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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English (en)
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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Array Biopharma Inc
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Priority to MX2012013467A priority Critical patent/MX2012013467A/es
Priority to SG2012084844A priority patent/SG185644A1/en
Priority to US13/698,922 priority patent/US8933084B2/en
Priority to EP18208279.2A priority patent/EP3521291A1/en
Priority to HK13108950.6A priority patent/HK1181756B/en
Priority to KR1020187011138A priority patent/KR102015402B1/ko
Priority to MYPI2012700967A priority patent/MY191934A/en
Priority to KR1020127033226A priority patent/KR101852169B1/ko
Priority to BR112012029405-9A priority patent/BR112012029405B1/pt
Priority to EP11728970.2A priority patent/EP2571883B1/en
Priority to EP17163978.4A priority patent/EP3205654B1/en
Priority to KR1020207019372A priority patent/KR20200085364A/ko
Priority to CA2800079A priority patent/CA2800079C/en
Priority to PL17163978T priority patent/PL3205654T3/pl
Priority to UAA201214588A priority patent/UA110701C2/uk
Priority to RU2012155278/04A priority patent/RU2594742C2/ru
Priority to BR122019024201-1A priority patent/BR122019024201B1/pt
Priority to MX2019000835A priority patent/MX382699B/es
Priority to KR1020197024602A priority patent/KR102132405B1/ko
Priority to CN201180025013.9A priority patent/CN102971322B/zh
Priority to CR20170098A priority patent/CR20170098A/es
Priority to MX2014013626A priority patent/MX365251B/es
Priority to ES11728970.2T priority patent/ES2534335T3/es
Application filed by Array Biopharma Inc filed Critical Array Biopharma Inc
Priority to NZ604708A priority patent/NZ604708A/en
Priority to JP2013511239A priority patent/JP5832527B2/ja
Priority to MX2019006154A priority patent/MX383400B/es
Priority to PH1/2012/502276A priority patent/PH12012502276A1/en
Priority to AU2011256380A priority patent/AU2011256380C1/en
Publication of WO2011146336A1 publication Critical patent/WO2011146336A1/en
Priority to IL223094A priority patent/IL223094B/en
Anticipated expiration legal-status Critical
Priority to US14/575,663 priority patent/US9493476B2/en
Priority to PH12015500190A priority patent/PH12015500190A1/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/el
Priority to US16/818,125 priority patent/US20200291026A1/en
Priority to AU2020205339A priority patent/AU2020205339A1/en
Ceased legal-status Critical Current

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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
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    • 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
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    • 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
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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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    • 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
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    • 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
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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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