5.2.02'6 07'12.021'251pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one
[00433] Prepared according to the method of Example 37, substituting tert-butyl 2- methylbut-3-yn-2-ylcarbamate with tert-butyl but-3-yn-2-ylcarbamate in Step B to afford the title compound as a 1 : 1 mixture of diastereomers. MS (apci) m/z = 381.2 (M+H).
Figure imgf000077_0002
(6R.13R)-9-fluoro- 13-methyl-2.1 1.15.19.20.23 -hexaazapentacvclo ri5.5.2.17'11.02'6 020'241pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25-dione
[00434] Step A: Preparation of (R)-methyl 5-(2-(5-fluoro-2-hvdroxypyridin-3- yl)pyrrolidin-l-yl)pyrazolori .5-alpyrimidine-3-carboxylate: To a suspension of (R)-5-(2-(5- fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxylic acid (Preparation B; 5.01 g, 14.0 mmol) in MeOH (150 mL) was added dropwise TMSCHN2 (8.41 mL, 16.8 mmol). The reaction was stirred for 30 minutes, and then quenched with 1 mL of acetic acid. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give the crude methyl ester. To the crude methyl ester was added 4N HC1 in dioxane (100 mL) and the reaction was sealed and heated to 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100 mL) and washed with saturated NaHCC (40 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give the crude desired product (4.67 g, 93.2 % yield). MS (apci) m/z = 357.9 (M+H).
[00435] Step B: Preparation of methyl 5-((R)-2-(l-((^-3-(1.3-dioxoisoindolin-2-yl)-2- methylpropyl)-5-fluoro-2-oxo- 1.2-dihydropyridin-3-yl)pyrrolidin-l -yl)pyrazolori .5- alpyrimidine-3-carboxylate: To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3- yl)pyrrolidin- l-yl)pyrazolo[ l ,5-a]pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in DMF (5 mL) was added lithium hydride (22.5 mg, 2.83 mmol) and (R)-2-(3-bromo-2- methylpropyl)isoindoline- l,3-dione (prepared according to the procedure described in Euro. J. Med. Chem. 2000, 147- 156) (239 mg, 0.848 mmol). The reaction was stirred for 2 hours at 70 °C, and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 10 mL). The organic layer was dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc/Hexanes to afford the product (1 10 mg, 34.8 % yield). MS (apci) m/z = 559.0 (M+H).
[00436] Step C: Preparation of methyl 5-((R)-2-(l-((R)-3-amino-2-methylpropyl)-5- fluoro-2-oxo- 1 ,2-dihydropyridin-3-yl)pyrrolidin-l -yDpyrazoloT 1 ,5-a1pyrimidine-3- carboxylate: To a solution of methyl 5-((R)-2-(l -((S)-3-(l,3-dioxoisoindolin-2-yl)-2- methylpropyl)-5-fluoro-2-oxo- l,2-dihydropyridin-3-yl)pyrrolidin-l -yl)pyrazolo[l ,5- a]pyrimidine-3-carboxylate (1 10 mg, 0.197 mmol) in MeOH/THF (3 mL/3 mL) was added hydrazine (31.6 mg, 0.985 mmol). The reaction was stirred for 14 hours at 50 °C. After cooling, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc (20 mL) and washed with saturated aqueous aHC03 (5 mL), water (2 x 5 mL) and brine (5 mL). The organic layer was dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with EtOAc/MeOH/ H4OH 10: 1 :0.1 to give the desired product (65 mg, 77 % yield). MS (apci) m/z = 429.2 (M+H). [00437] Step D: Preparation of (6R.13R)-9-fluoro-13-methyl-2,l 1.15.19.20.23- hexaazapentacvclori5.5.2.17'11.02'6.020'241pentacosa-l('23).7.9.17('24).18.21-hexaene-16.25- dione: To a solution of methyl 5-((R)-2-(l-((R)-3-amino-2-methylpropyl)-5-fluoro-2-oxo-l,2- dihydropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (65 mg, 0.15 mmol) in THF/MeOH (6 mL/2 mL) was added lithium hydroxide (455 μί, 0.91 mmol). The reaction was stirred at 70 °C for 3 hours, then quenched with hydrogen chloride (910 μί, 0.91 mmol). The solvent was removed under reduced pressure and the residue was dried under high vacuum. To the resulting crude residue was added DMF (10 mL), HATU (115 mg, 0.30 mmol) and N-ethyl-N-isopropylpropan-2-amine (78 mg, 0.61 mmol). The reaction was stirred for 3 hours, and the solvent was removed under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH/EtOAc to afford the title compound (6.0 mg, 10 % yield). MS (apci) m/z = 397.3 (M+H).
Figure imgf000079_0001
(6R.13^-9-fluoro-13-methyl-2.11.15.19.20.23-hexaazapentacvclo ri5.5.2.17'11.02'6 020'241pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25-dione
[00438] Prepared according to the method of Example 34, substituting (5)-2-(3-bromo-
2-methylpropyl)isoindoline-l,3-dione (prepared according to the procedure described in Euro. J. Med. Chem. 2000, 147-156) for (R)-2-(3-bromo-2-methylpropyl)isoindoline-l,3- dione in Step B. MS (apci) m/z = 397.3 (M+H).
Figure imgf000079_0002
(6R)-9-fluoro-l 5.15-dimethyl- 13-oxa-2.11.17.21.22.25-hexaazapentacvclo
Γ 17.5.2.02'6.07'12.022'261hexacosa- 1(25^.7.9.11.19(26).20,23 -heptaen- 18-one
[00439] Prepared according to the procedure for Example 3, substituting 3-amino-2,2- dimethylpropan-l-ol for 3-aminopropan-l-ol in Step A. MS (apci) m/z = 41 1.2 (M+H).
Figure imgf000080_0001
(6R)-9-fluoro- 15.15 -dimethyl-2.1 1.16.20.21.24-hexaazapentacyclo Γ 16.5.2.02'6 07'12.021'25lpentacosa- 1 (24),7.9.1 1.18(25).19.22-heptaen- 17-one
[00440] Step A: Preparation of (R)-methyl 5-(2-(5-fluoro-2-(trifluoromethyl- sulfonyloxy)pyridin-3 -vDpyrrolidin- 1 -vDpyrazolor 1.5-a1pyrimidine-3 -carboxylate: To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3 -carboxylate (Prepared according to Example 34, Step A; 2.31 g, 6.46 mmol) in DMF (20 mL) was added l, l,l-trifluoro-N-phenyl-N-(trifluoromethyl- sulfonyl)methanesulfonamide (2.54 g, 7.11 mmol) and triethylamine (0.785 g, 7.76 mmol). The reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 33% EtOAc/Hexanes to afford the desired product (2.36 g, 74.6 % yield). MS (apci) m/z = 490.0 (M+H).
[00441] Step B: Preparation of (R)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3- methylbutyl)-5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidine-3-carboxylate: To (R)-methyl 5-(2-(5-fluoro-2-(trifluoromethylsulfonyloxy)pyridin-3 -yl)pyrrolidin- 1 - yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (503 mg, 1.03 mmol) in DMF (2 mL) was added tert-butyl 2-methylbut-3-yn-2-ylcarbamate (377 mg, 2.06 mmol), copper(I) iodide (39.1 mg, 0.206 mmol), di-triphenylphosphine palladium(II) chloride (144 mg, 0.206 mmol), diisopropylamine (260 mg, 2.57 mmol). The reaction mixture was sealed and heated to 65 °C for 8 hours. The solvent was removed under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc/Hexanes to give (R)-methyl 5-(2- (2-(3-(tert-butoxycarbonylamino)-3-methylbut-l-ynyl)-5-fluoropyridin-3-yl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate mixed with PI13P, which was immediately hydrogenated using dihydroxypalladium on carbon (200 mg, 0.285 mmol) in MeOH (20 mL) under a ¾ balloon for 15 hours. After filtering through a pad of Celite® and washing with MeOH, the filtrate was concentrated under reduced pressure and purified by silica column chromatography, eluting with 66 % EtOAc/Hexanes to afford the product (166 mg, 30.7 % yield). MS (apci) m/z = 527.1 (M+H).
[00442] Step C: Preparation of (6R)-9-fluoro-15.15-dimethyl-2.1 1.16.20.21.24- hexaazapentacvclori6.5.2.02'6.07'12.021'251pentacosa-l(24).7.9.1 1.18(25).19.22-heptaen-17- one: To (R)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3-methylbutyl)-5-fluoropyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (166 mg, 0.315 mmol) in THF/MeOH (3 mL / 1 mL) was added lithium hydroxide (946 μί, 1.89 mmol). The reaction vessel was sealed and heated to 70 °C for 3 hours. The reaction mixture was then dried under reduced pressure and HC1 (4 mL, 4M in dioxane) was added. The reaction mixture was stirred for one hour, then the solvent was removed and the residue was dried under high vacuum for two hours. To the residue was then added DMF (8 mL), HOBT-H2O (96.5 mg, 0.630 mmol), EDCI (121 mg, 0.630 mmol) and triethylamine (159 mg, 1.58 mmol). The reaction mixture was stirred at 45 °C for 18 hours, then concentrated under vacuum The residue was purified by silica column chromatography eluting with 5% MeOH/DCM to afford the title compound (60.0 mg, 48.3 % yield). MS (apci) m/z = 395.1 (M+H).
Figure imgf000081_0001
(6R)-9-fluoro- 13 -oxa-2.1 1.16.17.21.25.26.29-octaazahexacyclo r21.5.2.02'6.07'12.016'20.026'301triaconta-l(29).7.9.1 1.17.19.23(30).24.27-nonaen-22-one
[00443] Step A: Preparation of l-(2-(/gr/-butyldiphenylsilyloxy)ethyl)-lH-pyrazol-5- amine: To a suspension of 2-(5-amino-lH-pyrazol-l-yl)ethanol (2.07 g, 16.0 mmol) and 1H- imidazole (5.43 g, 79.8 mmol) in DMF (10 mL) was added dropwise tert- butylchlorodiphenylsilane (4.96 mL, 19.1 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (40 mL). The organic layer was washed with IN HQ (10 mL), water (10 mL) and brine (10 mL), then concentrated to give crude desired product (5.62 g, 96.4 % yield), which was used in the next step without purification.
[00444] Step B: Preparation of (R)-N-( 1 -(2-(tert-butyldiphenylsiryloxy)ethyl)- 1H- pyrazol-5-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori .5- alpyrimidine-3-carboxamide: To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3- yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (220 mg, 0.616 mmol) in DMF (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 μί, 0.677 mmol) and triethylamine (81.0 mg, 0.800 mmol). The reaction was stirred for 2 hours, and \-(2-(tert- butyldiphenylsilyloxy)ethyl)-lH-pyrazol-5-amine (338 mg, 0.923 mmol) was added to the reaction mixture. The reaction was heated to 60 °C for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography to afford the desired product (201 mg, 46.3 % yield). MS (apci) m/z = 705.1 (M+H).
[00445] Step C: Preparation of (6R)-9-fluoro-13-oxa-2, l 1.16.17.21.25.26.29- octaazahexacvclor21.5.2.02'6.07'12.016'20.026'301triaconta-l('29).7.9.1 1.17.19.23G0).24.27- nonaen-22-one: A suspension of (R)-N-(l-(2-(tert-butyldiphenylsilyloxy)ethyl)-lH-pyrazol- 5 -yl)-5 -(2-(5 -fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [ 1 ,5-a]pyrimidine-3 - carboxamide (201 mg, 0.285 mmol) in 4M HQ in dioxane (6 mL) was sealed and heated to 100 °C for fours hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and washed with saturated NaHCC (5 mL), water (5 mL) and brine (5 mL). The organic layer was concentrated to give crude (R)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-l-yl)-N- ( 1 -(2-hydroxyethyl)- lH-pyrazol-5-yl)pyrazolo[ 1 ,5-a]pyrimidine-3 -carboxamide, to which was added THF (20 mL), DEAD (53.9 μΐ, 0.342 mmol) and triphenylphosphine (89.8 mg, 0.342 mmol). The reaction mixture was stirred for 18 hours, then concentrated under vacuum. The residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to afford the title compound (1.8 mg, 1.5 % yield). MS (apci) m/z = 435.3 (M+H).
Figure imgf000082_0001
(6R)-9-fluoro- 13-oxa-2.11.19.21 ,25,26,29-heptaazahexacvclo r21.5.2.02'^07'12.015'20.026'3Viaconta-l('29).7.9.1 1.15('20).16.18.23 0).24.27-decaen-22-one
[00446] Step A: Preparation of 3 -((ter?-butyldiphenylsilyloxy)methyl)pyridin-2-amine:
To a suspension of (2-aminopyridin-3-yl)methanol (2.19 g, 17.6 mmol) and IH-imidazole (6.00 g, 88.2 mmol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (5.49 mL, 21.2 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (4 OmL). The organic layer was washed with IN HQ (10 mL), water (10 mL) and brine (10 mL) and then concentrated to give crude product (6.03 g, 94.3 % yield). MS (apci) m/z = 363.1 (M+H). [00447] Step B: Preparation of (6R)-9-fluoro-13-oxa-2, l 1.19.21.25.26.29- heptaazahexacvclor21.5.2.02'^07'1 015'20.026'301triaconta ('29).7.9.11.15('20).16.18.23G0).24. 27-decaen-22-one: To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-
1- yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (303 mg, 0.848 mmol) in DMF (5 mL) was added triethylamine (103 mg, 1.02 mmol), followed by dropwise addition of 2,4,6- trichlorobenzoyl chloride (227 mg, 0.933 mmol). The reaction was stirred for two hours. 3- ((tert-Butyldiphenylsilyloxy)methyl)pyridin-2-amine (369 mg, 1.02 mmol) was added and the reaction mixture was heated to 60 °C for 5 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to give (R)-N-(3-((ter/-butyldiphenylsilyloxy)methyl)pyridin-2-yl)-5-(2- (5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, to which was added THF (5 mL) and TBAF (848 μϊ^, 0.848 mmol). The reaction mixture was stirred for one hour, then quenched with saturated NH4C1 (1 mL) and then concentrated under reduced pressure to give crude (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l- yl)-N-(3-(hydroxymethyl)pyridin-2-yl)pyrazolo[ 1 ,5-a]pyrimidine-3-carboxamide, to which was added HC1 (4M in dioxane, 5 mL). The reaction mixture was sealed and heated to 100 °C for four hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and the organic layer was washed with saturated aHC03 (5 mL), water (5 mL) and brine (5 mL). The organic layer was concentrated under reduced pressure to give crude (R)-N-(3-(chloromethyl)pyridin-
2- yl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide, to which was added DMF (lOmL) and CS2CO3 (276 mg, 0.848 mmol). The reaction mixture was heated to 60 °C for 4 hours, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to afford the title compound (8.0 mg, 2.2 % yield). MS (apci) m/z = 432.3 (M+H).
Figure imgf000083_0001
(6R)-9-fluoro- 13.13 -dimethyl-2.1 1.15.19.20.23 -hexaazapentacvclo ri5.5.2.17'11.02'6 020'241pentacosa-l('23).7.9.17('24).18.21-hexaene-16.25-dione
[00448] Step A: Preparation of 3-bromo-2.2-dimethylpropan-l-amine hydrobromide: A mixture of 2-(3-bromo-2,2-dimethylpropyl)isoindoline-l,3-dione (1.00 g, 3.38 mmol) in 48% aqueous HBr (10 mL) was refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and the solids formed were filtered off. The filtrate was concentrated under reduced pressure to give the crude material that was azeotroped with toluene (3x) followed by acetonitrile until solids formed. The crude material was triturated with ether and dried under reduced pressure to afford 3-bromo-2,2-dimethylpropan-l-amine hydrobromide (0.816 g, 3.07 mmol, 91.0 % yield) (confirmed by XH-NMR and posAPCI-MS). The isolated product was used directly without further purification.
[00449] Step B: Preparation of (R)-N-(3-bromo-2.2-dimethylpropyl)-5-(2-(5-fluoro-2- hvdroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidine-3-carboxamide: To a solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxylic acid (Preparation B; 150 mg, 0.420 mmol), EDCI (88.5 mg, 0.462 mmol), and HOBT-H20 (70.7 mg, 0.462 mmol) in DMF (10 mL) was added 3-bromo-2,2- dimethylpropan-1 -amine hydrobromide (124 mg, 0.504 mmol) followed by triethylamine (55.2 mg, 0.546 mmol). The reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 50% EtOAc/Hexanes to provide (R)-N-(3-bromo-2,2-dimethylpropyl)-5-(2-(5- fluoro-2-methoxypyridin-3 -yl)pyrrolidin- 1 -yl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carboxamide ( 180 mg), to which was added HC1 (5 mL, 4M in dioxane). The reaction was sealed and heated to 90 °C for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 20% Hexanes/ EtOAc to provide the desired product (130 mg, 63 % yield).
[00450] Step C: Preparation of (6R)-9-fluoro-13.13-dimethyl-2,l 1, 15.19.20,23- hexaazapentacvclori5.5.2.17'11.02'6.020'241pentacosa-l(23).7.9.17(24).18.21-hexaene-16.25- dione: To a solution of (R)-N-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2- hydroxypyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (30 mg, 0.061 mmol) in THF (5 mL) was added drop-wise potassium 2-methylpropan-2-olate (153 μί, 0.15 mmol). The reaction was heated at 50 °C for two hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to provide the title compound (15 mg, 60 % yield). MS (apci) m/z = 41 1.0 (M+H).
Figure imgf000085_0001
(4R.6R.15S)-9-fluoro-4.15-dihydroxy-13-oxa-2.17.21.22.25-pentaazapentacyclo ri7.5 .02^07,1 022,¾lhexacosa-l(25\7(12\8.10.19(26').20.23-heptaen-18-one
[00451] Step A: Preparation of N-^-B-chloro^-hydroxypropyn-S-C^^-fS-fluoro- 2-hvdroxyphenyl -4-hvdroxypyrrolidin-l-yl pyrazolorL5-a1pyrimidine-3-carboxami To a suspension of (R)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylic acid (Preparation D; 0.0339 g, 0.0946 mmol) and HATU (0.0540 g, 0.142 mmol) in DMF (0.5 mL) at 0 °C was added (5)-l-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0155 g, 0.142 mmol; prepared according to the method described in Org. Process Res. Dev. 2003, vol. 7, p. 533) and N,N-diisopropylethylamine (0.0494 mL, 0.284 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH/DCM to afford N-((5)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2- hydroxyphenyl)-4-hydroxypyrrolidin- 1 -yl)pyrazolo[l ,5-a]pyrimidine-3-carboxamide (as a mixture of cis and trans isomers, 0.0407 g, 82.2 % yield, 86 % purity). LC/MS (ES+APCI) m/z = 448.1 (M-H).
[00452] Step B: Preparation of (4R.6R.15S)-9-fluoro-4.15-dihvdroxy-13-oxa-
2.17.21.22.25-pentaazapentacvclori7.5.2.02'6 07'12.022'26lhexacosa-l('25).7a2).8.10.19('26).20. 23-heptaen-18-one: A mixture of N-((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2- hydroxyphenyl)-4-hydroxypyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (0.0407 g, 0.0778 mmol) and Cs2C03 (0.127 g, 0.389 mmol) in DMF (3.6 mL) was heated at 85 °C for 30 minutes. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH/EtOAc to afford the crude product. The crude material was purified using chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Isolation of the material having a retention time of about 21.8 minutes afforded the title compound (0.0052 g, 16.2 % yield). The stereochemistry of the title compound was confirmed by XH-NMR nOe experiment. LC/MS (ES+APCI) m/z = 414.1 (M+H).
-B
Figure imgf000086_0001
(4R.6S.15 S)-9-fluoro-4.15-dihydroxy- 13 -oxa-2.17.21.22.25-pentaazapentacyclo ri7.5 .02^07,1 022,¾lhexacosa- l(25\7(12\8.10.19(26').20.23-heptaen- 18-one
[00453] The title compound was isolated during chiral separation reported in Example
41 from fractions having a retention time of about 30.6 minutes, to provide 5.4 mg (16.8% yield) of the compound which may have been isolated along with the enantiomer and/or one or more diastereomers. The stereochemistry of the title compound was confirmed by 1H- NMR nOe experiment), LC/MS (ES+APCI) m/z = 414.1 (M+H).
Example 42
Figure imgf000086_0002
(4R.6R)-9-fluoro-4-hydroxy-13-oxa-2.17.21.22.25-pentaazapentacyclo ri7.5.2.02'6.07'12.022'261hexacosa- l(25).7(12),8.10.19(26).20,23-heptaen- 18-one
[00454] The title compound was prepared according to the method of Example 41, substituting 3-chloropropan- l-amine hydrochloride for (5)- l-amino-3-chloropropan-2-ol hydrochloride in Step A: 13.8 mg (16% yield; Chiral Tech OD-H column, 20% EtOH in hexanes, retention time about 17.2 minutes). The stereochemistry of the title compound was confirmed by XH-NMR nOe experiment. LC/MS (ES+APCI) m/z = 398.1 (M+H).
Example 42-B
Figure imgf000086_0003
(4R.6iS)-9-fluoro-4-hydroxy- 13-oxa-2.17.21.22.25-pentaazapentacyclo ri7.5.2.02'6.07'12.022'261hexacosa- l(25).7(12).8.10.19(26).20.23-heptaen- 18-one
[00455] The title compound was prepared during the chiral separation reported in
Example 42 by isolating the fractions having retention time about 26.2 minutes (21.1 mg, 24.5% yield) which may have been isolated along with enantiomer and/or one or more diastereomers. The stereochemistry of the title compound was confirmed by XH-NMR nOe experiment. LC/MS (ES+APCI) m/z = 398.1 (M+H).
Figure imgf000087_0001
(4R.6R)-9-fluoro-4-hydroxy-l 3-oxa-2.16,20,21.24-pentaazapentacyclo Γ 16.5.2.02'6 07'12.021'25lpentacosa- 1 (24X7.9.1 1.18(25).19.22-heptaen- 17-one
[00456] The title compound was prepared according to the method of Example 41, substituting 2-chloroethylamine hydrochloride for (5)-l-amino-3-chloropropan-2-ol hydrochloride in Step A. The title compound was purified using a Chiral Tech OJ-H column, 20% EtOH in hexanes, by isolating fractions having a retention time of about 15.7 minutes (10.7 mg, 14.2% yield). The stereochemistry of the title compound was confirmed by 1H- NMR nOe experiment. LC/MS (ES+APCI) m/z = 384.1 (M+H).
-B
Figure imgf000087_0002
(4R.6»S)-9-fluoro-4-hvdroxy-13-oxa-2.16,20,21 ,24-pentaazapentacvclo Γ 16.5.2.02'6 07'12.021'251pentacosa- 1 (24X7.9.1 1.18(25).19.22-heptaen- 17-one
[00457] The title compound was isolated during the chiral separation reported in
Example 43 by isolating fractions having a retention time of about 21.3 minutes (15.9 mg, 21.1% yield) which may have been isolated along with the enantiomer and/or one or more diastereomers. The stereochemistry of the title compound was confirmed by XH-NMR nOe experiment), LC/MS (ES+APCI) m/z = 384.1 (M+H).
Example 44
Figure imgf000087_0003
(4R.6R.15R)-9-fluoro-4.15-dihydroxy- 13-oxa-2.17.21.22.25-pentaazapentacyclo ri7.5 .02^07,1 022,¾lhexacosa-l(25\7(12\8.10.19(26').20.23-heptaen-18-one
[00458] The title compound was prepared according to the method of Example 41, substituting (R)-l-amino-3-chloropropan-2-ol hydrochloride (prepared according to the procedure described in Example 19, Step A using (R)-2-(chloromethyl)oxirane) for («S)-1- amino-3-chloropropan-2-ol hydrochloride in Step A. The crude material was purified on a silica gel column, eluting with CH2C12 to NH4OH:MeOH:CH2Cl2 (0.5:5:95) (4 runs). Fractions containing the earlier eluting compound were collected to provide 12 mg (10.9% yield) of the desired material. The stereochemistry of the title compound was confirmed by ^- MR nOe experiment. LC/MS (ES+APCI) m/z = 414.0 (M+H).
Example 44-B
Figure imgf000088_0001
(4R.6S.15R)-9-ffuoro-4.15-dihydroxy- 13 -oxa-2.17,21.22.25-pentaazapentacyclo ri7.5 .02^07,1 022,¾lhexacosa-l(25 7fl2 8.10.19f26').20.23-heptaen-18-one
[00459] The title compound was isolated during the purification reported in Example
44. Fractions containing the later eluting compound were collected to provide 15 mg (13.6% yield) of the title compound, which may have been isolated along with the enantiomer and/or one or more diastereomers. The stereochemistry of the title compound was confirmed by lH- NMR nOe experiment); LC/MS (ES+APCI) m/z = 414.1 (M+H).
Figure imgf000088_0002
Diastereomer 1 and Diastereomer 2 of (15»Sy4.4.9-trifluoro-15-hvdroxy-13-oxa-2.17.21.22.
25-pentaazapentacvclori7.5.2.02'6.07'12.022'261hexacosa-l(25).7(12).8.10.19(26).20.23- heptaen-18-one
[00460] Step A: Preparation of (R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride: To solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2- methoxyphenyl)pyrrolidine-l-carboxylate (1.01 g, 2.37 mmol) in CH2C12 (10 mL) at 0 °C was added 4 M HC1 in dioxane (5.93 mL, 23.7 mmol). The resulting mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was triturated with ether. The resulting solids were filtered and dried under reduced pressure to afford (R)-5-(5-fluoro-2- methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.577 g, 2.33 mmol, 98.2 % yield). MS (APCI) m/z = 212.0 (M+H).
[00461] Step B: Preparation of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4- hvdroxypyrrolidin-l -yl pyrazolorL5-a1pyrimidine-3-carboxylate: To a suspension of ethyl 5-hydroxypyrazolo[ l,5-a]pyrimidine-3-carboxylate (0.541 g, 2.61 mmol) and BOP reagent (1.57 g, 3.56 mmol) in DMF/CH2C12 (3 mL/3 mL) at 0 °C was added (R)-5-(5-fluoro-2- methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.588 g, 2.37 mmol) followed by DIEA (1.66 mL, 9.50 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was diluted again with EtOAc (30 mL). The organic layer was washed with saturated aqueous aHC03 followed by brine, dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography, eluting with CH2C12 to 5% MeOH in CH2C12 to afford (R)-ethyl 5-(2-(5- fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin- l-yl)pyrazolo[ l,5-a]pyrimidine-3-carboxylate (0.735 g, 1.84 mmol, 77.3 % yield). LC/MS (ES+APCI) m/z = 401.1 (M+H).
[00462] Step C: Preparation of ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4- oxopyrrolidin- l -yl)pyrazolori .5-a1pyrimidine-3-carboxylate: To a suspension of Dess-Martin periodinane (0.233 g, 0.549 mmol) in CH2C12 (2.2 mL) at 0 °C was added a solution of (R)- ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin- l -yl)pyrazolo[l ,5-a]pyrimidine- 3-carboxylate (0.200 g, 0.499 mmol) in CH2C12 (1.5 mL). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous aHC03 (5 mL) containing Na2S2C>3 (0.608 g, 3.85 mmol). The resulting mixture was warmed to ambient temperature and stirred for 10 minutes. The organic layer was separated, washed with saturated aqueous aHC03 (10 mL) followed by brine (10 mL), dried over MgS04, filtered, and concentrated under reduced pressure to afford ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-oxopyrrolidin- l -yl)pyrazolo[l ,5-a]pyrimidine-3- carboxylate (0.164 g, 82.4 % yield). LC/MS (ES+APCI) m/z = 399.1 (M+H).
[00463] Step D: Preparation of ethyl 5-(4.4-difluoro-2-(5-fluoro-2- methoxyphenvDpyrrolidin- l-vDpyrazolor 1 ,5-a1pyrimidine-3-carboxylate: To a solution of ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-oxopyrrolidin- l -yl)pyrazolo[l ,5-a]pyrimidine-3- carboxylate (0.162 g, 0.407 mmol) in CH2C12 (3 mL) was added a solution of bis(2- methoxyethyl)aminosulfur trifluoride (0.134 mL, 0.691 mmol) followed by EtOH (0.00475 mL, 0.0813 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was poured into saturated aqueous aHC03 (6 mL) and extracted with CH2CI2 (2 x 10 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica column chromatography, eluting with 0-50% EtOAc/Hexanes to afford ethyl 5-(4,4-difluoro- 2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate (0.126 g, 65.6 % yield). MS (APCI) m/z = 420.9 (M+H).
[00464] Step E: Preparation of 5-(4.4-difluoro-2-(5-fluoro-2- hydroxyphenvDpyrrolidin- 1 -vDpyrazolo Γ 1 ,5 -alpyrimidine-3 -carboxylic acid: To a solution of ethyl 5-(4,4-difluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (0.126 g, 0.267 mmol) in CH2CI2 (1.3 mL) at 0 °C was added 1 M BBr3 in CH2CI2 (1.50 mL, 1.50 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with CH2CI2 (5 mL) and poured into a mixture of ice and saturated aqueous aHC03 (3 mL). The aqueous layer was then acidified to about pH 3 with 1 N aqueous HC1. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give a mixture of ethyl 5-(4,4-difluoro-2-(5-fluoro-2- hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylate and 5-(4,4-difluoro- 2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid. This mixture was taken up in MeOH-THF (0.25 mL/0.75 mL) at ambient temperature, and 2 N aqueous LiOH (0.667 mL, 1.33 mmol) was added. The resulting mixture was heated at 50 °C for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to remove the organic solvents. The residue was diluted with 5 mL of EtOAc and acidified to pH 3 to 4 with 6 N aqueous HC1 with stirring. The organic layer was separated and the acidic aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to afford 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimi- dine-3-carboxylic acid (0.094 g, 93.1 % yield). MS (APCI) m/z = 378.9 (M+H).
[00465] Step F: Preparation of N-((y)-3-chloro-2-hvdroxypropyl)-5-(4.4-difluoro-2-(5- fluoro-2-hvdroxyphenyl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidine-3-carboxamide: To a mixture of 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin- l-yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxylic acid (0.047 g, 0.124 mmol) and HOBT (0.0252 g, 0.186 mmol) in DMF (1 mL) at ambient temperature was added EDCI (0.0357 g, 0.186 mmol). The resulting mixture was stirred for 1 hour. To this mixture was added (5)-l-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0218 g, 0.149 mmol) followed by DIEA (0.0656 mL, 0.373 mmol) at ambient temperature. The resulting mixture was stirred for 48 hours. The reaction mixture was diluted with EtOAc (10 mL), and the organic layer was washed with a 1 : 1 mixture of brine and water. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with a 1 : 1 mixture of brine and water (15 mL) and combined with the organic layer obtained previously. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to afford N-((5)-3- chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (0.061 g, 105 % yield). LC/MS (ES+APCI) m/z = 468.1 (M-H).
[00466] Step G: Preparation of Diastereomers 1 and 2 of (15S)-4.4.9-trifluoro-15- hvdroxy-13-oxa-2.17.21.22.25-pentaazapentacvclori7.5.2.02'6.07'12.022'261hexacosa-l(25).7 (12).8.10.19(26).20.23-heptaen-18-one: A mixture of N-((5)-3-chloro-2-hydroxypropyl)-5- (4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide (0.060 g, 0.128 mmol) and Cs2C03 (0.208 g, 0.639 mmol) in DMF (6.4 mL) was heated at 85 °C for 30 minutes. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude material which was purified by silica gel flash column chromatography ((¾(¾ to NH4OH:MeOH:CH2Cl2 = 0.5:5:95) to afford a mixture of the diastereomers. The isolated diastereomers were further purified by chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Fractions having a retention time of about 17.1 minutes were isolated to afford the title compound designated as Diastereomer 1 (11 mg, 20 % yield.; MS (APCI) m/z = 434.2 (M+H). Fractions having a retention time of about 21.0 minutes were isolated to provide the title compound designated as Diastereomer 2 (13 mg; 24 % yield); MS (APCI) m/z = 434.2 (M+H).

Claims

i claimed is:
1. A compound of the general Formula I
Figure imgf000092_0001
I
or pharmaceutically acceptable salts thereof, wherein:
ring A is selected from rings A- 1 , A-2 and A-3 having the structures:
1 1 1
Figure imgf000092_0002
A-1 A-2 A-3
wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is N or CH;
Y is H or F;
R1 is H, (l-3C)alkoxy or halogen;
ring B is selected from rings B-1 and B-2 having the structures:
Figure imgf000092_0003
3 3
B-1 B-2
wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[ l,5-a]pyrimidine ring of Formula I;
W is O, NH or CH2, wherein when ring A is A-2, then W is CH2;
m is 0, 1 or 2;
D is carbon, R2 and R2a are independently H, F, (1-3 C)alkyl or OH (provided that R2 and R2a are not both OH), and R3 and R3a are independently H, (1-3 Qalkyl or hydroxy(l -3 Qalkyl, or D is carbon or nitrogen, R2 and R3 are absent, and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;
Z is *-NR4aC(=0)-, *-ONHC(=0)-, *-NR4bCH2- or *-OC(=0)-, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R3;
R4a is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl);
R4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar^CO)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar2(S02)-, H02CCH2- or (1-6C alkyl)NH(CO)-;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-6C)alkyl.
2. A compound of claim 1 having the general Formula
Figure imgf000093_0001
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from rings A-1, A-2 and A-3 having the structures:
1 1 1
Figure imgf000093_0002
A-1 A-2 A-3
wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is or CH; Y is H or F;
R1 is H, (l-3C)alkoxy or halogen;
W is O, NH or CH2, wherein when ring A is A-2, then W is CH2;
m is 0, 1 or 2;
R2 and R2a are independently H, F, or OH, provided that R2 and R2a are not both
OH;
R3 is H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl;
Z is *-NR4aC(=0)-, *-ONHC(=0)-, *-NR4bCH2- or *-OC(=0)-, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R3;
R4a is H, ( 1 -6C)alkyl, fluoro( 1 -6C)alkyl, difluoro( 1 -6C)alkyl, trifluoro( 1 -6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl);
R4b is H, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, A^ O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar2(S02)-, H02CCH2- or (1-6C alkyl)NH(CO)-;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy;
Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, and (l-6C)alkoxy; and
R5 and R6 are independently H, halogen, OH, (l-6C)alkyl or hydroxy(l-6C)alkyl.
3. A compound according to claim 1 or 2, wherein ring A is ring A-1 having the structure
Figure imgf000094_0001
A-1
4. A compound according to claim 3, wherein X is CH.
5. A compound according to claim 3, wherein X is N.
6. A compound according to claim 1 or 2, wherein ring A is ring A-3 having the structure
Figure imgf000095_0001
A-3
7. A compound according to any of claims 1-6, wherein W is O.
8. A compound according to any of claims 1-6, wherein W is NH.
9. A compound according to any of claims 1-6, wherein W is CH.
10. A compound according to claim 1 or 2, wherein ring A is ring A-2 having the structure
Figure imgf000095_0002
A-2
11. A compound according to any of claims 1-10, wherein Y is F.
12. A compound according to any of claims 1-10, wherein Y is H.
13. A compound according to any of claims 1-12, wherein R1 is H.
14. A compound according to any of claims 1-12, wherein R1 is (1-3 C)alkyl or (l-3C)alkoxy.
15. A compound according ; to claim 14, wherein R1 is methyl or methoxy.
16. A compound according ; to any of claims 1-12, wherein R1 is halogen.
17. A compound according ; to claim 16, wherein R1 is fluoro.
18. A compound according ; to any of claims 1-17, wherein Z is *-NR4aC(=0)-.
19. A compound according ; to claim 18, wherein R4a is hydrogen.
20. A compound according I to claim 18, wherein R4a is (l-6C)alkyl, fluoro(l
6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2 6C alkyl).
21. A compound according to claim 20, wherein R4a is ( 1 -6C)alkyl.
22. A compound according to any of claims 1-17, wherein Z is *-ONHC(=0)-.
23. A compound according to any of claims 1-17, wherein Z is *-NR4bCH2- .
24. A compound according to claim 23, wherein R4b is H.
25. A compound according to claim 23, wherein R4b is selected from (1- 6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl and trifluoro(l-6C)alkyl.
26. A compound according to claim 25, wherein R4b is (l-6C)alkyl.
27. A compound according to claim 23, wherein R4b is selected from (1-6C alkyl)C(O)-, (3-6C cycloalkyl)C(O)-, Ar^O)- and HOCH2C(0)-.
28. A compound according to claim 27, wherein R4b is (1-6C alkyl)C(O)-.
29. A compound according to claim 23, wherein R4b is selected from (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, and Ar2(S02)-.
30. A compound according to claim 29, wherein R4b is (1-6C alkyl)sulfonyl.
31. A compound according to claim 23, wherein R4b is HO2CCH2-.
32. A compound according to claim 23, wherein R4b is (1-6C alkyl)NH(CO)-.
33. A compound according to any of claims 1 or 3-32, wherein D is carbon, R2 and R2a are independently H, F, (1-3 C)alkyl or OH (provided that R2 and R2a are not both OH), and R3 and R3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl.
34. A compound according to any of claims 1-33, wherein R2 and R2a are each hydrogen.
35. A compound according to any of claims 1-33, wherein R2 and R2a are each fluoro.
36. A compound according to any of claims 1-33, wherein R2 is hydrogen and R2a is fluoro.
37. A compound according to any of claims 1-33, wherein R2 is hydrogen and R2a is OH.
38. A compound according to claim 1 or 3-33, wherein R2 is H and R2a is methyl, or R2 and R2a are both methyl.
39. A compound according to claim 1 or 3-33, wherein:
R3 and R3a are H; or
R3a is methyl and R3 is H; or
R3a and R3a are both methyl.
40. A compound according to claim 1 or 3-32, wherein D is carbon or nitrogen, R2 and R3 are absent, and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.
41. A compound according to any of claims 1 -40, wherein ring B is ring B- 1 :
Figure imgf000097_0001
3
B-1 and
R5 and R6 are independently H, F, OH, methyl, ethyl, HOCH2- or HOCH2CH2-.
42. A compound according to claim 41, wherein R5 is hydrogen and R6 is H, F, OH, methyl, ethyl, HOCH2- or HOCH2CH2-.
43. A compound according to claim 42, wherein R6 is H.
44. A compound according to claim 1 or 3-40, wherein ring B is ring B-2:
Figure imgf000097_0002
3
B-2
45. A compound according to any of claims 1-44, wherein m is 0.
46. A compound according to any of claims 1-44, wherein m is 1.
47. A compound according to any of claims 1-44, wherein m is 2.
48. A compound according to any of claims 1-47 having the absolute configuration of Figure 1-a:
Figure imgf000097_0003
49. A compound according to any of claims 1-47 having the absolute configuration of Figure 1-b
Figure imgf000097_0004
1-b
50. A pharmaceutical composition, which comprises a compound of Formula I as defined in any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
51. A method for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I as defined in any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof.
52. The method of claim 51, wherein the disease or disorder is pain.
53. A compound of Formula I as defined in any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection.
54. A process for the preparation of a compound of claim 1, which comprises: (a) for a compound of Formula I wherein Z is *-NHC(=0)-, and ring A, ring B,
W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula II
Figure imgf000098_0001
II
where P1 is H or a carboxyl protecting group, in the presence of a coupling reag base; or
(b) for a compound of Formul is O, ring A is formula A- 1 :
Figure imgf000098_0002
A-1
X is N, and ring B, D, Z, Y, R1, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula III
Figure imgf000099_0001
where n is 1, 2, 3 or 4 and L1 is a leaving group or atom, in the presence of a base; or (c) for a compound of Formula I wherein W is CH2, ring A is formula A-2:
Figure imgf000099_0002
A-2
and ring B, Z, D, Y, R1, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula IV
Figure imgf000099_0003
IV
where L2 is a leaving group or atom, in the presence of a base; or
(d) for a compound of Formula I wherein Z is *-NHC(=0)-, and ring A, ring B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula V
Figure imgf000099_0004
in the presence of a base and a coupling reagent; or (e) for a compound of Formula I wherein Z is *-NHCH2-, and ring A, ring B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VI
Figure imgf000100_0001
VI
in the presence of a reducing agent; or
(f) for a compound of Formula I wherein Z is *-NHCH2-, and ring A, ring B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VII
Figure imgf000100_0002
VII
in the presence of triphenylphosphine; or
(g) for a compound of Formula I wherein ring A, ring B, W, D, m, R2, R2a, R3, and R3a are as defined for Formula I, Z is *-NR4bCH2-, and R4b is (1-6C alkyl)C(O)-, (3- 6C cycloalkyl)C(O)-, Ar^O)-, HOCH2C(0)-, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, or Ar2(S02)-, coupling a corresponding compound having the formula VIII
Figure imgf000100_0003
VIII with a reagent having the formula (1-6C alkyl)C(0)-L3, (3-6C cycloalkyl)C(0)-L3, A^CCC -L3, HOCH2C(0)-L3, (1-6C alkyl)(S02)-L3, (3-6C cycloalkyl)(S02)-L3, or Ar2(S02)-L3, respectively, where L3 is a leaving atom, in the presence of a base; or
(h) for a compound of Formula I wherein ring A, ring B, W, D, R2, R2a, R3, R3a and m are as defined for Formula I, Z is *-NR4bCH2-, and R4b is (1-6C alkyl)NH(CO)-, reacting a compound having the formula VIII
Figure imgf000101_0001
VIII
with a reagent having the formula (1-6C alkyl)N=C=0 in the presence of a base; or
(i) for a compound of Formula I wherein R2 is F, R2a is H, and ring A, ring B, Z, W, D, R3, R3a, and m are as defined for Formula I, reacting a corresponding compound having the formula IX
Figure imgf000101_0002
IX
with a fluorination reagent;
(j) for a compound of Formula is O, ring A is formula A-l,
Figure imgf000101_0003
A-1
X is CH, and Y, R1, D, ring B, Z, R2, R2a, R3 and m are as defined for Formula I, cyclizing a corresponding compound having the formula X
Figure imgf000102_0001
X
where n is 1, 2, 3 or 4 and L1 is a leaving group or atom, in the presence of a base; and optionally removing any protecting groups and optionally preparing a salt thereof.
55. The method of claim 54, wherein:
ring B is ring B-l having the structure:
Figure imgf000102_0002
B-1
D is carbon;
R2 and R2a are independently H, F, (1-3 Qalkyl or OH, provided that R2 and R2a are not both OH; and
R3 and R3a are independently H, (1-3 Qalkyl or hydroxy(l-3 Qalkyl.
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Cited By (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104169286A (en) * 2012-03-06 2014-11-26 辉瑞大药厂 Macrocyclic derivatives for the treatment of proliferative diseases
WO2016042087A1 (en) * 2014-09-17 2016-03-24 Oncodesign S.A. Macrocyclic rip2 kinase inhibitors
WO2016077841A1 (en) 2014-11-16 2016-05-19 Array Biopharma, Inc. Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
WO2016097869A1 (en) 2014-12-15 2016-06-23 Cmg Pharmaceutical Co., Ltd. Fused ring heteroaryl compounds and their use as trk inhibitors
US9447104B2 (en) 2008-10-22 2016-09-20 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
US9493476B2 (en) 2010-05-20 2016-11-15 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
WO2016196671A1 (en) 2015-06-01 2016-12-08 Loxo Oncology, Inc. Methods of diagnosing and treating cancer
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
WO2017011776A1 (en) 2015-07-16 2017-01-19 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
WO2017075107A1 (en) 2015-10-26 2017-05-04 Nanda Nisha Point mutations in trk inhibitor-resistant cancer and methods relating to the same
US9682979B2 (en) 2009-07-09 2017-06-20 Array Biopharma, Inc. Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors
WO2017176744A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2017176751A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9795611B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2018071447A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
WO2018071454A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
CN108026108A (en) * 2015-07-06 2018-05-11 Tp生物医药公司 diaryl macrocyclic polymorphs
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2018081417A3 (en) * 2016-10-26 2018-06-07 Qian Zhao PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2018170381A1 (en) 2017-03-16 2018-09-20 Andrews Steven W Macrocyclic compounds as ros1 kinase inhibitors
EP3317285A4 (en) * 2015-07-02 2019-02-27 TP Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
WO2019037761A1 (en) 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
US10246466B2 (en) 2014-01-24 2019-04-02 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T Crystalline forms
WO2019084285A1 (en) 2017-10-26 2019-05-02 Qian Zhao Formulations of a macrocyclic trk kinase inhibitor
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
US10377775B2 (en) 2014-12-04 2019-08-13 Shin-Etsu Chemical Co., Ltd. Method for producing polyalkylene glycol derivative having amino group at end
WO2019184955A1 (en) * 2018-03-28 2019-10-03 Fochon Pharmaceuticals, Ltd. Macrocyclic compounds as trk kinases inhibitors
WO2019191659A1 (en) 2018-03-29 2019-10-03 Loxo Oncology, Inc. Treatment of trk-associated cancers
US10472377B2 (en) 2014-12-04 2019-11-12 Shin-Etsu Chemical Co., Ltd. Method for producing polyalkylene glycol derivative having amino group at end, polymerization initiator for use in the same, and alcohol compound as raw material for the polymerization initiator
WO2020028258A1 (en) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Spray-dried dispersions and formulations of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1h-pyrazole-4-carboxamide
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
WO2020063965A1 (en) * 2018-09-29 2020-04-02 南京明德新药研发有限公司 Pyrazolopyrimidine derivative as selective trk inhibitor
WO2020094112A1 (en) 2018-11-09 2020-05-14 山东轩竹医药科技有限公司 Macrocyclic tyrosine kinase inhibitor and uses thereof
US10689400B2 (en) 2016-07-28 2020-06-23 Turning Point Therapeutics, Inc. Macrocycle kinase inhibitors
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
US10745416B2 (en) 2017-12-19 2020-08-18 Turning Point Therapeutics, Inc. Macrocyclic compounds for treating disease
WO2020187291A1 (en) 2019-03-19 2020-09-24 华中师范大学 Pyrazolopyrimidine compound, pharmaceutical composition, and application therefor
EP3642399A4 (en) * 2017-06-22 2020-10-14 Cyclenium Pharma Inc. Libraries of pyridine-containing macrocyclic compounds and methods of making and using the same
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
EP3706749A4 (en) * 2017-11-10 2021-03-03 Angex Pharmaceutical, Inc. Macrocyclic compounds as trk kinase inhibitors and uses thereof
US10981931B2 (en) 2015-09-24 2021-04-20 Cyclenium Pharma Inc. Libraries of heteroaryl-containing macrocyclic compounds and methods of making and using the same
EP3770161A4 (en) * 2018-04-16 2021-04-28 Shenzhen TargetRx, Inc. Di(hetero)aryl macrocyclic compound for inhibiting protein kinase activity
EP3760632A4 (en) * 2018-02-28 2021-04-28 Simcere Pharmaceutical Co. Ltd. Pyrazolopyrimidine derivative and use thereof
WO2021083345A1 (en) * 2019-10-30 2021-05-06 先声药业有限公司 Preparation method for pyrazolopyrimidine compound and intermediate thereof
EP3744723A4 (en) * 2018-01-23 2021-05-19 Shenzhen TargetRx, Inc. Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound
EP3786167A4 (en) * 2018-04-25 2021-06-09 Primegene (Beijing) Co., Ltd. Diaryl macrocyclic compound and pharmaceutical composition, and use thereof
WO2021115401A1 (en) 2019-12-13 2021-06-17 成都倍特药业股份有限公司 Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
US11155563B2 (en) 2017-07-28 2021-10-26 Turning Point Therapeutics, Inc. Macrocyclic compounds and uses thereof
CN113582994A (en) * 2021-09-28 2021-11-02 北京鑫开元医药科技有限公司 Compound with TRK kinase inhibitory activity, preparation method, composition and application thereof
WO2021223748A1 (en) 2020-05-08 2021-11-11 山东轩竹医药科技有限公司 Crystal form of macrocyclic tyrosine kinase inhibitor and preparation method therefor
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
WO2022052925A1 (en) * 2020-09-10 2022-03-17 上海希迈医药科技有限公司 Repotrectinib crystal form and preparation method therefor
US11291667B2 (en) 2017-01-25 2022-04-05 Turning Point Therapeutics, Inc. Combination therapy involving diaryl macrocyclic compounds
EP3822276A4 (en) * 2018-06-25 2022-04-06 Beijing InnoCare Pharma Tech Co., Ltd. Heterocyclic compound as trk inhibitor
RU2779497C2 (en) * 2017-08-23 2022-09-08 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Macrocycle containing aminopyrazole and pyrimidine, and its pharmaceutical composition and use
US11453672B2 (en) 2017-12-22 2022-09-27 Shenzhen Targetrx, Inc. Substituted pyrazolo[1,5-a]pyrimidines as tropomyosin receptor kinase inhibitors
US11452725B2 (en) 2015-07-21 2022-09-27 Turning Point Therapeutics, Inc. Chiral diaryl macrocycles and uses thereof
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
WO2023025141A1 (en) * 2021-08-23 2023-03-02 正大天晴药业集团股份有限公司 Use of macrocyclic compound containing amino in treatment of trk kinase-mediated tumors
US11597729B2 (en) 2018-06-08 2023-03-07 Jiangsu Vcare Pharmatech Co., Ltd. Tropomyosin receptor kinase inhibitor, preparation method therefor and use thereof
EP4023648A4 (en) * 2019-08-28 2023-09-27 Simcere Pharmaceutical Co. Ltd. Crystal of carcinogenic fused kinase inhibitor and applications thereof

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2016013027A (en) 2014-04-04 2017-05-23 Del Mar Pharmaceuticals Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer.
TWI688567B (en) * 2014-09-11 2020-03-21 美商特普醫葯公司 Diaryl macrocycles as modulators of protein kinases
CN107108641A (en) * 2014-09-17 2017-08-29 昂科迪塞恩股份有限公司 Big ring LRRK2 kinase inhibitors
JP6460937B2 (en) * 2014-12-04 2019-01-30 信越化学工業株式会社 Method for producing polyalkylene glycol derivative having amino group at terminal
BR112017015760A2 (en) 2015-01-23 2018-03-27 Gvk Biosciences Private Limited trka kinase inhibitors
CN109516999B (en) * 2017-11-01 2021-08-17 郑州泰基鸿诺医药股份有限公司 Compounds useful as protein kinase modulators and uses thereof
WO2019120267A1 (en) * 2017-12-22 2019-06-27 成都先导药物开发股份有限公司 Imidazo[1,2-b]pyridazine macrocyclic kinase inhibitor
WO2019149131A1 (en) * 2018-01-30 2019-08-08 上海吉倍生物技术有限公司 Compound having macrocyclic molecular structure and use thereof
CN110156813B (en) * 2018-02-13 2023-07-25 北京诺诚健华医药科技有限公司 Heterocyclic compounds as TRK inhibitors
MX2020009586A (en) * 2018-03-14 2020-10-05 Fochon Biosciences Ltd SUBSTITUTED (2-AZABICYCLO [3.1.0] HEXAN-2-YL) PYRAZOLO [1, 5-a] PYRIMIDINE AND IMIDAZO [1, 2-b] PYRIDAZINE COMPOUNDS AS TRK KINASES INHIBITORS.
CN111918868B (en) * 2018-05-04 2022-12-30 正大天晴药业集团股份有限公司 Diaryl macrocycles as protein kinase modulators
WO2019233461A1 (en) * 2018-06-08 2019-12-12 江苏威凯尔医药科技有限公司 Tropomyosin receptor kinase inhibitor, preparation method therefor and use thereof
EP3870579A4 (en) 2018-10-22 2022-10-19 Alumis Inc. Tyk2 inhibitors and uses thereof
CN111171049B (en) * 2018-11-09 2021-06-04 山东轩竹医药科技有限公司 Tyrosine kinase inhibitors and uses thereof
CN111253402B (en) * 2018-11-30 2021-08-03 广州白云山医药集团股份有限公司白云山制药总厂 Intermediate compound of TRK kinase inhibitor compound and preparation method thereof
EP3946350A4 (en) * 2019-03-26 2022-09-07 Ventyx Biosciences, Inc. Tyk2 pseudokinase ligands
JP7318009B2 (en) * 2019-05-21 2023-07-31 浙江海正薬業股▲ふん▼有限公司 Macrolide derivative, production method and use thereof
CN112110938B (en) * 2019-06-21 2021-11-09 成都海博为药业有限公司 Compound as protein kinase inhibitor and preparation method and application thereof
CN110804059B (en) * 2019-09-30 2024-03-12 郑州泰基鸿诺医药股份有限公司 Carbamate compound, pharmaceutical composition and application thereof
IL292785A (en) 2019-11-08 2022-07-01 Ventyx Biosciences Inc Tyk2 pseudokinase ligands
US20230002410A1 (en) * 2019-11-18 2023-01-05 Guangzhou Joyo Pharmatech Co., Ltd. Compound as highly selective ros1 inhibitor and use thereof
CN113004305B (en) * 2019-12-19 2024-04-09 赛诺哈勃药业（成都）有限公司 Macrocyclic compounds, their preparation and use
CN111777549A (en) * 2020-07-07 2020-10-16 中瀚(齐河县)生物医药科技有限公司 Synthesis process of 2-methoxy-3-bromo-5-fluoropyridine
CN114073704B (en) * 2020-08-14 2023-08-11 赛诺哈勃药业（成都）有限公司 Use of fluorine-containing heterocyclic derivative with macrocyclic structure
CN111875620B (en) * 2020-09-28 2020-12-11 上海美迪西生物医药股份有限公司 Pyrazolopyrimidine macrocyclic derivative and application thereof
WO2022150584A1 (en) * 2021-01-08 2022-07-14 Yale University Non-covalent inhibitors of the main protease of sars-cov-2 and methods of use
WO2022213980A1 (en) * 2021-04-07 2022-10-13 上海齐鲁制药研究中心有限公司 Tyk2 inhibitor and use thereof
CN115368379A (en) * 2021-05-18 2022-11-22 广州嘉越医药科技有限公司 Crystal form of macrocyclic compound containing cyano substitution and preparation method thereof
WO2022262671A1 (en) * 2021-06-15 2022-12-22 中国医药研究开发中心有限公司 Macro heterocyclic compound and medical use thereof
WO2023133375A1 (en) * 2022-01-05 2023-07-13 Blossomhill Therapeutics, Inc. Macrocyclic compounds and use as kinase inhibitors
WO2023208244A1 (en) * 2022-04-29 2023-11-02 南京明德新药研发有限公司 Macrocyclic compound and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1873157A1 (en) * 2006-06-21 2008-01-02 Bayer Schering Pharma Aktiengesellschaft Pyrazolopyrimidines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
WO2010048314A1 (en) * 2008-10-22 2010-04-29 Array Biopharma Inc. SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Family Cites Families (322)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US755047A (en) * 1902-03-17 1904-03-22 Alexander Roth Robertson Bottle-seal.
EP0009517A1 (en) 1978-10-04 1980-04-16 THE PROCTER &amp; GAMBLE COMPANY Vaginal contraceptive
DK0923933T3 (en) 1993-11-30 2002-10-21 Searle & Co Substituted pyrazolylbenzenesulfonamides for use in the treatment of inflammation
US5430021A (en) 1994-03-18 1995-07-04 Pharmavene, Inc. Hydrophobic drug delivery systems
US5844092A (en) 1994-03-18 1998-12-01 Genentech, Inc. Human TRK receptors and neurotrophic factor inhibitors
US5877016A (en) 1994-03-18 1999-03-02 Genentech, Inc. Human trk receptors and neurotrophic factor inhibitors
US6677135B1 (en) 1996-05-08 2004-01-13 Biogen, Inc. Ret ligand (RetL) for stimulating neutral and renal growth
CA2253871C (en) 1996-05-08 2005-04-26 Biogen, Inc. Ret ligand (retl) for stimulating neural and renal growth
CA2206201A1 (en) 1996-05-29 1997-11-29 Yoshiaki Isobe Pyrazole derivatives and their pharmaceutical use
US6682921B1 (en) 1996-08-21 2004-01-27 New York University Crystals of the tyrosine kinase domain of non-insulin receptor tyrosine kinases
JP3898296B2 (en) 1996-08-28 2007-03-28 ポーラ化成工業株式会社 Pyrrolopyrazolopyrimidine compounds and pharmaceuticals containing the same as active ingredients
AU7079998A (en) 1997-04-25 1998-11-24 Takeda Chemical Industries Ltd. Condensed pyridazine derivatives, their production and use
US6531152B1 (en) 1998-09-30 2003-03-11 Dexcel Pharma Technologies Ltd. Immediate release gastrointestinal drug delivery system
UA74546C2 (en) * 1999-04-06 2006-01-16 Boehringer Ingelheim Ca Ltd Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition
WO2001016169A2 (en) 1999-09-01 2001-03-08 Biogen, Inc. RET LIGAND 5 (Retl5) FROM HUMAN AND MOUSE
US6534085B1 (en) 1999-09-23 2003-03-18 Bioresponse L.L.C. Phytochemicals for promoting weight loss
FI20000403A0 (en) 2000-02-22 2000-02-22 Hannu Sariola Use of GDNF family-related compounds for the preparation of testicular cancer treatment products
KR100823764B1 (en) 2000-06-22 2008-04-21 제넨테크, 인크. Agonist anti-trk-C monoclonal antibodies
TWI312347B (en) 2001-02-08 2009-07-21 Eisai R&D Man Co Ltd Bicyclic nitrogen-containing condensed ring compounds
DK1401498T3 (en) 2001-05-30 2011-11-21 Genentech Inc Anti-NGF antibodies for the treatment of various diseases
AU2002334355A1 (en) 2001-09-06 2003-03-18 Prochon Biotech Ltd. Protein tyrosine kinase inhibitors
US20030199525A1 (en) 2002-03-21 2003-10-23 Hirst Gavin C. Kinase inhibitors
MXPA04010441A (en) 2002-04-23 2005-02-14 Shionogi & Co PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE AND NAD(P)H OXIDASE INHIBITOR CONTAINING THE SAME.
US7449488B2 (en) 2002-06-04 2008-11-11 Schering Corporation Pyrazolopyrimidines as protein kinase inhibitors
EP1526854A1 (en) 2002-07-24 2005-05-04 University Of Cincinnati 4-4(methylpiperazin-1-ylmethyl)-n- 4-methyl-3-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl -benzamide for treating mutated-ret kinase associated diseases
JP4024624B2 (en) 2002-08-26 2007-12-19 富士通株式会社 Semiconductor device manufacturing method and manufacturing apparatus
US7119200B2 (en) 2002-09-04 2006-10-10 Schering Corporation Pyrazolopyrimidines as cyclin dependent kinase inhibitors
US7196078B2 (en) 2002-09-04 2007-03-27 Schering Corpoartion Trisubstituted and tetrasubstituted pyrazolopyrimidines as cyclin dependent kinase inhibitors
WO2004022561A1 (en) 2002-09-04 2004-03-18 Schering Corporation Pyrazolopyrimidines as cyclin-dependent kinase inhibitors
US8580782B2 (en) 2002-09-04 2013-11-12 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
RU2357967C2 (en) * 2002-09-16 2009-06-10 Глаксо Груп Лимитед PYRAZOLO[3,4-b]PURIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITION (VERSIONS), APPLICATION (VERSIONS), COMBINATION (VERSIONS)
US7550470B2 (en) * 2002-12-11 2009-06-23 Merck & Co. Inc. Substituted pyrazolo[1,5-A]pyrimidines as tyrosine kinase inhibitors
WO2004052286A2 (en) 2002-12-11 2004-06-24 Merck & Co., Inc. Tyrosine kinase inhibitors
GB0303910D0 (en) 2003-02-20 2003-03-26 Merck Sharp & Dohme Therapeutic agents
US20070037150A1 (en) 2003-02-21 2007-02-15 The Johns Hopkins University Tyrosine kinome
JP2004277337A (en) * 2003-03-14 2004-10-07 Sumitomo Pharmaceut Co Ltd PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE
EP1608652A1 (en) 2003-03-31 2005-12-28 Vernalis (Cambridge) Limited Pyrazolopyrimidine compounds and their use in medicine
WO2004089471A2 (en) 2003-04-11 2004-10-21 Novo Nordisk A/S NEW PYRAZOLO[1,5-a] PYRIMIDINES DERIVATIVES AND PHARMACEUTICAL USE THEREOF
EP1615667A2 (en) 2003-04-11 2006-01-18 Novo Nordisk A/S Combinations of an 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist
US20060094699A1 (en) 2003-04-11 2006-05-04 Kampen Gita Camilla T Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy
CN1795206A (en) 2003-04-28 2006-06-28 株式会社嘉尔药物 Galectin 9-inducing factors
PA8603801A1 (en) * 2003-05-27 2004-12-16 Janssen Pharmaceutica Nv DERIVATIVES OF QUINAZOLINE
JP2005008581A (en) 2003-06-20 2005-01-13 Kissei Pharmaceut Co Ltd NEW PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME AND APPLICATION THEREOF
MEP31508A (en) 2003-07-15 2010-10-10 Amgen Inc Human anti-ngf neutralizing antibodies as selective ngf pathway inhibitors
JP4704342B2 (en) * 2003-09-22 2011-06-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Macrocyclic peptide active against hepatitis C virus
US7491794B2 (en) * 2003-10-14 2009-02-17 Intermune, Inc. Macrocyclic compounds as inhibitors of viral replication
US20090143399A1 (en) 2003-10-14 2009-06-04 Arizona Board Of Regents On Behalf Of The University Of Arizona Protein Kinase Inhibitors
MY141220A (en) 2003-11-17 2010-03-31 Astrazeneca Ab Pyrazole derivatives as inhibitors of receptor tyrosine kinases
EP1687305B1 (en) 2003-11-21 2008-07-09 Novartis AG 1h-imidazoquinoline derivatives as protein kinase inhibitors
CA2546673A1 (en) 2003-11-28 2005-06-09 Novartis Ag Diaryl urea derivatives in the treatment of protein kinase dependent diseases
UA83881C2 (en) * 2003-12-18 2008-08-26 Янссен Фармацевтика Н.В. Pyrido- and pyrimidopyrimidine derivatives as anti-proliferative agents
PT1696920E (en) 2003-12-19 2015-01-14 Plexxikon Inc Compounds and methods for development of ret modulators
GB0330043D0 (en) 2003-12-24 2004-01-28 Pharmacia Italia Spa Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions comprising them
GB0330042D0 (en) 2003-12-24 2004-01-28 Pharmacia Italia Spa Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions them
US20050222171A1 (en) 2004-01-22 2005-10-06 Guido Bold Organic compounds
AR049769A1 (en) 2004-01-22 2006-09-06 Novartis Ag DERIVATIVES OF PIRAZOLO (1,5-A) PIRIMIDIN 7-IL-AMINA TO BE USED IN THE TREATMENT OF DEPENDENT DISEASES OF PROTEIN KINASE
WO2005099363A2 (en) 2004-03-26 2005-10-27 Whitehead Institute For Biomedical Research Methods of diagnosing, preventing and treating cancer metastasis
UA91677C2 (en) * 2004-03-30 2010-08-25 Интермюн, Инк. Macrocyclic compounds as inhibitors of hcv replication
WO2006001310A1 (en) 2004-06-25 2006-01-05 Mitsubishi Materials Corporation Metal colloid particles, metal colloid and use of the colloid
AR050365A1 (en) 2004-08-02 2006-10-18 Osi Pharm Inc INHIBITING COMPOUNDS OF ARIL-AMINO PIRROLOPIRIMIDINE PULROLOPIRIMIDINE REPLACED
PE20060664A1 (en) 2004-09-15 2006-08-04 Novartis Ag BICYCLE AMIDAS AS KINASE INHIBITORS
WO2006050076A1 (en) 2004-10-29 2006-05-11 Janssen Pharmaceutica, N.V. Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders
US20060127982A1 (en) 2004-10-29 2006-06-15 Shih Jason C Development of an asporogenic bacillus licheniformis and production of keratinase therefrom
US7452847B2 (en) 2004-11-02 2008-11-18 Ricoh Company, Ltd. Reversible thermosensitive recording medium, reversible thermosensitive recording label, reversible thermosensitive recording device, image processing apparatus, and image processing method
EP1812440B1 (en) 2004-11-04 2010-09-22 Vertex Pharmaceuticals, Inc. Pyrazolo[1,5-a]pyrimidines useful as inhibitors of protein kinases
JO3088B1 (en) * 2004-12-08 2017-03-15 Janssen Pharmaceutica Nv Macrocyclic Quinazoline derivatives and their use as MTKI
DE102005003687A1 (en) 2005-01-26 2006-07-27 Sphingo Tec Gmbh Immunodiagnostic determination of neurotensin in mammal blood, comprises injecting immune active N-terminal mammal proneurotensin in to the serum- or plasma- sample
GB0501999D0 (en) 2005-02-01 2005-03-09 Sentinel Oncology Ltd Pharmaceutical compounds
CN101119996A (en) 2005-02-16 2008-02-06 阿斯利康(瑞典)有限公司 Chemical compouns
CA2598076A1 (en) 2005-02-16 2006-08-24 Astrazeneca Ab Chemical compounds
CN101257948A (en) 2005-02-18 2008-09-03 阿特努奥恩公司 Pyrimidine-fused diazepine derivatives and indole-fused pteridines
DK1869049T3 (en) 2005-03-21 2009-05-18 Lilly Co Eli Imidazopyridazine compounds
GB0507575D0 (en) 2005-04-14 2005-05-18 Novartis Ag Organic compounds
CA2604787A1 (en) 2005-04-15 2006-10-26 Cylene Pharmaceuticals, Inc. Quinobenzoxazine analogs and methods of using thereof
JP2008540335A (en) 2005-04-27 2008-11-20 アストラゼネカ・アクチエボラーグ Use of pyrazolyl pyrimidine derivatives in the treatment of pain
US20080287437A1 (en) 2005-05-16 2008-11-20 Astrazeneca Ab Pyrazolylaminopyrimidine Derivatives Useful as Tyrosine Kinase Inhibitors
US20100047777A1 (en) 2005-05-26 2010-02-25 The Johns Hopkins University Methods for identifying mutations in coding and non-coding dna
US7541367B2 (en) 2005-05-31 2009-06-02 Janssen Pharmaceutica, N.V. 3-benzoimidazolyl-pyrazolopyridines useful in treating kinase disorders
EP1896462A2 (en) 2005-05-31 2008-03-12 The Pfahl Family Trust (Dated 9 July 1996) Substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases
CN100406650C (en) 2005-06-05 2008-07-30 徐斌 Modular comb type expansion joint installation of girder capable of resisting super displacement
ITRM20050290A1 (en) 2005-06-07 2006-12-08 Lay Line Genomics Spa USE OF MOLECULES ABLE TO INHIBIT THE BOND BETWEEN NGF AND ITS TRKA RECEPTOR AS AN EXTENDED EFFECT ANALGESICS.
RS52010B (en) 2005-06-22 2012-04-30 Plexxikon Inc. Pyrrolo [2, 3-b]pyridine derivatives as protein kinase inhibitors
US20070025540A1 (en) 2005-07-07 2007-02-01 Roger Travis Call center routing based on talkativeness
GB0515026D0 (en) 2005-07-21 2005-08-31 Novartis Ag Organic compounds
EP2305697A3 (en) * 2005-07-25 2011-07-27 Intermune, Inc. Macrocyclic inhibitors of Hepatitis C virus replication
JP2009502734A (en) 2005-07-29 2009-01-29 アステラス製薬株式会社 Fused heterocycles as Lck inhibitors
JP2009503071A (en) 2005-08-03 2009-01-29 イーストマン ケミカル カンパニー Tocopheryl polyethylene glycol succinate powder and method for producing the same
WO2007024680A1 (en) 2005-08-22 2007-03-01 Amgen Inc. Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators
SI1919979T2 (en) 2005-08-25 2017-07-31 Creabilis Therapeutics S.P.A. Polymer conjugates of k-252a and derivatives thereof
WO2007025090A2 (en) 2005-08-25 2007-03-01 Kalypsys, Inc. Heterobicyclic and - tricyclic inhibitors of mapk/erk kinase
DE102005042742A1 (en) 2005-09-02 2007-03-08 Schering Ag Substituted imidazo [1,2b] pyridazines as kinase inhibitors, their production and use as pharmaceuticals
US20070078136A1 (en) 2005-09-22 2007-04-05 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US20070082900A1 (en) 2005-10-06 2007-04-12 Schering Corporation Methods for inhibiting protein kinases
AR057979A1 (en) 2005-10-06 2008-01-09 Schering Corp PIRAZOLPIRIMIDINAS AS INHIBITORS OF PROTEIN QUINASA. PHARMACEUTICAL COMPOSITIONS.
DE602006019323D1 (en) * 2005-10-11 2011-02-10 Intermune Inc COMPOUNDS AND METHOD FOR INHIBITING THE REPLICATION OF THE HEPATITIS C VIRUS
JP5030961B2 (en) 2005-10-11 2012-09-19 サーントゥル ナシオナル ドゥ ラ ルシェルシュ シャーンティフィク Compounds and kits for detection and quantification of cellular apoptosis
WO2007048065A2 (en) 2005-10-21 2007-04-26 Exelixis, Inc. Pyrimidinones as casein kinase ii (ck2) modulators
JP2009519218A (en) 2005-11-03 2009-05-14 エスジーエックス ファーマシューティカルズ、インコーポレイテッド Pyrimidinyl-thiophene kinase modulator
EP1785420A1 (en) 2005-11-14 2007-05-16 4Sc Ag Thiazole analogues and uses thereof
US20070149523A1 (en) 2005-11-14 2007-06-28 Jan Ehlert Thiazole Analogues and Uses Thereof
WO2007057397A1 (en) 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Treatment of cancer
GB0524436D0 (en) 2005-11-30 2006-01-11 Novartis Ag Organic compounds
WO2007065664A2 (en) 2005-12-08 2007-06-14 Novartis Ag Pyrazolo[1,5-a]pyridine-3-carboxylic acids as ephb and vegfr2 kinase inhibitors
WO2007084815A2 (en) 2006-01-19 2007-07-26 Janssen Pharmaceutica, N.V. Substituted thienopyrimidine kinase inhibitors
EP1973910B1 (en) 2006-01-27 2013-06-26 Shanghai Hengrui Pharmaceutical Co. Ltd. Pyrrolo[3,2-c]pyridine-4-one 2-indolinone protein kinase inhibitors
KR100846988B1 (en) 2006-03-06 2008-07-16 제일약품주식회사 Novel thienopyrimidine derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same
AU2007224020A1 (en) 2006-03-07 2007-09-13 Array Biopharma Inc. Heterobicyclic pyrazole compounds and methods of use
EP2001864A1 (en) 2006-03-16 2008-12-17 Novartis Pharma AG Heterocyclic organic compounds for the treatment of in particular melanoma
WO2007109120A2 (en) 2006-03-17 2007-09-27 Ambit Biosciences Corporation Imidazolothiazole compounds for the treatment of disease
GB0606805D0 (en) 2006-04-04 2006-05-17 Novartis Ag Organic compounds
AU2007246793B2 (en) 2006-04-26 2013-02-07 F. Hoffmann-La Roche Ag Thieno [3, 2-D] pyrimidine derivative useful as PI3K inhibitor
RU2008149245A (en) 2006-05-15 2010-06-20 Айрм Ллк (Bm) COMPOSITIONS AND METHODS FOR INHIBITING RECEPTOR KINASES FGF
US7389632B2 (en) 2006-06-10 2008-06-24 Uhlmann Pac-Systeme Gmbh & Co. Kg Apparatus for distributing small objects in a fill station
TWI419889B (en) 2006-07-05 2013-12-21 Mitsubishi Tanabe Pharma Corp A pyrazolo [1,5-a] pyrimidine compound
EP2058309A4 (en) 2006-08-04 2010-12-22 Takeda Pharmaceutical Fused heterocyclic compound
US7531539B2 (en) 2006-08-09 2009-05-12 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
US8063225B2 (en) 2006-08-14 2011-11-22 Chembridge Corporation Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders
US20110021513A1 (en) 2006-09-07 2011-01-27 Biogen Idec Ma Inc. Modulators of interleukin-1 receptor-associated kinase
WO2008031551A2 (en) 2006-09-12 2008-03-20 Novartis Forschungsstiftung, Zweigniederlassung Non-neuroendocrine cancer therapy
WO2008033562A2 (en) 2006-09-15 2008-03-20 Xcovery, Inc. Kinase inhibitor compounds
CA2664378A1 (en) 2006-09-29 2008-04-03 Novartis Ag Pyrazolopyrimidines as pi3k lipid kinase inhibitors
US20120225057A1 (en) 2006-10-11 2012-09-06 Deciphera Pharmaceuticals, Llc Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases
EP1918291A1 (en) 2006-10-30 2008-05-07 Novartis AG 3-Aminocarbonyl-substituted fused pyrazolo-derivatives as protein kinase modulators
CA2667962A1 (en) 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
JP5357763B2 (en) 2006-11-06 2013-12-04 トレロ ファーマシューティカルズ， インコーポレイテッド Imidazo [1,2-b] pyridazine derivatives and pyrazolo [1,5-a] pyridazine derivatives and their use as protein kinase inhibitors
EP3048099A3 (en) 2006-11-15 2016-09-21 YM BioSciences Australia Pty Ltd Inhibitors of kinase activity
US20080199426A1 (en) 2007-01-11 2008-08-21 Sukhatme Vikas P Methods and compositions for the treatment and diagnosis of vascular inflammatory disorders or endothelial cell disorders
WO2008089388A2 (en) 2007-01-19 2008-07-24 Bayer Healthcare Llc Treatment of cancers having resistance to chemotherapeutic agents
CN105254637A (en) * 2007-02-08 2016-01-20 爱尔兰詹森科学公司 Pyrimidine substituted macrocyclic inhibitors
US20080234267A1 (en) 2007-03-20 2008-09-25 Karen Elizabeth Lackey Compounds and Methods of Treatment
US20080234262A1 (en) 2007-03-21 2008-09-25 Wyeth Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors
EP2137187A1 (en) 2007-03-28 2009-12-30 Inovacia AB Pyrazolo [1,5-a]pyrimidines as inhibitors of stearoyl-coa desaturase
WO2008124323A1 (en) 2007-04-03 2008-10-16 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
US20110189167A1 (en) 2007-04-20 2011-08-04 Flynn Daniel L Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases
CN101720322A (en) 2007-05-04 2010-06-02 Irm责任有限公司 Compounds and compositions as c-kit and pdgfr kinase inhibitors
WO2008138184A1 (en) 2007-05-14 2008-11-20 Shanghai Hengrui Pharmaceutical Co.Ltd. Derivatives of pyrroloazacycles, the method of making them and the use thereof as inhibitors of protein kinases
DK2170827T3 (en) * 2007-06-21 2013-11-18 Janssen Pharmaceutica Nv Indoline-2-ones and aza-indoline-2-ones
US20090012045A1 (en) 2007-06-26 2009-01-08 Rigel Pharmaceuticals, Inc. Methods of Treating Cell Proliferative Disorders
WO2009012262A1 (en) 2007-07-16 2009-01-22 The Regents Of The University Of California Protein kinase modulating compounds and methods for making and using them
CA2693901C (en) 2007-07-20 2015-12-29 Nerviano Medical Sciences S.R.L. Substituted indazole derivatives active as kinase inhibitors
WO2009021137A2 (en) 2007-08-07 2009-02-12 Purdue Research Foundation Kinase inhibitors and uses thereof
MX2010001395A (en) 2007-08-10 2010-03-10 Regeneron Pharma High affinity human antibodies to human nerve growth factor.
EP2025678A1 (en) 2007-08-17 2009-02-18 Oncalis AG Pyrazolo[3,4-d]pyrimidine compounds and their use as modulators of protein kinase
WO2009042646A1 (en) 2007-09-24 2009-04-02 Curis, Inc. Anti-proliferative agents
US8129371B2 (en) 2007-10-16 2012-03-06 Wyeth Llc Thienopyrimidine and pyrazolopyrimidine compounds and their use as mTOR kinase and PI3 kinase inhibitors
JP2011501760A (en) 2007-10-23 2011-01-13 ノバルティス アーゲー Use of TRKB antibodies for the treatment of respiratory diseases
EP2217601A1 (en) 2007-11-08 2010-08-18 Centro Nacional de Investigaciones Oncológicas (CNIO) Imidazopyridazines for use as protein kinase inhibitors
JP2011504931A (en) 2007-11-28 2011-02-17 シェーリング コーポレイション 2-Fluoropyrazolo [1,5-a] pyrimidine as a protein kinase inhibitor
CL2009000090A1 (en) 2008-01-17 2009-07-24 Irm Llc Antibody that binds to receptor tyrosine kinase b (trkb); composition comprising the antibody; method of reducing blood glucose levels and / or body weight in an individual.
TW200942537A (en) 2008-02-01 2009-10-16 Irm Llc Compounds and compositions as kinase inhibitors
US20090209496A1 (en) 2008-02-15 2009-08-20 David Chaplin Methods and compositions for enhancing the efficacy of rtk inhibitors
MX2010010272A (en) 2008-03-19 2011-05-25 Chembridge Corp Novel tyrosine kinase inhibitors.
MX2010012457A (en) 2008-05-13 2010-12-07 Irm Llc Fused nitrogen containing heterocycles and compositions thereof as kinase inhibitors.
EP2303890A4 (en) 2008-06-19 2012-04-11 Progenics Pharm Inc Phosphatidylinositol 3 kinase inhibitors
US8629135B2 (en) 2008-07-14 2014-01-14 Queen's University At Kingston Pharmaceutical compositions comprising RET inhibitors and methods for the treatment of cancer
JP5677296B2 (en) 2008-07-29 2015-02-25 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ Use of CDK inhibitors for the treatment of glioma
WO2010028254A2 (en) 2008-09-05 2010-03-11 Auspek Pharmaceuticals, Inc. Substituted quinazoline inhibitors of growth factor receptor tyrosine kinases
EP2161271A1 (en) 2008-09-08 2010-03-10 Università Degli Studi Di Milano - Bicocca Alpha-carboline inhibitors of NMP-ALK, RET, and Bcr-Abl
RS53350B (en) 2008-09-22 2014-10-31 Array Biopharma, Inc. Substituted imidazo[1,2b] pyridazine compounds as trk kinase inhibitors
EP2331530B8 (en) 2008-09-26 2013-12-25 National Health Research Institutes Fused multicyclic compounds as protein kinase inhibitors
CN102271515B (en) 2008-10-31 2014-07-02 健泰科生物技术公司 Pyrazolopyrimidine jak inhibitor compounds and methods
JP5686736B2 (en) 2008-11-06 2015-03-18 アムビト ビオスシエンセス コルポラチオン Imidazolothiazole compounds as protein kinase modulators
JP2012509859A (en) 2008-11-24 2012-04-26 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ CDK inhibitors for the treatment of mesothelioma
KR101061599B1 (en) 2008-12-05 2011-09-02 한국과학기술연구원 Novel indazole derivatives that are protein kinase inhibitors for the treatment of abnormal cell growth diseases, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same as active ingredients
EP3266795A1 (en) 2009-02-12 2018-01-10 Cell Signaling Technology, Inc. Method for detecting a fig-ros fusion polynucleotide
TWI410418B (en) 2009-04-29 2013-10-01 Ind Tech Res Inst Azaazulene compound, pharmaceutical composition, and method of inhibiting the activity of protein kinsae in a cell
MX2011011875A (en) 2009-05-08 2011-12-08 Astellas Pharma Inc Diamino heterocyclic carboxamide compound.
US8765747B2 (en) 2009-06-12 2014-07-01 Dana-Farber Cancer Institute, Inc. Fused 2-aminothiazole compounds
AR077468A1 (en) 2009-07-09 2011-08-31 Array Biopharma Inc PIRAZOLO COMPOUNDS (1,5-A) PYRIMIDINE SUBSTITUTED AS TRK-QUINASA INHIBITORS
KR101256018B1 (en) 2009-08-20 2013-04-18 한국과학기술연구원 1,3,6-Substituted indole derivatives having inhibitory activity for protein kinase
KR101147550B1 (en) 2009-10-22 2012-05-17 한국과학기술연구원 2,7-Substituted thieno[3,2-d]pyrimidine compounds as protein kinase inhibitors
KR101116756B1 (en) 2009-10-27 2012-03-13 한국과학기술연구원 Novel 1,6-disubstituted indole compounds as protein kinase inhibitors
KR101690358B1 (en) 2009-10-29 2017-01-09 제노스코 Kinase inhibitors
MY160820A (en) 2009-11-13 2017-03-31 Genosco Kinase inhibitors
KR101094446B1 (en) 2009-11-19 2011-12-15 한국과학기술연구원 2,4,7-Substituted thieno[3,2-d]pyrimidine compounds as protein kinase inhibitors
US9180127B2 (en) 2009-12-29 2015-11-10 Dana-Farber Cancer Institute, Inc. Type II Raf kinase inhibitors
EP2528925B1 (en) 2010-01-29 2017-07-05 Hanmi Science Co., Ltd. THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON PROTEIN KINASES
KR101483215B1 (en) 2010-01-29 2015-01-16 한미약품 주식회사 Bicyclic heteroaryl derivatives having inhibitory activity for protein kinases
ES2594927T3 (en) 2010-02-18 2016-12-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods to prevent cancerous metastases
CA2795776A1 (en) 2010-04-06 2011-10-13 Caris Life Sciences Luxembourg Holdings, S.A.R.L. Circulating biomarkers for disease
US8383793B2 (en) 2010-04-15 2013-02-26 St. Jude Children's Research Hospital Methods and compositions for the diagnosis and treatment of cancer resistant to anaplastic lymphoma kinase (ALK) kinase inhibitors
TWI619713B (en) 2010-04-21 2018-04-01 普雷辛肯公司 Compounds and methods for kinase modulation, and indications therefor
US8543395B2 (en) 2010-05-18 2013-09-24 Shazam Entertainment Ltd. Methods and systems for performing synchronization of audio with corresponding textual transcriptions and determining confidence values of the synchronization
ES2534335T3 (en) 2010-05-20 2015-04-21 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
ES2910305T3 (en) 2010-08-19 2022-05-12 Zoetis Belgium S A Anti-NGF antibodies and their use
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
UY33597A (en) 2010-09-09 2012-04-30 Irm Llc COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF THE TRK
WO2012037155A2 (en) 2010-09-13 2012-03-22 Gtx, Inc. Tyrosine kinase inhibitors
WO2012047017A2 (en) 2010-10-05 2012-04-12 크리스탈지노믹스(주) 2,3-dihydro-isoindol-1-one derivative and a composition comprising the same
JP6190723B2 (en) 2010-12-01 2017-08-30 アルダーバイオ ホールディングス エルエルシー Anti-NGF compositions and uses thereof
US8618146B2 (en) 2011-01-03 2013-12-31 Dr. Reddy's Laboratories Limited Epothilone compound formulations
CN102093421B (en) 2011-01-28 2014-07-02 北京康辰药业有限公司 Phosphorus substituent group-containing quinoline compound and preparation method of quinoline compound as well as pharmaceutical composition containing quinoline compound and application of pharmaceutical composition
SG192795A1 (en) 2011-02-25 2013-09-30 Irm Llc Compounds and compositions as trk inhibitors
WO2012135631A1 (en) 2011-03-30 2012-10-04 Arrien Pharmaeuticals Llc Substituted 5-(pyrazin-2-yl)-1h-pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-b] pyridine derivatives as protein kinase inhibitors
EP3628665B1 (en) 2011-04-01 2022-11-02 University of Utah Research Foundation Substituted n-phenylpyrimidin-2-amine analogs as inhibitors of the axl kinase
CN108329246B (en) 2011-05-13 2021-02-26 阵列生物制药公司 Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as TRKA kinase inhibitors
RU2477723C2 (en) 2011-06-16 2013-03-20 Общество С Ограниченной Ответственностью "Фьюжн Фарма" Protein kinase inhibitor (versions), use thereof for treating oncological diseases and based pharmaceutical composition
WO2013016720A2 (en) 2011-07-28 2013-01-31 Gerinda Therapeutics, Inc. Novel substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases
US9216172B2 (en) 2011-08-04 2015-12-22 National Cancer Center Method for determining effectiveness of cancer treatment by assessing the presence of a KIF5B-RET chimeric gene
BR112014004213A2 (en) 2011-08-23 2017-06-20 Found Medicine Inc new kif5b-ret fusion molecules and their uses
MX370814B (en) 2011-09-02 2020-01-08 Univ California Substituted pyrazolo[3,4-d]pyrimidines and uses thereof.
WO2013036232A2 (en) 2011-09-08 2013-03-14 Deciphera Pharmaceuticals, Llc Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases
CN102408411B (en) 2011-09-19 2014-10-22 北京康辰药业股份有限公司 Hydroximic acid compound containing quinolyl and preparation method thereof, and drug composition containing the compound and use thereof
WO2013042137A1 (en) 2011-09-19 2013-03-28 Aurigene Discovery Technologies Limited Bicyclic heterocycles as irak4 inhibitors
WO2013059740A1 (en) 2011-10-21 2013-04-25 Foundation Medicine, Inc. Novel alk and ntrk1 fusion molecules and uses thereof
BR112014011465A2 (en) 2011-11-14 2017-05-09 Tesaro Inc modulation of certain tyrosine kinases
BR112014014276A2 (en) 2011-12-12 2017-06-13 Dr Reddys Laboratories Ltd compound, pharmaceutical composition, method for inhibiting a receptor kinase, and methods for treating conditions, diseases and / or disorders, and pain
RS59420B1 (en) 2011-12-30 2019-11-29 Hanmi Pharmaceutical Co Ltd Thieno[3,2-d]pyrimidine derivatives having inhibitory activity for protein kinases
JP2015109806A (en) 2012-03-22 2015-06-18 アステラス製薬株式会社 Method for detecting new ret fused body
JP6160613B2 (en) 2012-04-26 2017-07-12 小野薬品工業株式会社 Trk inhibitory compound
WO2013170159A1 (en) 2012-05-10 2013-11-14 Synta Pharmaceuticals Corp. Treating cancer with hsp90 inhibitory compounds
NZ716487A (en) 2012-05-23 2017-01-27 Nerviano Medical Sciences Srl Process for the preparation of n-[5-(3,5-difluoro-benzyl)-1h-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide
TWI585088B (en) 2012-06-04 2017-06-01 第一三共股份有限公司 Imidazo[1,2-b]pyridazine analogues as kinase inhibitors
EP2878672A4 (en) 2012-07-26 2016-02-17 Nat Cancer Ct Fusion gene of cep55 gene and ret gene
EP2689778A1 (en) 2012-07-27 2014-01-29 Pierre Fabre Medicament Derivatives of azaindoles or diazaindoles for treating pain
JP6223451B2 (en) 2012-08-31 2017-11-01 ザ リージェンツ オブ ザ ユニヴァーシティ オブ コロラド，ア ボディ コーポレイト Cancer diagnosis and treatment methods
ES2726605T3 (en) 2012-09-07 2019-10-08 Exelixis Inc MET, VEGFR and RET inhibitors for use in the treatment of lung adenocarcinoma
US20140084039A1 (en) 2012-09-24 2014-03-27 Electro Scientific Industries, Inc. Method and apparatus for separating workpieces
DK2902029T3 (en) 2012-09-25 2018-10-29 Chugai Pharmaceutical Co Ltd RET INHIBITOR
JP2014082984A (en) 2012-10-23 2014-05-12 Astellas Pharma Inc Method for detecting novel ntrk2 activating mutation
CN108047219A (en) 2012-11-07 2018-05-18 内尔维阿诺医学科学有限公司 Substituted pyrimidine radicals and Pyridylpyrrole and pyridinone, its preparation method and its purposes as kinase inhibitor
MX2015005805A (en) 2012-11-12 2016-04-15 Ignyta Inc Bendamustine derivatives and methods of using same.
WO2014078372A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078331A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
PL2920166T3 (en) 2012-11-13 2017-05-31 Array Biopharma, Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
WO2014078325A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-(monocyclic aryl),n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
CN107857755B (en) 2012-11-13 2020-10-27 阵列生物制药公司 N-pyrrolidinyl, N' -pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TRKA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
RU2015125332A (en) 2012-11-29 2017-01-10 Йеда Ресеарч Энд Девелопмент Ко. Лтд. METHODS FOR PREVENTING TUMOR METASTASIS, TREATMENT AND FORECASTING OF CANCER AND IDENTIFICATION OF AGENTS WHICH ARE PROPOSED METASTASIS INHIBITORS
WO2014086284A1 (en) 2012-12-04 2014-06-12 上海医药集团股份有限公司 Deuterated 3-cyano quinoline compound, pharmaceutical composition, preparation method and use thereof
FR3000494B1 (en) 2012-12-28 2015-08-21 Oribase Pharma NOVEL AZAINDOLE DERIVATIVES AS INHIBITORS OF PROTEIN KINASES
FR3000492B1 (en) 2012-12-28 2015-09-11 Oribase Pharma NOVEL AZAINDOLE DERIVATIVES AS MULTIKINASE INHIBITORS
CA2896711C (en) 2012-12-28 2019-12-31 Crystalgenomics, Inc. 2,3-dihydro-isoindol-1-one derivatives and methods of use thereof as btk inhibitor
FR3000493A1 (en) 2012-12-28 2014-07-04 Oribase Pharma NEW INHIBITORS OF PROTEIN KINASES
US9127055B2 (en) 2013-02-08 2015-09-08 Astellas Pharma Inc. Method of treating pain with anti-human NGF antibody
EP3800183A1 (en) 2013-02-19 2021-04-07 ONO Pharmaceutical Co., Ltd. Urea derivatives as trk-inhibiting compounds
US20160010068A1 (en) 2013-02-22 2016-01-14 Boris C. Bastian Fusion polynucleotides and fusion polypeptides associated with cancer and particularly melanoma and their uses as therapeutic and diagnostic targets
US20140243332A1 (en) 2013-02-27 2014-08-28 Oregon Health & Science University Methods of treating cancers characterized by aberrent ros1 activity
MA38394B1 (en) 2013-03-15 2018-04-30 Glaxosmithkline Ip Dev Ltd Pyridine derivatives used as inhibitors of rearranged kinase during transfection (ret)
KR20150129847A (en) 2013-03-15 2015-11-20 더 트러스티스 오브 컬럼비아 유니버시티 인 더 시티 오브 뉴욕 Fusion proteins and methods thereof
TW201524958A (en) 2013-03-15 2015-07-01 Glaxosmithkline Ip Dev Ltd Novel compounds as rearranged during transfection (RET) inhibitors
WO2014152777A2 (en) 2013-03-15 2014-09-25 Insight Genetics, Inc. Methods and compositions for the diagnosis and treatment of cancers resistant to ros1 inhibitors
EP4253558A1 (en) 2013-03-15 2023-10-04 The Board of Trustees of the Leland Stanford Junior University Identification and use of circulating nucleic acid tumor markers
CN105378110B (en) 2013-04-17 2024-06-25 生命技术公司 Gene fusions and gene variants associated with cancer
RU2656591C2 (en) 2013-07-11 2018-06-06 Бетта Фармасьютикалз Ко., Лтд Protein tyrosine kinase modulators and methods of use
JP6534930B2 (en) 2013-07-26 2019-06-26 公益財団法人がん研究会 Detection method of NTRK3 fusion
EP3027655B1 (en) 2013-07-30 2019-08-21 Blueprint Medicines Corporation Ntrk2 fusions
CN105658814A (en) 2013-08-20 2016-06-08 日本国立癌症研究中心 New fusion gene detected in lung cancer
KR20160055170A (en) 2013-08-30 2016-05-17 암비트 바이오사이언시즈 코포레이션 Biaryl acetamide compounds and methods of use thereof
KR20160065986A (en) 2013-10-24 2016-06-09 조지타운 유니버시티 Methods and compositions for treating cancer
JPWO2015064621A1 (en) 2013-10-29 2017-03-09 公益財団法人がん研究会 Novel fusion and detection method thereof
EP3075236B1 (en) 2013-11-27 2019-04-24 Enplas Corporation Emitter, and tube for drip irrigation
GB201321146D0 (en) 2013-11-29 2014-01-15 Cancer Rec Tech Ltd Quinazoline compounds
US9801880B2 (en) 2013-12-02 2017-10-31 Bergenbio As Use of kinase inhibitors
PT3636649T (en) 2014-01-24 2024-04-09 Turning Point Therapeutics Inc Diaryl macrocycles as modulators of protein kinases
DK3102555T3 (en) 2014-02-05 2021-08-09 VM Oncology LLC COMPOSITIONS OF THE COMPOUNDS AND USES THEREOF
US10501418B2 (en) 2014-02-14 2019-12-10 Exelixis, Inc. Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
US10231965B2 (en) 2014-02-20 2019-03-19 Ignyta, Inc. Molecules for administration to ROS1 mutant cancer cells
HUE045340T2 (en) 2014-05-15 2019-12-30 Array Biopharma Inc 1-((3s,4r)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1h-pyrazol-5-yl)urea as a trka kinase inhibitor
WO2015183837A1 (en) 2014-05-27 2015-12-03 Brian Haynes Compositions, methods, and uses related to ntrk2-tert fusions
US20170114415A1 (en) 2014-05-30 2017-04-27 The Regents Of The University Of Colorado, A Body Corporate Activating ntrk1 gene fusions predictive of kinase inhibitor therapy
CN105222097A (en) 2014-06-26 2016-01-06 欧普照明股份有限公司 A kind of light fixture and optics module thereof
HUE046008T2 (en) 2014-07-17 2020-02-28 Sunshine Lake Pharma Co Ltd 1-(5-(tert.-butyl)isoxazol-3-yl)-3-(4-((phenyl)ethynyl)phenyl)urea derivatives and related compounds as flt3 inhibitors for treating cancer
CN106714804A (en) 2014-08-01 2017-05-24 药品循环有限责任公司 Biomarkers for predicting response of dlbcl to treatment with a btk inhibitor
CN110655502A (en) 2014-08-18 2020-01-07 小野药品工业株式会社 Acid addition salts of Trk inhibiting compounds
US20170283404A1 (en) 2014-09-08 2017-10-05 Glaxosmithkline Intellectual Property Development Limited Crystalline forms of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-n-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide
MX2017003118A (en) 2014-09-10 2018-05-07 Glaxosmithkline Ip Dev Ltd Novel compounds as rearranged during transfection (ret) inhibitors.
UA122213C2 (en) 2014-09-10 2020-10-12 Глаксосмітклайн Інтеллектьюел Проперті Девелопмент Лімітед Pyridone derivatives as rearranged during transfection (ret) kinase inhibitors
TWI538914B (en) 2014-10-03 2016-06-21 國立交通大學 Selective inhibitors for protein kinases, a pharmaceutical composition and an use thereof
BR112017007379A2 (en) 2014-10-14 2017-12-19 Dana Farber Cancer Inst Inc antibody molecules to pd-l1 and uses thereof
FI3699181T3 (en) 2014-11-16 2023-03-28 Array Biopharma Inc Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
KR20240055170A (en) * 2014-12-15 2024-04-26 주식회사 씨엠지제약 Fused ring heteroaryl compounds and their use as trk inhibitors
WO2016096709A1 (en) 2014-12-16 2016-06-23 Eudendron S.R.L. Heterocyclic derivatives modulating activity of certain protein kinases
US10202365B2 (en) 2015-02-06 2019-02-12 Blueprint Medicines Corporation 2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors
KR101675984B1 (en) 2015-02-23 2016-11-14 한양대학교 에리카산학협력단 Thienodiazepine derivatives or pharmaceutically acceptable salt thereof, and pharmaceutical composition comprising the same as an active ingredient
US20180045727A1 (en) 2015-03-03 2018-02-15 Caris Mpi, Inc. Molecular profiling for cancer
CA2980078C (en) 2015-03-16 2024-03-12 Personal Genome Diagnostics Inc. Systems and methods for analyzing nucleic acid
US10364247B2 (en) 2015-04-21 2019-07-30 Ruijin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine Preparation and use of novel protein kinase inhibitors
CN116196401A (en) 2015-05-20 2023-06-02 博德研究所 Consensus neoantigens
CN107849113B (en) 2015-05-29 2022-03-22 亚尼塔公司 Compositions and methods for treating patients with RTK mutant cells
CN107849615A (en) 2015-06-01 2018-03-27 洛克索肿瘤学股份有限公司 Diagnosis and the method for the treatment of cancer
US9782400B2 (en) 2015-06-19 2017-10-10 Macau University Of Science And Technology Oncogenic ROS1 and ALK kinase inhibitor
AU2015101722A4 (en) 2015-06-19 2016-05-19 Macau University Of Science And Technology Oncogenic ros1 and alk kinase inhibitor
GB201511546D0 (en) 2015-07-01 2015-08-12 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers
WO2017004342A1 (en) 2015-07-02 2017-01-05 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
GB201512365D0 (en) 2015-07-15 2015-08-19 King S College London Novel therapy
DK3322706T3 (en) 2015-07-16 2021-02-01 Array Biopharma Inc SUBSTITUTED PYRAZOLO [1,5-A] PYRIDINE COMPOUNDS AS RIGHT CHINESE INHIBITORS
EP3120851A1 (en) 2015-07-21 2017-01-25 Pangaea Biotech S.L. 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)-pyrido[2,3-d]pyrimidin-7(8h)-one for treatment of solid cancers
KR101766194B1 (en) 2015-08-07 2017-08-10 한국과학기술연구원 Novel 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine compounds as RET kinase inhibitor
WO2017027883A1 (en) 2015-08-13 2017-02-16 San Diego State University Research Foundation Atropisomerism for increased kinase inhibitor selectivity
MA41559A (en) 2015-09-08 2017-12-26 Taiho Pharmaceutical Co Ltd CONDENSED PYRIMIDINE COMPOUND OR A SALT THEREOF
WO2017049462A1 (en) 2015-09-22 2017-03-30 合肥中科普瑞昇生物医药科技有限公司 Novel flt3 kinase inhibitor and uses thereof
CN105255927B (en) 2015-09-30 2018-07-27 温州医科大学附属第一医院 A kind of KIAA1217-RET fusions
MX2018005087A (en) 2015-10-26 2019-05-16 Loxo Oncology Inc Point mutations in trk inhibitor-resistant cancer and methods relating to the same.
NZ742351A (en) 2015-11-02 2023-03-31 Blueprint Medicines Corp Inhibitors of ret
WO2017097697A1 (en) 2015-12-08 2017-06-15 Boehringer Ingelheim International Gmbh Method using a ret fusion gene as a biomarker to select non-small cell lung cancer (nsclc) and thyroid cancer patients for a cancer treatment
JP6871869B2 (en) 2016-01-15 2021-05-19 公益財団法人がん研究会 New fusion and its detection method
US20170224662A1 (en) 2016-01-22 2017-08-10 The Medicines Company Aqueous Formulations and Methods of Preparation and Use Thereof
TWI620748B (en) 2016-02-05 2018-04-11 National Health Research Institutes Aminothiazole compounds and use thereof
WO2017145050A1 (en) 2016-02-23 2017-08-31 Glaxosmithkline Intellectual Property Development Limited Pyridylpyridone derivative useful as a ret kinase inhibitor in the treatment of ibs and cancer
MD3269370T2 (en) 2016-02-23 2020-05-31 Taiho Pharmaceutical Co Ltd Novel condensed pyrimidine compound or salt thereof
WO2017155018A1 (en) 2016-03-11 2017-09-14 小野薬品工業株式会社 THERAPEUTIC AGENT FOR Trk INHIBITOR-RESISTANT CANCER
US10183928B2 (en) 2016-03-17 2019-01-22 Blueprint Medicines Corporation Inhibitors of RET
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
JP7061602B2 (en) 2016-04-04 2022-04-28 ロクソ オンコロジー， インコーポレイテッド (S) -N- (5-((R) -2- (2,5-difluorophenyl) -pyrrolidin-1-yl) -pyrazolo [1,5-a] pyrimidin-3-yl) -3-hydroxy Liquid formulation of pyrrolidine-1-carboxamide
BR122023026297A2 (en) 2016-04-15 2024-01-16 Cancer Research Technology Limited HETEROCYCLIC COMPOUND AS RET KINASE INHIBITOR, PHARMACEUTICAL COMPOSITION AND ITS USE
PL3442535T3 (en) 2016-04-15 2022-10-24 Cancer Research Technology Limited Heterocyclic compounds as ret kinase inhibitors
CN109475545A (en) 2016-04-19 2019-03-15 埃克塞里艾克西斯公司 Triple negative breast cancer treatment method
EP3455219A4 (en) 2016-05-10 2019-12-18 C4 Therapeutics, Inc. Amine-linked c3-glutarimide degronimers for target protein degradation
WO2017201156A1 (en) 2016-05-18 2017-11-23 Duke University Method of treating kras wild-type metastatic colorectal cell carcinoma using cabozantinib plus panitumumab
DK3458456T3 (en) 2016-05-18 2020-12-14 Array Biopharma Inc PREPARATION OF (S) -N- (5 - ((R) -2- (2,5-DIFLUOROPHENYL) PYRROLIDIN-1-YL) PYRAZOLE [1,5-A] PYRIMIDIN-3-YL) -3-HYDROXYPYRROLIDIN- 1-CARBOXAMID
US20170349953A1 (en) 2016-06-01 2017-12-07 Roche Sequencing Solutions, Inc. Novel mutations in anaplastic lymphoma kinase predicting response to alk inhibitor therapy in lung cancer patients
US10227329B2 (en) 2016-07-22 2019-03-12 Blueprint Medicines Corporation Compounds useful for treating disorders related to RET
TWI704148B (en) 2016-10-10 2020-09-11 美商亞雷生物製藥股份有限公司 Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
JOP20190092A1 (en) 2016-10-26 2019-04-25 Array Biopharma Inc PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF
IL268138B (en) 2017-01-20 2022-08-01 Exelixis Inc Combinations of cabozantinib and atezolizumab to treat cancer
CN108456163A (en) 2017-02-20 2018-08-28 中国科学院上海药物研究所 Compound and its preparation method and application containing adjacent amino heteroaryl cycloalkynyl radical
JOP20190213A1 (en) 2017-03-16 2019-09-16 Array Biopharma Inc Macrocyclic compounds as ros1 kinase inhibitors
CA3080157A1 (en) 2017-10-26 2019-05-02 Array Biopharma Inc. Formulations of a macrocyclic trk kinase inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1873157A1 (en) * 2006-06-21 2008-01-02 Bayer Schering Pharma Aktiengesellschaft Pyrazolopyrimidines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
WO2010048314A1 (en) * 2008-10-22 2010-04-29 Array Biopharma Inc. SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Non-Patent Citations (47)

* Cited by examiner, † Cited by third party
Title
"Protecting Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC.
BARDELLI, A., SCIENCE, vol. 300, 2003, pages 949
BRODEUR, G. M., NAT. REV. CANCER, vol. 3, 2003, pages 203 - 216
DAVIDSON. B. ET AL., CLIN. CANCER RES., vol. 9, 2003, pages 2248 - 2259
DE MELO-JORGE, M. ET AL., CELL HOST & MICROBE, vol. 1, no. 4, 2007, pages 251 - 261
DELAFOY, L. ET AL., PAIN, vol. 105, 2003, pages 489 - 497
DI MOLA, F. F., GUT, vol. 46, no. 5, 2000, pages 670 - 678
DOU, Y.-C., ARCHIVES OF DERMATOLOGICAL RESEARCH, vol. 298, no. 1, 2006, pages 31 - 37
DU, J. ET AL., WORLD JOURNAL OF GASTROENTEROLOGY, vol. 9, no. 7, 2003, pages 1431 - 1434
EGUCHI, M. ET AL., BLOOD, vol. 93, no. 4, 1999, pages 1355 - 1363
ERIC ADRIAENSSENS, E. ET AL., CANCER RES, vol. 68, no. 2, 2008, pages 346 - 351
EURO. J. MED. CHEM., 2000, pages 147 - 156
EUTHUS, D.M. ET AL., CANCER CELL, vol. 2, no. 5, 2002, pages 347 - 348
EXPERT OPIN. THER. PATENTS, vol. 19, no. 3, 2009
FREUND-MICHEL, V, FROSSARD, N., PHARMACOLOGY & THERAPEUTICS, vol. 117, no. 1, 2008, pages 52 - 76
GRECO, A. ET AL., MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 321, no. 1, 2010, pages 44 - 49
GRUBER-OLIPITZ, M. ET AL., JOURNAL OFPROTEOME RESEARCH, vol. 7, no. 5, 2008, pages 1932 - 1944
GWAK, Y. S. ET AL., NEUROSCI. LETT., vol. 336, 2003, pages 117 - 120
H. IMAMURA ET AL., TETRAHEDRON, vol. 56, 2000, pages 7705
HERZBERG, U. ET AL., NEUROREPORT, vol. 8, 1997, pages 1613 - 1618
HU VIVIAN, Y., THE JOURNAL OF UROLOGY, vol. 173, no. 3, 2005, pages 1016 - 21
JAGGAR, S. I. ET AL., BR. J. ANAESTH., vol. 83, 1999, pages 442 - 448
JIN, W. ET AL., CARCINOGENESIS, vol. 31, no. 11, 2010, pages 1939 - 1947
LAMB, K. ET AL., NEUROGASTROENTEROL. MOTIL., vol. 15, 2003, pages 355 - 361
LI, C.-Q. ET AL., MOLECULAR PAIN, vol. 4, no. 28, 2008, pages 1 - 11
LI, Y.-G. ET AL., CHINESE JOURNAL OF CANCER PREVENTION AND TREATMENT, vol. 16, no. 6, 2009, pages 428 - 430
MA, Q. P., WOOLF, C. J., NEUROREPORT, vol. 8, 1997, pages 807 - 810
MATAYOSHI, S., J. PHYSIOL., vol. 569, 2005, pages 685 - 95
MCMAHON, S. B. ET AL., NAT. MED., vol. 1, 1995, pages 774 - 780
MEYER, J. ET AL., LEUKEMIA, 2007, pages 1 - 10
NAKAGAWARA, A., CANCER LETTERS, vol. 169, 2001, pages 107 - 114
ORG. PROCESS RES. DEV., vol. 7, 2003, pages 533
PATAPOUTIAN, A. ET AL., CURRENT OPINION IN NEUROBIOLOGY, vol. 11, 2001, pages 272 - 280
PIEROTTIA, M.A., GRECO A., CANCER LETTERS, vol. 232, 2006, pages 90 - 98
RAMER, M. S., BISBY, M. A., EUR. J. NEUROSCI., vol. 11, 1999, pages 837 - 846
RAYCHAUDHURI, S. P. ET AL., J. INVESTIGATIVE DERMATOLOGY, vol. 122, no. 3, 2004, pages 812 - 819
RICCI A. ET AL., AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, vol. 25, no. 4, pages 439 - 446
RO, L. S. ET AL., PAIN, vol. 79, 1999, pages 265 - 274
SHELTON, D. L. ET AL., PAIN, vol. 116, 2005, pages 8 - 16
SOHRABJI, F., LEWIS, DANIELLE K., FRONTIERS IN NEUROENDOCRINOLOGY, vol. 27, no. 4, 2006, pages 404 - 414
THEODOSIOU, M. ET AL., PAIN, vol. 81, 1999, pages 245 - 255
THOMPSON, S.W., PROC. NATL. ACAD. SCI. USA, vol. 96, 1999, pages 7714 - 18
TRUZZI, F. ET AL., DERMATO-ENDOCRINOLOGY, vol. 3, no. 1, 2008, pages 32 - 36
WADHWA, S. ET AL., JOURNAL OFBIOSCIENCES, vol. 28, no. 2, 2003, pages 181 - 188
WOOLF, C.J. ET AL., NEUROSCIENCE, vol. 62, 1994, pages 327 - 331
YILMAZ, T. ET AL., CANCER BIOLOGY AND THERAPY, vol. 10, no. 6, 2010, pages 644 - 653
ZAHN, P.K. ET AL., J. PAIN, vol. 5, 2004, pages 157 - 163

Cited By (181)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10011604B2 (en) 2008-09-22 2018-07-03 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US10590139B2 (en) 2008-09-22 2020-03-17 Array Biopharma Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9796723B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9795611B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US10774085B2 (en) 2008-10-22 2020-09-15 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US11267818B2 (en) 2008-10-22 2022-03-08 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10047097B2 (en) 2008-10-22 2018-08-14 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10005783B2 (en) 2008-10-22 2018-06-26 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US9447104B2 (en) 2008-10-22 2016-09-20 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
US9676783B2 (en) 2008-10-22 2017-06-13 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US9682979B2 (en) 2009-07-09 2017-06-20 Array Biopharma, Inc. Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors
US10758542B2 (en) 2009-07-09 2020-09-01 Array Biopharma Inc. Substituted pyrazolo[l,5-a]pyrimidine compounds as Trk kinase inhibitors
US10251889B2 (en) 2009-07-09 2019-04-09 Array BioPharm Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9782415B2 (en) 2009-07-09 2017-10-10 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9796724B2 (en) 2009-07-09 2017-10-24 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9750744B2 (en) 2010-05-20 2017-09-05 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9718822B2 (en) 2010-05-20 2017-08-01 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9493476B2 (en) 2010-05-20 2016-11-15 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9902741B2 (en) 2010-05-20 2018-02-27 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9840519B2 (en) 2010-05-20 2017-12-12 Array Biopharma, Inc. Macrocyclic compounds as TRK kinase inhibitors
US10323022B2 (en) 2011-05-13 2019-06-18 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9878997B2 (en) 2011-05-13 2018-01-30 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
CN104169286A (en) * 2012-03-06 2014-11-26 辉瑞大药厂 Macrocyclic derivatives for the treatment of proliferative diseases
CN104169286B (en) * 2012-03-06 2016-06-08 辉瑞大药厂 Be used for the treatment of the macrocyclic derivatives of proliferative diseases
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10889589B2 (en) 2012-11-13 2021-01-12 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10851080B2 (en) 2012-11-13 2020-12-01 Array Biopharma Inc. Methods of treatment using pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds
US10618912B2 (en) 2014-01-24 2020-04-14 Turning Point Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US10246466B2 (en) 2014-01-24 2019-04-02 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
US10676486B2 (en) 2014-09-17 2020-06-09 Oncodesign S.A. Macrocyclic RIP2 kinase inhibitors
KR102563829B1 (en) 2014-09-17 2023-08-03 온코디자인 에스.에이. Macrocyclic RIP2 kinase inhibitors
KR20170048596A (en) * 2014-09-17 2017-05-08 온코디자인 에스.에이. Macrocyclic RIP2 kinase inhibitors
EA032872B1 (en) * 2014-09-17 2019-07-31 Онкодизайн С.А. Macrocyclic rip2 kinase inhibitors
WO2016042087A1 (en) * 2014-09-17 2016-03-24 Oncodesign S.A. Macrocyclic rip2 kinase inhibitors
US10285993B2 (en) 2014-11-16 2019-05-14 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10813936B2 (en) 2014-11-16 2020-10-27 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-YL)-pyrazolo[1,5-A]pyrimidin-3-YL)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10172861B2 (en) 2014-11-16 2019-01-08 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
EP3699181A1 (en) 2014-11-16 2020-08-26 Array Biopharma, Inc. Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
WO2016077841A1 (en) 2014-11-16 2016-05-19 Array Biopharma, Inc. Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10799505B2 (en) 2014-11-16 2020-10-13 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10472377B2 (en) 2014-12-04 2019-11-12 Shin-Etsu Chemical Co., Ltd. Method for producing polyalkylene glycol derivative having amino group at end, polymerization initiator for use in the same, and alcohol compound as raw material for the polymerization initiator
US10550136B2 (en) 2014-12-04 2020-02-04 Shin-Etsu Chemical Co., Ltd. Method for producing polyalkylene glycol derivative having amino group at end
US10377775B2 (en) 2014-12-04 2019-08-13 Shin-Etsu Chemical Co., Ltd. Method for producing polyalkylene glycol derivative having amino group at end
US11066430B2 (en) 2014-12-04 2021-07-20 Shin-Etsu Chemical Co., Ltd. Method for producing polyalkylene glycol derivative having amino group at end
RU2708674C2 (en) * 2014-12-15 2019-12-11 СиЭмДжи ФАРМАСЬЮТИКАЛ КО., ЛТД. Condensed ring heteroaryl compounds and use thereof as trk inhibitors
AU2015365587B2 (en) * 2014-12-15 2020-07-23 Cmg Pharmaceutical Co., Ltd. Fused ring heteroaryl compounds and their use as TRK inhibitors
US9701681B2 (en) 2014-12-15 2017-07-11 Cmg Pharmaceutical Co., Ltd. Fused ring heteroaryl compounds and their use as Trk inhibitors
CN107207514A (en) * 2014-12-15 2017-09-26 康联制药有限公司 Fused ring heteroaryl compound and its purposes as TRK inhibitor
WO2016097869A1 (en) 2014-12-15 2016-06-23 Cmg Pharmaceutical Co., Ltd. Fused ring heteroaryl compounds and their use as trk inhibitors
WO2016196671A1 (en) 2015-06-01 2016-12-08 Loxo Oncology, Inc. Methods of diagnosing and treating cancer
EP3722441A1 (en) 2015-06-01 2020-10-14 Loxo Oncology Inc. Method of diagnosing a cancer for a treatment with a trk inhibitor
US11008337B2 (en) 2015-07-02 2021-05-18 Turning Point Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
RU2732405C2 (en) * 2015-07-02 2020-09-16 Тёрнинг Поинт Терапьютикс, Инк. Chiral diaryl macrocycles as modulators of protein kinases
EP3317285A4 (en) * 2015-07-02 2019-02-27 TP Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
US10316044B2 (en) 2015-07-02 2019-06-11 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
CN108026108B (en) * 2015-07-06 2021-06-22 特普医药公司 Diaryl macrocyclic polymorphs
CN108026108A (en) * 2015-07-06 2018-05-11 Tp生物医药公司 diaryl macrocyclic polymorphs
US10294242B2 (en) 2015-07-06 2019-05-21 Tp Therapeutics, Inc. Diaryl macrocycle polymorph
WO2017011776A1 (en) 2015-07-16 2017-01-19 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10174027B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10174028B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10138243B2 (en) 2015-07-16 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11452725B2 (en) 2015-07-21 2022-09-27 Turning Point Therapeutics, Inc. Chiral diaryl macrocycles and uses thereof
US10981931B2 (en) 2015-09-24 2021-04-20 Cyclenium Pharma Inc. Libraries of heteroaryl-containing macrocyclic compounds and methods of making and using the same
US10907215B2 (en) 2015-10-26 2021-02-02 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10655186B2 (en) 2015-10-26 2020-05-19 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
RU2744852C2 (en) * 2015-10-26 2021-03-16 Локсо Онколоджи, Инк. Point mutations in trk inhibitor-resistant malignant tumors and related methods
US10724102B2 (en) 2015-10-26 2020-07-28 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10378068B2 (en) 2015-10-26 2019-08-13 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10370727B2 (en) 2015-10-26 2019-08-06 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
WO2017075107A1 (en) 2015-10-26 2017-05-04 Nanda Nisha Point mutations in trk inhibitor-resistant cancer and methods relating to the same
WO2017176751A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10668072B2 (en) 2016-04-04 2020-06-02 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US11484535B2 (en) 2016-04-04 2022-11-01 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10588908B2 (en) 2016-04-04 2020-03-17 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10137127B2 (en) 2016-04-04 2018-11-27 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US11191766B2 (en) 2016-04-04 2021-12-07 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2017176744A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US10689400B2 (en) 2016-07-28 2020-06-23 Turning Point Therapeutics, Inc. Macrocycle kinase inhibitors
WO2018071454A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US11648243B2 (en) 2016-10-10 2023-05-16 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172851B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018071447A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
EP4144735A1 (en) 2016-10-10 2023-03-08 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10881652B2 (en) 2016-10-10 2021-01-05 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10953005B1 (en) 2016-10-10 2021-03-23 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10441581B2 (en) 2016-10-10 2019-10-15 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
EP3753939A1 (en) 2016-10-10 2020-12-23 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10137124B2 (en) 2016-10-10 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US11998545B2 (en) 2016-10-10 2024-06-04 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172845B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10555944B2 (en) 2016-10-10 2020-02-11 Eli Lilly And Company Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
WO2018081417A3 (en) * 2016-10-26 2018-06-07 Qian Zhao PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF
AU2017348259B2 (en) * 2016-10-26 2021-12-02 Array Biopharma Inc. Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US11168090B2 (en) 2017-01-18 2021-11-09 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors
US11851434B2 (en) 2017-01-18 2023-12-26 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyrazine compounds as ret kinase inhibitors
US11291667B2 (en) 2017-01-25 2022-04-05 Turning Point Therapeutics, Inc. Combination therapy involving diaryl macrocyclic compounds
WO2018170381A1 (en) 2017-03-16 2018-09-20 Andrews Steven W Macrocyclic compounds as ros1 kinase inhibitors
CN110769820A (en) * 2017-03-16 2020-02-07 阿雷生物药品公司 Macrocyclic compounds as ROS1 kinase inhibitors
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
EP3642399A4 (en) * 2017-06-22 2020-10-14 Cyclenium Pharma Inc. Libraries of pyridine-containing macrocyclic compounds and methods of making and using the same
WO2019005796A1 (en) 2017-06-26 2019-01-03 Qian Zhao PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF
US11286264B2 (en) 2017-07-28 2022-03-29 Turning Point Therapeutics, Inc. Macrocyclic compounds and uses thereof
US11155563B2 (en) 2017-07-28 2021-10-26 Turning Point Therapeutics, Inc. Macrocyclic compounds and uses thereof
US11981684B2 (en) 2017-07-28 2024-05-14 Turning Point Therapeutics, Inc. Macrocyclic compounds and uses thereof
RU2779497C2 (en) * 2017-08-23 2022-09-08 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Macrocycle containing aminopyrazole and pyrimidine, and its pharmaceutical composition and use
AU2018320021B2 (en) * 2017-08-23 2022-04-21 Centaurus Biopharma Co., Ltd. Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
JP2021501738A (en) * 2017-08-23 2021-01-21 正大天晴▲藥▼▲業▼集▲団▼股▲フン▼有限公司 Aminopyrazolopyrimidine-containing macrocycles and their pharmaceutical compositions, as well as their use
JP7239563B2 (en) 2017-08-23 2023-03-14 正大天晴▲藥▼▲業▼集▲団▼股▲フン▼有限公司 Aminopyrazolopyrimidine-containing macrocycles, pharmaceutical compositions thereof, and uses thereof
US11098060B2 (en) 2017-08-23 2021-08-24 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
WO2019037761A1 (en) 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
AU2018320021C1 (en) * 2017-08-23 2023-02-23 Centaurus Biopharma Co., Ltd. Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T Crystalline forms
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
US20190247398A1 (en) * 2017-10-26 2019-08-15 Array Biopharma Inc. Formulations of a macrocyclic trk kinase inhibitor
WO2019084285A1 (en) 2017-10-26 2019-05-02 Qian Zhao Formulations of a macrocyclic trk kinase inhibitor
AU2018364938B2 (en) * 2017-11-10 2021-11-11 Angex Pharmaceutical, Inc. Macrocyclic compounds as TRK kinase inhibitors and uses thereof
US11098046B2 (en) 2017-11-10 2021-08-24 Angex Pharmaceutical, Inc. Macrocyclic compounds as TRK kinase inhibitors and uses thereof
EP3706749A4 (en) * 2017-11-10 2021-03-03 Angex Pharmaceutical, Inc. Macrocyclic compounds as trk kinase inhibitors and uses thereof
US10745416B2 (en) 2017-12-19 2020-08-18 Turning Point Therapeutics, Inc. Macrocyclic compounds for treating disease
US11286265B2 (en) 2017-12-19 2022-03-29 Turning Point Therapeutics, Inc. Macrocyclic compounds for treating disease
US11453672B2 (en) 2017-12-22 2022-09-27 Shenzhen Targetrx, Inc. Substituted pyrazolo[1,5-a]pyrimidines as tropomyosin receptor kinase inhibitors
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
US11603374B2 (en) 2018-01-18 2023-03-14 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
US11472802B2 (en) 2018-01-18 2022-10-18 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
US11345703B2 (en) 2018-01-23 2022-05-31 Shenzhen Targetrx, Inc. Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound
EP3744723A4 (en) * 2018-01-23 2021-05-19 Shenzhen TargetRx, Inc. Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound
EP3760632A4 (en) * 2018-02-28 2021-04-28 Simcere Pharmaceutical Co. Ltd. Pyrazolopyrimidine derivative and use thereof
US11464780B2 (en) 2018-02-28 2022-10-11 Simcere Pharmaceutical Co. Ltd. Pyrazolopyrimidine derivative and use thereof
US11555042B2 (en) 2018-03-28 2023-01-17 Fochon Biosciences, Ltd. Macrocyclic compounds as TRK kinases inhibitors
WO2019184955A1 (en) * 2018-03-28 2019-10-03 Fochon Pharmaceuticals, Ltd. Macrocyclic compounds as trk kinases inhibitors
WO2019191659A1 (en) 2018-03-29 2019-10-03 Loxo Oncology, Inc. Treatment of trk-associated cancers
EP3770161A4 (en) * 2018-04-16 2021-04-28 Shenzhen TargetRx, Inc. Di(hetero)aryl macrocyclic compound for inhibiting protein kinase activity
EP3786167A4 (en) * 2018-04-25 2021-06-09 Primegene (Beijing) Co., Ltd. Diaryl macrocyclic compound and pharmaceutical composition, and use thereof
US11597729B2 (en) 2018-06-08 2023-03-07 Jiangsu Vcare Pharmatech Co., Ltd. Tropomyosin receptor kinase inhibitor, preparation method therefor and use thereof
US11878987B2 (en) 2018-06-25 2024-01-23 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compound as TRK inhibitor
RU2803817C2 (en) * 2018-06-25 2023-09-20 Бэйджинг Иннокэйр Фарма Тек Ко., Лтд. Heterocyclic compounds as trk inhibitors
AU2019296085B2 (en) * 2018-06-25 2024-02-15 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compound as TRK inhibitor
EP3822276A4 (en) * 2018-06-25 2022-04-06 Beijing InnoCare Pharma Tech Co., Ltd. Heterocyclic compound as trk inhibitor
WO2020028258A1 (en) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Spray-dried dispersions and formulations of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1h-pyrazole-4-carboxamide
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
US11964988B2 (en) 2018-09-10 2024-04-23 Array Biopharma Inc. Fused heterocyclic compounds as RET kinase inhibitors
WO2020063965A1 (en) * 2018-09-29 2020-04-02 南京明德新药研发有限公司 Pyrazolopyrimidine derivative as selective trk inhibitor
EP3858834A4 (en) * 2018-09-29 2022-06-22 Shandong Luye Pharmaceutical Co., Ltd. Pyrazolopyrimidine derivative as selective trk inhibitor
WO2020094112A1 (en) 2018-11-09 2020-05-14 山东轩竹医药科技有限公司 Macrocyclic tyrosine kinase inhibitor and uses thereof
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
WO2020187291A1 (en) 2019-03-19 2020-09-24 华中师范大学 Pyrazolopyrimidine compound, pharmaceutical composition, and application therefor
EP4023648A4 (en) * 2019-08-28 2023-09-27 Simcere Pharmaceutical Co. Ltd. Crystal of carcinogenic fused kinase inhibitor and applications thereof
WO2021083345A1 (en) * 2019-10-30 2021-05-06 先声药业有限公司 Preparation method for pyrazolopyrimidine compound and intermediate thereof
EP4074715A4 (en) * 2019-12-13 2023-12-20 Scinnohub Pharmaceutical Co., Ltd Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
WO2021115401A1 (en) 2019-12-13 2021-06-17 成都倍特药业股份有限公司 Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
WO2021223748A1 (en) 2020-05-08 2021-11-11 山东轩竹医药科技有限公司 Crystal form of macrocyclic tyrosine kinase inhibitor and preparation method therefor
WO2022052925A1 (en) * 2020-09-10 2022-03-17 上海希迈医药科技有限公司 Repotrectinib crystal form and preparation method therefor
WO2023025141A1 (en) * 2021-08-23 2023-03-02 正大天晴药业集团股份有限公司 Use of macrocyclic compound containing amino in treatment of trk kinase-mediated tumors
CN113582994B (en) * 2021-09-28 2022-02-11 北京鑫开元医药科技有限公司 Compound with TRK kinase inhibitory activity, preparation method, composition and application thereof
CN113582994A (en) * 2021-09-28 2021-11-02 北京鑫开元医药科技有限公司 Compound with TRK kinase inhibitory activity, preparation method, composition and application thereof

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