WO2014078331A1 - N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors - Google Patents

N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors Download PDF

Info

Publication number
WO2014078331A1
WO2014078331A1 PCT/US2013/069750 US2013069750W WO2014078331A1 WO 2014078331 A1 WO2014078331 A1 WO 2014078331A1 US 2013069750 W US2013069750 W US 2013069750W WO 2014078331 A1 WO2014078331 A1 WO 2014078331A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
optionally substituted
formula
ring
Prior art date
Application number
PCT/US2013/069750
Other languages
French (fr)
Inventor
James F. Blake
Barbara J. Brandhuber
Julia Haas
Brad Newhouse
Allen A. Thomas
Shannon L. Winski
Original Assignee
Array Biopharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Array Biopharma Inc. filed Critical Array Biopharma Inc.
Priority to US14/442,576 priority Critical patent/US9969694B2/en
Publication of WO2014078331A1 publication Critical patent/WO2014078331A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present 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 arylalkyl and heteroarylalkyl urea, thiourea , guanidine and cyanoguanidine compounds which exhibit TrkA kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.
  • the current treatment regimens 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 the 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.
  • TrkA kinase may serve as a mediator of NGF driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide an effective treatment for chronic pain states.
  • 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.
  • 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 TrkA.
  • 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) 117(1), 52-76), interstitial cystitis (Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016-21), bladder pain syndrome (Liu, H.-T., et al, (2010) BJU International, 106 (11), pp.
  • inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Di Mola, F. F, et. al., Gut (2000) 46(5), 670-678) and inflammatory skin diseases such as atopic dermatitis (Dou, Y.-C, et. al. Archives of Dermatological Research (2006) 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S. P., et al., J Investigative Dermatology (2004) 122(3), 812-819).
  • TrkA receptor is also thought to be critical to the disease process 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 inhibitors may also find use in treating disease related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • Bone metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer and in approximately 15 to 30 percent of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney.
  • Osteolytic metastases can cause severe pain, pathologic fractures, life- threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. For these reasons, bone metastasis is a serious and costly complication of cancer.
  • TrkA receptors have been observed in the bone-forming area in mouse models of bone fracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). In addition, localization of NGF was observed in almost all bone-forming cells (K. Asaumi, et al.). Recently, it was demonstrated that a Trk inhibitor inhibits the signaling activated by neurotrophins binding to all three of the Trk receptors in human hFOB osteoblasts (J. Pinski, et al., (2002) 62, 986-989). These data support the rationale for the use of Trk inhibitors for the treatment of bone remodeling diseases, such as bone metastases in cancer patients.
  • Trk inhibitors may also find use in treating diseases and disorders such as
  • Trk kinases 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), 305-319).
  • pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds are inhibitors of TrkA, and useful for treating disorders and diseases such as pain, including chronic and acute pain.
  • Compounds of the invention useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.
  • compounds of the invention are useful for treating cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • Another aspect of the present invention provides methods of treating a disease or disorder modulated by TrkA, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.
  • the disease and disorders include chronic and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.
  • the disease and disorders include, but are not limited to, cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • the treatment includes treating the mammal with a compound of this invention in combination with an additional therapeutic agent.
  • Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides the compounds of the present invention for use in therapy.
  • Another aspect of the present invention provides the compounds of the present invention for use in the treatment of disease and disorders such as chronic and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.
  • Another aspect of the present invention provides the compounds of the present invention for use in the treatment of disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of disease and disorders such as chronic and acute pain including, but not limited to, inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.
  • Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • Another aspect of the present invention provides intermediates for preparing compounds of Formula I.
  • Another aspect of the present invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention.
  • a representative compound of the invention (See Table B below), was found to be highly selective for TrkA over a panel of about 230 other kinases at 10 ⁇ concentration.
  • compounds of the invention such as those shown in Table A below, were found to be at least 1000 fold more selective for TrkA versus p38a.
  • X is O, S, NH or N-CN
  • Ring A is formula A- 1 or A-2
  • n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A is formula A-
  • G 1 , G 2 and G 3 are independently CR X or N, wherein no more than 2 of G 1 , G 2 and G can be N;
  • each R x is independently H, halogen, ( 1 -4C)alkyl or ( 1 -4C)alkoxy;
  • R 1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH 3 CH 2 NR y , CF 3 CH 2 NR y , HCF 2 CH 2 NR y , H 2 CFCH 2 NR y , CH 3 NR y CH 2
  • each R y is independently H or methyl
  • R 2 is selected from the group consisting of H, halogen, (1-
  • 6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH 2 0-, amino(l-3C)alkyl, CF 3 CH 2 NHCH 2 , HCF 2 CH 2 NHCH 2 , a C5-C8 bridged cycloalkyl, hetCyc 3 , hetCyc a CH 2 , Cyc a , hetAr 1 and Ar 1 , and
  • R 2 is selected from the group consisting of H, halogen, CF 3 ,
  • hetCyc a is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1 -3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
  • Cyc a is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1-
  • hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
  • R a is H, (1 -3C)alkyl, cyclopropyl,cyclobutyl, or CF 3 , and
  • R b is H, methyl or ethyl
  • R c is H, methyl or ethyl
  • R d is CF 3 CH 2 CH 2 , phenyl or phenylCH 2 - wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl;
  • Ring C is formula C- 1 or C-2
  • R 3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar 2 , hetCyc 1 , (3-7C)cycloalkyl, a C5-
  • Ar 2 is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
  • hetCyc 1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
  • hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (l-6C)alkoxy,
  • hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo;
  • hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
  • hetCyc 4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • Cyc 1 is a 3-6 membered carbocycle optionally substituted with an amino group
  • hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
  • Ar 3 is phenyl optionally substituted with (l-4C)alkoxy
  • hetAr 5 is a group selected from the structures:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
  • R 5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
  • R 3a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 5a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • compounds of Formula I include compounds of Formula
  • X is O, S, NH or N-CN
  • Rin A is formula A-l or A-2
  • n is 0 or 1 when Ring A is formula A-l, and n is 0 when Ring A is formula A-
  • G 1 , G 2 and G 3 are independently CR X or N, wherein no more than 2 of G 1 , G 2 and G can be N;
  • each R x is independently H, halogen, ( 1 -4C)alkyl or ( 1 -4C)alkoxy;
  • R 1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH 3 CH 2 NR y , CF 3 CH 2 NR y , HCF 2 CH 2 NR y , H 2 CFCH 2 NR y , CH 3 NR y CH 2
  • each R y is independently H or methyl
  • R 2 is selected from the group consisting of H, halogen, (1-
  • 6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH 2 0-, amino(l-3C)alkyl, CF 3 CH 2 NHCH 2 , HCF 2 CH 2 NHCH 2 , a C5-C8 bridged cycloalkyl, hetCyc 3 , hetCyc a CH 2 , Cyc a , hetAr 1 and Ar 1 , and
  • R is selected from the group consisting of H, halogen, CF 3 ,
  • hetCyc 3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
  • Cyc a is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1-
  • hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
  • R a is H, (l-3C)alkyl, cyclopropyl or cyclobutyl, and
  • R b is H, methyl or ethyl
  • R° is H, methyl or ethyl
  • R d is CF 3 CH 2 CH 2 , phenyl or phenylCH 2 - wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen and methoxy;
  • Ring C is formula C- 1 or C-2
  • R 3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar 2 , hetCyc 1 , (3-7C)cycloalkyl, a C5-
  • Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
  • hetCyc 1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
  • hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, (1-3 C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (l-6C)alkoxy, monofluoro(
  • hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
  • hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
  • Ar is phenyl optionally substituted with (l-4C)alkoxy
  • hetAr 5 is a group selected from the structures:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
  • R 3a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 5a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • compounds of Formula I include compounds of Formula I-B
  • X is O, S, NH or N-CN
  • Rin A is formula A-l or A-2
  • n is 0 or 1 when Ring A is formula A-l, and n is 0 when Ring A is formula A-
  • G 1 , G 2 and G 3 are independently CR X or N, wherein no more than 2 of G 1 , G 2 and G can be N;
  • each R x is independently H, halogen, (l-4C)alkyl or (l-4C)alkoxy;
  • R 1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH 3 CH 2 NR y , CF 3 CH 2 NR y
  • each R y is independently H or methyl
  • R is selected from the group consisting of H, halogen, (1- 6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH 2 0-, amino(l-3C)alkyl, CF 3 CH 2 NHCH 2 , HCF 2 CH 2 NHCH 2 , a C5-C8 bridged cycloalkyl, hetCyc 3 , hetCyc a CH 2 , Cyc a , hetAr 1 and Ar 1 , and
  • R is selected from the group consisting of H, halogen, CF 3 , F 2 CH, FCH 2 , methyl and methoxy.
  • hetCyc 3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
  • Cyc a is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1- 4C)alkyl, F or OH;
  • hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
  • R a is H, (l-3C)alkyl, cyclopropyl or cyclobutyl, and
  • R b is H, methyl or ethyl
  • R a and R b together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl ring;
  • R c is H, methyl or ethyl
  • R d is CF 3 CH 2 CH 2 , phenyl or phenylCH 2 - wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen and methoxy;
  • Ring C is formula C-1 or C-2
  • R 3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar 2 , hetCyc 1 , (3-7C)cycloalkyl, a C5- C8 bridged cycloalkyl, or hetAr 2 ;
  • Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
  • hetCyc 1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
  • hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (l-6C)alkoxy,
  • hetCyc 2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkylcarboxy)(l-6C)alkyl, and (l-6C)acyl;
  • hetCyc 3 is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
  • hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
  • Ar is phenyl optionally substituted with (l-4C)alkoxy
  • hetAr 5 is a group selected from the structures:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
  • R 3a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • compounds of Formula I include compounds of Formula I-C
  • X is O, S, NH or N-CN
  • Rin A is formula A-1 or A-2
  • n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A is formula A-
  • G 1 , G 2 and G 3 are independently CR X or N, wherein no more than 2 of G 1 , G 2 and G can be N;
  • each R x is independently H, halogen, ( 1 -4C)alkyl or ( 1 -4C)alkoxy;
  • R 1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH 3 CH 2 NR y , CF 3 CH 2 NR y , HCF 2 CH 2 NR y , H 2 CFCH 2 NR y , CH 3 NR y CH 2
  • each R y is independently H or methyl
  • R 2 is selected from the group consisting of H, halogen, (1- 6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH 2 0-, amino(l-3C)alkyl, CF 3 CH 2 NHCH 2 , HCF 2 CH 2 NHCH 2 , a C5-C8 bridged cycloalkyl, hetCyc 3 , hetCyc a CH 2 , Cyc a , hetAr 1 and Ar 1 , and
  • R 2 is selected from the group consisting of H, halogen, CF 3 , F 2 CH, FCH 2 , methyl and methoxy.
  • hetCyc 3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
  • Cyc a is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1- 4C)alkyl, F or OH;
  • hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl;
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
  • R a is H, (1 -3C)alkyl, cyclopropyl, cyclobutyl, or CF 3 , and
  • R b is H, methyl or ethyl
  • R a and R b together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl ring; [00169] R c is H, methyl or ethyl
  • R d is CF 3 CH 2 CH 2 , phenyl or phenylCH 2 - wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl;
  • Ring C is formula C-1 or C-2
  • R 3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar 2 , hetCyc 1 , (3-7C)cycloalkyl, a C5- C8 bridged cycloalkyl, or hetAr 2 ;
  • Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
  • hetCyc 1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
  • hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 4 is OH, (l-6C)alk l, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, (1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (l-6C)alkoxy,
  • hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo;
  • hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
  • hetCyc 4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • Cyc 1 is a 3-6 membered carbocycle optionally substituted with an amino group
  • hetAr is a 5 -membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
  • Ar is phenyl optionally substituted with (l-4C)alkoxy
  • hetAr is a group selected from the structures:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
  • R 3a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
  • R 5a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • M (l-6C)alkyl refers to saturated linear monovalent hydrocarbon radicals of one to six carbon atoms, one to four carbon atoms, and one to three carbon atoms, respectively, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, three to four carbon atoms, or three carbon atoms, respectively.
  • Examples include, but are not limited to, methyl, ethyl, 1- propyl, 2-propyl, 1 -butyl, 2-methyl-l -propyl, 2-butyl, 2-methyl-2 -propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l -butyl, 2-methyl- 1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.
  • (l-4C)Alkoxy refers to an -OR radical where R is (l-4C)alkyl, (l-3C)alkyl, (l-6C)alkyl, or (2-6C)alkyl, respectively, as defined above. Examples include methoxy, ethoxy, and the like.
  • (1-3C Alkoxy)(l-6C)alkyl and "(1-3C alkoxy)(l-4C)alkyl” mean a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms or three to four carbon atoms, respectively, wherein one of the carbon atoms is substituted with one (l-3C)alkoxy group as defined herein.
  • (1-3C Alkoxy)(l-6C)alkoxy means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a (l-3C)alkoxy group as defined herein. Examples include methoxymethoxy, methoxyethoxy, and the like.
  • (1-3C Alkoxy)hydroxycarbonylalkyl means a hydroxycarbonylalkyl group as defined herein wherein one of the carbon atoms is substituted with one (1-3C alkoxy) group.
  • Amino means a -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein. Examples include H 2 N-, CH 3 NH-, (CH 3 ) 2 N, and the like.
  • Amino(l-6C)alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, wherein one of the carbon atoms is substituted with one -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein. Examples include aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, and the like.
  • Amino(2-6C)alkoxy means a (2-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with one -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein.
  • Aminocarbonyl means a RR"NCO- radical where R and R' are independently hydrogen or (l-6C)alkyl as defined herein. Examples include H 2 NCO-, dimethylaminocarbonyl, and the like.
  • Aminocarbonyl(l-6C)alkyl means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons wherein one of the carbon atoms is substituted with one aminocarbonyl group as defined herein, e.g., 2-aminocarbonylethyl, 1-, 2-, or 3-dimethylaminocarbonylpropyl, and the like.
  • aminocarbonyl(l-6C)alkoxy means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one aminocarbonyl group as defined herein.
  • Aminohydroxy(l-6C)alkoxy means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one amino group as defined herein, and one of the carbon atoms (other than the carbon atom substituted with the amino group) is substituted with one OH group.
  • (1-4C alkylsiloxy)(l-6C)alkoxy means a (l-6C)alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1-4C alkyl)siloxy group, e.g., a (1-4C alkyl)Si-0- group such as a tert-butylsiloxy group.
  • (l-3C)Alkylsulfonamido means a (l-3C)alkylS0 2 NH- radical where (1- 3C)alkyl is as defined herein
  • (1-3C Alkylsulfonamido)(l-6C)alkyl means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one (l-3C)alkylsulfonamido group as defined herein.
  • (l-3C)Alkylsulfonamido(l-6C)alkoxy means a (l -6C)alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1- 3C)alkylsulfonamido group as defined herein.
  • (l-3C)Alkylsulfonyl means a -S0 2 R radical where R is (l-3C)alkyl as defined above, e.g., methylsulfonyl, and the like.
  • (1-3C Alkylsulfonyl)(l-6C)alkoxy means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a (l-3C)alkylsulfonyl group.
  • (1-4C alkyl)carboxy(l-6C)alkyl means a (l-6C)alkyl group as defined herein wherein one of the carbon atoms is substituted with a (1-4C alkyl)carboxy group as defined herein.
  • Cyano(l-6C)alkyl means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with a cyano (CN) group.
  • (3-6C)Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Dihydroxy(2-6C)alkyl means a linear saturated hydrocarbon radical of two to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with two hydroxy (OH) groups, provided that two hydroxy groups are not both on the same carbon atom.
  • Dihydroxy(2-6C)alkoxy means a (2-6C)alkoxy group as defined herein, wherein two of the carbon atoms are substituted with a hydroxy group.
  • Halogen as used herein means F, CI, Br or I.
  • Heterocycle refers to a saturated or partially unsaturated ring system having one or more ring heteroatoms as recited for the specific heterocyclic group, wherein the heterocycle is optionally substituted with substituents as defined for that particular heterocyclic group.
  • Heteroaryl refers to a 5-6 membered unsaturated ringsystem having one or more ring heteroatoms as recited for the specific heteroaryl group, wherein the heteroaryl is optionally substituted with substituents as defined for that particular heteroaryl group.
  • Hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, respectively, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms or three to four carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy (OH) group.
  • Hydroxy(l-6C)alkoxy means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
  • Hydroxy(l-3C alkoxy)(l-6C)alkoxy means a (1-3C alkoxy)(l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
  • Hydroxydifluoro(l-6C)alkyl means a difluoro(l-6C)alkyl group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
  • Hydrofluoro(l-6C)alkoxy means a trifluoro(l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
  • Hydrocarbonylalkyl means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one -COOH group. Examples include 2-hydroxycarbonylethyl, 1-, 2-, or 3-hydroxycarbonylpropyl, and the like.
  • Isoindoline-l,3-dionyl(l-6C)alkoxy means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with an isoindoline-l,3-dionyl group.
  • Tetrafluoro(2-6C)alkyl and "pentafluoro(2-6C)alkyl” refer to a linear saturated monovalent hydrocarbon radical of two to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms wherein four to five hydrogen atoms, respectively, is replaced by a fluoro group.
  • Trifluoro(l-6C)alkoxy means a (l-6C)aIkoxy group as defined herein, wherein one of the carbon atoms is substituted with three fluoros.
  • Sulfamido(l-6C)alkyl means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one sulfamido (H 2 NS0 2 NH-) group.
  • compounds of the invention may contain groups that may exist in tautomeric forms, such as heteroatom substituted heteroaryl or heterocyclic groups and the like, which are illustrated in the following general and specific examples:
  • G' O, S, or NR, and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.
  • X is O.
  • X is S.
  • X is NH
  • X is N-CN.
  • Ring A is Formula A-l :
  • G 1 , G 2 and G 3 are independently CR X or N, wherein no more than 2 of G 1 , G 2 and G 3 can be N; and R 1 and R 2 are as defined for Formula I.
  • G 1 , G 2 and G 3 are CR X and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • each R x is hydrogen.
  • G 1 is N and G 2 and G 3 are CR X , and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • each R x is hydrogen.
  • G 2 is N and G 1 and G 3 are CR X , and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • each R x is hydrogen.
  • G 3 is N and G 1 and G 2 are CR X , and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • each R x is hydrogen.
  • G 1 and G 2 are N and G 3 is CR X , and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • R x is hydrogen.
  • G 1 and G 3 are N and G 2 is CR X , and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • R x is hydrogen.
  • G 1 is CR x and G 2 and G 3 are N, and Formula A-l has the structure:
  • R x , R 1 and R 2 are as defined for Formula I.
  • each R x is independently H or F.
  • R x is hydrogen.
  • F A is Formula A-2:
  • F a A-2 has the structure:
  • Formula A-2 has the structure:
  • R is H.
  • R 1 is halogen. In one embodiment of Formula I, R 1 is Br.
  • R 1 is (l-3C)alkoxy(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R 1 is (l-3C)alkoxy(l-3C)alkyl. In one embodiment, R 1 is (l-3C)alkoxy(l-3C)alkyl which is substituted with 1-5 fluoros. In one embodiment, R 1 is CH 3 OCH 2 -, CF 3 OCH 2 -, or CH 3 OCF 2 -. In one embodiment, R 1 is CH 3 OCH 2 -.
  • R 1 is (1-3C alkyl)sulfanyl(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R 1 is (1-3C alkyl)sulfanyl(l- 3C)alkyl. In one embodiment, R 1 is (1-3C alkyl)sulfanyl(l-3C)alkyl substituted with 1-5 fluoros In one embodiment, R 1 is CH 3 SCH 2 or CF 3 SCH 2 . [00269] In one embodiment of Formula I, R 1 is (l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment of Formula I, R 1 is (l-3C)alkyl.
  • R 1 is (l-3C)alkyl substituted with 1-3 fluoros. In one embodiment, R 1 is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or 2,2,2-trifluoroethyl.
  • R 1 is (l-3C)alkoxy optionally substituted with 1-5 fluoros. In one embodiment, R 1 is (l-3C)alkoxy. In one embodiment, R 1 is (1- 3C)alkoxy substituted with 1-5 fluoros. In one embodiment, R 1 is CH 3 0-, CH 3 CH 2 0-, or CF 3 0-.
  • R 1 is (1-3C alkyl)sulfanyl optionally substituted with 1-5 fluoros. In one embodiment R 1 is (1-3C alkyl)sulfanyl. In one embodiment, R 1 is (1-3C alkyl)sulfanyl substituted with 1-5 fluoros. In one embodiment, R 1 is CH 3 S, CF 3 S or CH 3 CH 2 S.
  • R 1 is cyano(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R 1 is CNCH 2 CH 2 CH 2 .
  • R 1 is hydroxy(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R 1 is HOCH 2 CH 2 CH 2 .
  • R 1 is (l-4C)alkyl optionally substituted with
  • R 1 is CF 3 CH 2 CH 2 CH 2 .
  • R 1 is CH 3 CH 2 NR y , CF 3 CH 2 NR y , HCF 2 CH 2 NR y , H 2 FCH 2 NR y , CH 3 NR y CH 2 , R y R y NCH 2 CH 2 or R y R y NCH 2 CF 2 , where each R y is independently H or methyl.
  • n is 0;
  • R 2 is selected from the group consisting of H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)0-, (3- 6C cycloalkyl)CH 2 0-, amino(l-3C)alkyl, CF 3 CH 2 NHCH 2 , HCF 2 CH 2 NHCH 2 , a C5-C8 bridged cycloalkyl, hetCyc 3 , hetCyc a CH 2 , Cyc a , hetAr 1 and Ar 1 ; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • n is 0; R 2 is H; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • n is 0; R 2 is halogen; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3 , and R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R 2 is F or CI.
  • n is 0; R 2 is (l-6C)alkyl [optionally substituted with 1-5 fluoros]; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3 , and R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R is methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl.
  • n is 0; R is (l-6C)alkoxy [optionally substituted with 1-5 fluoros]; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R is methoxy, ethoxy, fiuoromethoxy, trifluoromethoxy, difluoromethoxy, or 2,2,2-trifluoroethoxy; and R a and R b are as defined for Formula I.
  • n is 0; R 2 is (1-3C alkoxy)(l-4C)alkyl; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF 3 , and R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R 2 is CH 3 OCH 2 -.
  • n is 0; R 2 is (3-6C cycloalkyl)0-; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3 , and R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R 2 has the structure:
  • n is 0; R is (3-6C cycloalkyl)CH 2 0-; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF 3 , and R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R 2 is cyclopropylmethoxy.
  • n is 0; R is amino(l-3C)alkyl; and R , X, Ring C, R a and R b are as defined for Formula I.
  • R 2 is NH 2 CH 2 - .
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3 , and R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • n is a C5-C8 bridged cycloalkyl; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R 2 has the structure:
  • n is 0;
  • R 2 is hetCyc a , where hetCyc 3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy and (l-6C)alkyl [optionally substituted with 1-3 fluoros]; and
  • R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • R 2 is hetCyc 3 , where hetCyc 3 is a 4-6 membered heterocyclic ring having a ring oxygen atom and optionally substituted with OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros].
  • n is 0 and R has the structure:
  • n is 0; R 2 is hetCyc a CH 2 ; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • n is 0;
  • R 2 is Cyc a , where Cyc a is a (3- 6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (l-4C)alkyl, F or OH; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H. In one embodiment, R a is CF 3 and R b is H. In one embodiment, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, 2,2-difluorocyclopropyl, 3,3-diflorocyclobutyl, or 1- methoxycyclobutyl.
  • n is 0;
  • R is hetAr , where hetAr is a 5-6 membered heteroaryl having 1 -3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R b is H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • n is 0;
  • R 2 is Ar 1 , where Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN; and R 1 , X, Ring C, R a and R b are as defined for Formula I.
  • Ar 1 is phenyl.
  • R a is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF 3
  • R b is H, methyl or ethyl.
  • R a and R b are both H.
  • R a is cyclopropyl and R s H.
  • R a is methyl and R b is H.
  • R a is CF 3 and R b is H.
  • X and Ring C are as defined for Formula I.
  • X is O and Ring C is as defined for Formula I.
  • X is O and Ring C is formula C-l.
  • n is 1 ; Ring A is A-l ; R 2 is selected from the group consisting of H, halogen, CF 3 , F 2 CH, FCH 2 , MeO and methyl; and R a , R b , R c , R d , X, R 1 and Ring C are as defined for Formula I.
  • n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF 3 , F 2 CH, FCH 2 , MeO and methyl; R a and R b are hydrogen; and R c , R d , X, R 1 and Ring C are as defined for Formula I.
  • n is 1; Ring A is A-l; R 2 is H; and R a , R b , R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n is 1 ; Ring A is A-l ; R 2 is H; R a and R b are hydrogen; and R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n is 1; Ring A is A-l ; R 2 is halogen; and R a , R b , R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n is 1 ; Ring A is A-l; R 2 is halogen; R a and R b are hydrogen; and R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n is 1 ; Ring A is A-l; R is CF 3 , F 2 CH, FCH 2 or methyl; and R a , R b , R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n is 1 ; Ring A is A-l; R 2 is CF 3 , F 2 CH, FCH 2 or methyl; R a and R b are hydrogen; and R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • R a , R b , R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n is 1 ;
  • Ring A is A-l ;
  • R 2 is methoxy;
  • R a and R b are hydrogen;
  • R c , R d , X, R 1 , and Ring C are as defined for Formula I.
  • n 1 is selected from the structures:
  • X and Ring C are as defined for Formula I.
  • X is O and Ring C is as defined for Formula I.
  • X is O and Ring C is formula C- 1.
  • Ring C is formula C-l:
  • R 3 , R 4 and R 5 are as defined for Formula I.
  • R 3 is (l-6C)alkyl. In one embodiment, R 3 is methyl or ethyl.
  • R 3 is hydroxy(l-6C)alkyl.
  • An example of R 3 is 2- hydroxyethyl.
  • R is Ar , where Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl.
  • R when represented by Ar is phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3- chlorophenyl, 3-chloro-4-fluorophenyl or 3-chloro-2-fluorophenyl.
  • R when represented by Ar 2 is phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2- methylphenyl, 3-methylphenyl or 4-methylphenyl. In one embodiment, R is phenyl.
  • R is hetCyc , where hetCyc is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1 -2 ring heteroatoms independently selected from N and O.
  • R 3 is a pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl ring.
  • R 3 is tetrahydro-2H-pyran-4-yl .
  • R 3 is (3-7C)cycloalkyl. In one embodiment R 3 is cyclohexyl.
  • R 3 is hetAr 2 , where hetAr 2 is 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (l-6C)alkyl and halogen.
  • R 3 is thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl and halogen.
  • R 3 is pyrazolyl, pyridyl or pyridazinyl optionally substituted with one or more groups independently selected from (1- 6C)alkyl and halogen.
  • R is pyrazolyl, pyridyl or pyridazinyl optionally substituted with (l-6C)alkyl or halogen.
  • R when represented by hetAr is 1 -methyl- 1 H-pyrazol-4-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyridazinyl or 3-chloropyrid- 5-yl.
  • R 3 is selected from Ar 2 and hetAr 2 .
  • R is Ar . In one embodiment, R is phenyl.
  • R 4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino( 1 -6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido(l-6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (1- 6C)alkyl, (1- 6
  • R 4 is OH. In one embodiment, R 4 is OH and R 3 is H. Examples of C-l rings when R 4 is OH and R 3 is H include the following tautomeric structures:
  • R 4 is (l-6C)alkyl. In one embodiment, R 4 is methyl, ethyl, isopropyl or tert-butyl.
  • R 4 is monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl.
  • R 4 is fluoromethyl, 2-fluoroethyl, difluoromethyl and 2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl or 2,2,3,3,3- pentafluoropropyl
  • R 4 is trifluoro(l-6C)alkyl. In one embodiment, R 4 is CF 3 . [00323] In one embodiment, R 4 is cyano(l-6C)alkyl. In one embodiment, R 4 is cyanomethyl or 2-cyanopropan-2-yl.
  • R 4 is hydroxy(l-6C)alkyl. In one embodiment, R 4 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl or 1-hydroxy- 2-methylpropan-2-yl.
  • R 4 is dihydroxy(2-6C)alkyl. In one embodiment, R 4 is 2,3-dihydroxypropyl.
  • R 4 is (1-3C alkoxy)(l-6C)alkyl. In one embodiment, R 4 is methoxymethyl, 2-methoxyethyl or 3-methoxypropyl.
  • R 4 is amino(l-6C)alkyl. In one embodiment, R 4 is aminomethyl, 2-aminoethyl or 3-aminopropyl.
  • R 4 is aminocarbonyl(l-6C)alkyl. In one embodiment, R 4 is aminocarbonylmethyl and 2-(aminocarbonyl)ethyl.
  • R 4 is (l-3C)alkylsulfonamido(l-6C)alkyl. In one embodiment, R 4 is CH 3 S0 2 NHCH 2 - or CH 3 S0 2 NHCH 2 CH 2 -.
  • R 4 is hetAr 3 (l-6C)alkyl, where hetAr 3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, S and O and optionally substituted with (l-6C)alkyl.
  • hetAr 3 is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (l-6C)alkyl.
  • R 4 when represented by hetAr 3 (l-6C)alkyl is (l-methyl-lH-l,2,4-triazol-3-yl)methyl or (5-methyl-l,3,4-oxadiazol-2- yl)methyl.
  • R 4 is Ar 3 (l-6C)alkyl, where phenyl optionally substituted with (l-4C)alkoxy or hydroxy(l-4C)alkyl.
  • Ar (l-6C)alkyl is benzyl.
  • R 4 is (l-6C)alkoxy. Examples include methoxy and ethoxy.
  • R 4 is monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifiuoro(l-6C)alkoxy, tetrafluoro(2-6C)alkoxy or pentafluoro(2-6C)alkoxy.
  • R 4 is fluoromethoxy, 2-fluoroethoxy, 2,2-difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or 2,2-difluoroethoxy.
  • R 4 is 2-fluoroethoxy.
  • R 4 is cyano(l-6C)alkoxy. In one embodiment, R 4 is cyanomethoxy or 2-cyanoethoxy. [00336] In one embodiment, R 4 is hydroxy(l-6C)alkoxy. In one embodiment, R 4 is 2- hydroxy-2-methylpropoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2- methylpropoxy or 2-hydroxybutoxy.
  • R 4 is dihydroxy(2-6C)alkoxy. In one embodiment, R 4 is
  • R 4 is amino(2-6C)alkoxy. In one embodiment, R 4 is H 2 NCH 2 CH 2 0- or H 2 NCH(CH 3 )CH 2 0-.
  • R is hetCyc (l-6C)alkoxy, where hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc is optionally substituted with 1-2 groups independently selected from (1- 6C)alkyl, (1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo.
  • hetCyc is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or and 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo.
  • R is hetCyc (l-6C)alkoxy, where hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 2 is optionally substituted with 1-2 groups independently selected from (1- 6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl.
  • hetCyc 2 is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or and 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl.
  • R 4 when represented by hetCyc 2 (l-6C)alkoxy is oxetan-2-ylmethoxy, 2- (oxetan-2-yl)propoxy, 2-morpholinoethoxy, piperazinylethyoxy or piperidinylethoxy optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl.
  • R 4 is represented by the structures:
  • R 4 is hetAr 3 (l-6C)alkoxy, where hetAr 3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, S and O and optionally substituted with (l-6C)alkyl.
  • hetAr 3 is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (l-6C)alkyl.
  • hetAr 3 is triazolyl or oxadiazolyl ring optionally substituted with a (l-6C)alkyl group such as a methyl group.
  • R 4 when represented by hetAr 3 (l-6C)alkoxy is (1 -methyl- lH-l,2,4-triazol- 3-yl)methoxy or (5-methyl-l,3,4-oxadiazol-2-yl)methoxy, which can be represented by the structures:
  • R 4 is Ar 3 (l-6C)alkoxy, where Ar 3 is phenyl optionally substituted with (l-4C)alkoxy.
  • R 4 is phenylmethoxy or (4- methoxyphenyl)methoxy having the structures:
  • R 4 is (1-4C alkoxy)(l-6C)alkoxy. In one embodiment, R 4 is(2-methoxy)ethoxy having the structure:
  • R 4 is (l-3Calkylsulfonyl)(l-6C)alkoxy.
  • 4 is (2-methylsulfonyl)ethoxy having the structure:
  • R 4 is (3-6C)cycloalkyl optionally substituted with F, OH,
  • (1-6C alkyl), (l-6C)alkoxy or (1-3C alkoxy)(l -6C)alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-hydroxycyclobutyl.
  • R 4 is cyclopropyl or 2-hydroxycyclobutyl. In one embodiment, R 4 is cyclopropyl.
  • R 4 is hetAr 4 , where hetAr 4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1 ,2,4-oxadiazolyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H 2 N-, (CH 3 ) 2 N-, 2- hydroxyethyl, 2-methoxyethyl, 1 -(2,2,2-trifluoroethoxy)-2,2,2-trifluoroeth
  • R 4 is hetAr 4 , where hetAr 4 is pyridyl, pyrimidinyl or pyridazinyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2- trifluoroethyl, methoxy, ethoxy, CN, H 2 N-, CH 3 NH-, (CH 3 ) 2 N-, and cyclopropylNH-.
  • R 4 when represented by hetAr 4 is selected from the structures:
  • R 4 is hetAr 4 -0-, where hetAr 4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1,2,4-oxadiazolyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H 2 N-, (CH 3 ) 2 N-, 2- hydroxyethyl, 2-methoxyethyl, 1 -(2,2,2-trifluoroethoxy)-2,2,2-trifluoroe
  • R 4 is hetAr 4 -0-, where hetAr 4 is pyridyl, pyrimidinyl or pyridazinyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2- trifluoroethyl, methoxy, ethoxy, CN, H 2 N-, CH 3 NH-, (CH 3 ) 2 N-, and cyclopropylNH-.
  • R 4 when represented by hetAr 4 -0- is a group having the structure:
  • Ar 4 is phenyl optionally substituted with one or two of said substituents.
  • Ar 4 is selected from the structures:
  • R 4 is hetCyc 2 (0)CH 2 , where hetCyc 2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc is optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl.
  • hetCyc 2 examples include oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl.
  • R 4 when represented by hetCyc (0)CH 2 is selected from the structures:
  • R 4 is (1-4C alkoxycarbonyl)(l-6C)alkoxy. In one embodiment, R 4 is methoxycarbonyl(l-6C)alkoxy or ethylcarbonyl(l-6C)alkoxy. A particular example is ethoxycarbonylmethoxy.
  • R 4 is hydroxycarbonyl(l-6C)alkoxy. In one embodiment, R 4 is hydroxycarbonylmethoxy.
  • R 4 is aminocarbonyl(l-6C)alkoxy.
  • hetCyc 2 is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl.
  • hetCyc 2 is morpholinyl.
  • R 4 is hydroxy(l-3C alkoxy)(l-6C)alkoxy.
  • R 4 is 2-hydroxy-3-methoxypropoxy, having the structure:
  • R 4 is hydroxytrifluoro(l-6C)alkoxy. In one embodiment, R 4 is 3,3,3-difluoro-2-hydroxypropoxy having the structure:
  • R 4 is (l-3C)alkylsulfonamido(l-6C)alkoxy. In one embodiment, R 4 is methanesulfonamido(l-6C)alkoxy. In one embodiment, R 4 is 2- methanesulfonamidoethoxy having the structure:
  • R 4 is (l-3C)alkylamido(l-6C)alkoxy. In one embodiment, R 4 is 2-(methylamido)ethox having the structure:
  • R 4 is di(l-3C alkyl)aminocarboxy. In one embodiment, R 4 is dimethylaminocarboxy having the structure:
  • hetCyc is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl.
  • hetCyc is morpholinyl.
  • R 4 is hydroxydifluoro(l-6C)alkyl. In one embodiment, R 4 is 2,2-difluro-2-hydroxyethyl. [00370] In one embodiment, R 4 is (1-4C alkylcarboxy)(l-6C)alkyl. In one embodiment, R 4 is methylcarboxy(l-6C)alkyl. In one embodiment, R 4 is 2- (methylcarboxy)ethyl .
  • R 4 is (l-6C)alkoxycarbonyl. In one embodiment, R 4 is methoxycarbonyl or ethoxycarbonyl.
  • R 4 is hydroxycarbonyl
  • R 4 is aminocarbonyl, that is, a RR'NCO- radical where R and R' are independently hydrogen or (l-6C)alkyl as defined herein. In one embodiment, R 4 is aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylcarbonyl or isopropylaminocarbonyl.
  • R 4 is (1-3C alkoxy)aminocarbonyl. In one embodiment, R 4 is methoxyaminocarbonyl.
  • R 4 is hetCyc 3 , where is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, CF 3 , (l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl.
  • hetCyc is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc is optionally substituted with one or two of said substituents.
  • R 4 when represented by hetCyc 3 is selected from the structures:
  • R 4 is halogen. In one embodiment, R 4 is Br.
  • R 4 is CN
  • R 4 is trifluoromethylsulfonyl.
  • R 4 is hetAr 5 , where hetAr 5 is a group selected from the structures:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros.
  • R 4 when represented by hetAr 5 is selected from the structures:
  • R 4 is N-(1-3C alkyl)oxadiazolonyl. In one embodiment, R 4 is represented by the structures:
  • R 4 is phenoxy.
  • R 4 is hetCyc 4 -0-, where hetCyc 4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • R 4 is hetCyc 4 -0-, where hetCyc 4 is pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, l-azaspiro[3.3]heptane or quinuclidinyl, optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • R 4 when represented by hetCyc 4 -0- is selected from the strutures:
  • R 4 is Cyc'-O, where Cyc 1 is a 3-6 membered carbocycle optionally substituted with an amino group. In one embodiment, R 4 is Cyc'-O, where Cyc 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with NH 2 , NHCH 3 or N(C3 ⁇ 4) 2 . In one embodiment, R 4 is cyclobutyl optionally substituted with an amino group. In one embodiment, R 4 is cyclobutyl optionally substituted with NH 2 , NHCH 3 or N(CH 3 ) 2 . In one embodiment, R 4 when represented by Cyc'-O- is selected from the structures:
  • R 4 is aminohydroxy(l-6C)alkoxy. In one embodiment,
  • R 4 is 2-amino-3-hydroxypropoxy.
  • R 4 is selected from H, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, cyano(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2- 6C)alkoxy, hetCyc 2 (l-6C)alkoxy, Ar 3 (l-6C)alkoxy, (1 -4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl, hetAr 4 , hetAr 4 -0-, Ar 4 , and hetAr 5 .
  • R 4 is hetAr 4 , Ar 4 , or hetAr 5 .
  • R 4 is hetAr 4 or hetAr 5 .
  • R 4 is pyrazolyl optionally substituted with one or more groups independently selected from (l-6C alkyl, or a hetAr 5 group having the structure:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein said hetAr 5 group is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros.
  • R 5 is (l-6C)alkyl. In one embodiment, R 5 is methyl, ethyl, propyl, isopropyl or butyl.
  • R 5 is monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl or pentafluro(2-6C)alkyl.
  • R 5 is fluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, l,3-difluoroprop-2-yl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1,1,2,2-tetrafluoropropane or 2,2,3,3,3-pentafluoropropyl.
  • R 5 is halogen. In one embodiment, R 5 is F. In one embodiment, R 5 is CI. In one embodiment, R 5 is Br.
  • R 5 is CN
  • R 5 is (l-4C)alkoxy. In one embodiment, R 5 is methoxy or ethoxy.
  • R 5 is hydroxy(l-4C)alkyl. In one embodiment, R 5 is hydroxymethyl or 3-hydroxypropyl.
  • R 5 is (l-6C)alkylthio. In one embodiment, R 5 is methylthio (MeS-).
  • R 5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy. In one embodiment, R 5 is phenyl optionally substituted with one or more groups independently selected from F, CI, methyl, ethyl, methoxy and ethoxy. In one embodiment, R 5 is phenyl.
  • R 5 is (3-4C)cycloalkyl. In one embodiment, R 5 is cyclopropyl. In one embodiment, R 5 is cyclobutyl.
  • R 5 is amino. In one embodiment, R 5 is NH 2 .
  • R 5 is aminocarbonyl. In one embodiment, R 5 is
  • R 5 is halogen, CN, ( 1 -6C)alkyl, ( 1 -4C)alkoxy, hydroxy( 1 - 4C)alkyl, or phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy.
  • R 5 is selected from halogen, and (l-6C)alkyl.
  • R 5 is selected from methyl, CI and Br.
  • R 4 is selected from H, (l-6C)alkyl, trifluoro(l-6C)alkyI, cyano(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, cyano(l-
  • R 5 is selected from halogen, CN, (l-6C)alkyl, (l-4C)alkoxy, hydroxy(l- 4C)alkyl, (l-6C)alkylthio, and phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy.
  • R 4 is selected from (l-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, hetAr 4 , hetAr 5 , Ar 4 -0-, hetCyc 4 -0-, Cyc'- ⁇ -, or aminohydroxy(l-6C)alkoxy.
  • R 4 is selected from (l-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, hetAr 4 and hetAr 5 .
  • R 4 is selected from hetAr 4 , Ar 4 , and hetAr 5 ; and R 5 is selected from (l-6C)alkyl.
  • R 4 is selected from hetAr 4 and hetAr 5 ; and R 5 is selected from (l-6C)alkyl.
  • R 4 is hetAr 4 and R 5 is selected from (1-
  • R 4 is pyrazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl; and R 5 is selected from (l-6C)alkyl.
  • R 4 is hetAr 5 ; and R 5 is selected from (1- 6C)alkyl.
  • R 4 is a hetAr 5 group having the structure:
  • R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein said hetAr 5 group is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros; and R 5 is selected from (l-6C)alkyl.
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl.
  • Ring C when R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated or unsaturated carbocyclic ring is selected from the structures:
  • R is as defined for Formula I.
  • R is phenyl
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl.
  • Ring C when R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated carbocyclic ring is selected from the structures:
  • R 3 is as defined for Formula I. In one embodiment of the above structures, R 3 is phenyl.
  • Ring C when R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring is selected from the structures:
  • R 3 is as defined for Formula I. In one embodiment of the above structures, R 3 is phenyl.
  • Ring C when R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring is selected from the structures:
  • R 3 is as defined for Formula I.
  • R is phenyl
  • R 3a , R 4a and R 5a are as defined for Formula I.
  • R 3a is hydrogen
  • R 3a is halogen
  • R 3a is (l-6C)alkyl. In one embodiment, R 3a is methyl.
  • R 3a is trifluoro(l-6C)alkyl. In one embodiment, R 3a is
  • R 3a is (3-6C)cycloalkyl. In one embodiment, R 3a is cyclopropyl.
  • R 3a is phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl.
  • R 3a is phenyl, fluorophenyl or methylphenyl, for example include phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3 -methylphenyl, 4-methylphenyl, 3- chlorophenyl, 3-chloro-4-fluorophenyl or 3-chloro-2-fluorophenyl.
  • R 3a is phenyl.
  • R 3a is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • R 3a is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl ring optionally substituted with (l-6C)alkyl or halogen.
  • R 3a is pyrazolyl, pyridyl or pyridazinyl optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
  • R 3a is pyrazolyl, pyridyl or pyridazinyl optionally substituted with (l-6C)alkyl or halogen.
  • R 4a is hydrogen.
  • R 4a is (l-6C)alkyl. In one embodiment, R 4a is methyl, ethyl or isopropyl.
  • R 4a is trifluoro(l-6C)alkyl. In one embodiment, R 4a is 2,2,2-trifluoroethyl.
  • R 4a is phenyl optionally substituted with one or two of said substituents. In one embodiment, R 4a is phenyl.
  • R 5a is as defined for Formula I.
  • R 5a is selected from hydrogen, halogen, (l-6C)alkyl and phenyl.
  • R 5a is hydrogen
  • R 5a is halogen
  • R 5a is (l-6C)alkyl. In one embodiment, R 5a is methyl.
  • R 5a is phenyl.
  • Ring C is formula C-2, in which R 3a is (l-6C)alkyl, trifluoro(l-6C)alkyl or phenyl; R 4a is (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl or pyrazinyl; and R 5a is hydrogen, (l-6C)alkyl or phenyl.
  • Ring A is A- 1 , and R 1 , R 2 , R a , R b , n, R c , R d ,
  • G 1 , G 2 , G 3 , X, Ring C, R 3 , R 4 , R 5 , R 3a , R 4a and R 5a are as defined for Formula I.
  • Ring A is A-1 ; n is 0; and G 1 , G 2 , G 3 , R 1 , R 2 ,
  • R a , R b , X, Ring C, R 3 , R 4 , R 5 , R 3a , R 4a and R 5a are as defined for Formula I.
  • Ring A is A-1 ; n is 0; X is O; and G ⁇ G
  • Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; and G 1 , G 2 , G 3 , R 1 , R 2 , R a , R b , R 3 , R 4 and R 5 are as defined for Formula I.
  • R 4 is hetAr 4 or hetAr 5 ; and G 1 , G 2 , G 3 , R 1 , R 2 , R a , R b , R 3 , and R 5 are as defined for Formula
  • Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; and G 1 , G 2 , G 3 , R 1 , R 2 , R a , R b , and R 5 are as defined for Formula I.
  • Ring A is A-1 ; n is 0; Ring C is C-1 ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; and G 1 , G 2 , G 3 , R 1 , R 2 , R a , and R b are as defined for Formula I.
  • Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; R b is H; and G 1 , G 2 , G 3 , R 1 , R 2 , and R a are as defined for Formula I.
  • Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; R b is H; R a is H; and G 1 , G 2 , G 3 , R 1 , and R 2 are as defined for Formula I.
  • Ring A is A-1 ; n is 0; X is O; Ring C is C-1; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; R b is H; R a is H; R 1 is (l-3C)alkoxy(l- 3C)alkyl; and G 1 , G 2 , G 3 , and R 2 are as defined for Formula I.
  • Ring A is A-l ; n is 0; X is O; Ring C is C-1 ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; R b is H; R a is H; R 1 is (l-3C)alkoxy(l- 3C)alkyl; R 2 is H, halogen, CF 3 , F 2 CH, FCH 2 or methoxy; G 1 and G 2 are N; and G 3 is CR X .
  • G 1 , G 2 , G 3 , R a , R b , R c , R d , X, R 1 , R 3 , R 4 , and R 5 are as defined for Formula I-C.
  • Ring A is A-2, and R a , R b , X, Ring C, R 3 , R 4 , R 5 , R 3a , R 4a and R 5a are as defined for Formula I.
  • R a , R b , X, Ring C, R 3 , R 4 , R 5 , R 3a , R 4a and R Sa are as defined for Formula I-C.
  • Ring A is A-2; X is O; and R a , R b , Ring C, R 3 , R 4 , R 5 , R 3a , R 4a and R 5a are as defined for Formula I.
  • R a , R b , Ring C, R 3 , R 4 , R 5 , R 3a , R 4a and R 5a are as defined for Formula I-C.
  • Ring A is A-2; X is O; Ring C is C-1 ; and R a , R b , R 3 , R 4 , and R 5 are as defined for Formula I. In one embodiment, R a , R b , R 3 , R 4 , and R 5 are as defined for Formula I-C.
  • Ring A is A-2; X is O; Ring C is C-1 ; R 4 is hetAr 4 or hetAr 5 ; and R a , R b , R 3 and R 5 are as defined for Formula I. In one embodiment, R a , R b , R 3 and R 5 are as defined for Formula I-C.
  • Ring A is A-2; X is O; Ring C is C-l ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; and R a , R b and R 5 are as defined for Formula I. In one embodiment, R a , R b and R 5 are as defined for Formula I-C.
  • Ring A is A-2; X is O; Ring C is C-l ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; and R a and R b are as defined for Formula I. In one embodiment, R a and R b are as defined for Formula I-C.
  • Ring A is A-2; X is O; Ring C is C-l ; R 4 is hetAr 4 or hetAr 5 ; R 3 is Ar 2 ; R 5 is (l-6C)alkyl; and R a and R are H.
  • certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
  • the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
  • compounds of Formula I can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compounds of Formula I include pharmaceutically acceptable salts thereof.
  • the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which are useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I.
  • Particular examples of salts include hydrochloride salts and trifluoroacetate salts.
  • the compounds of Formula I include the free base form of compounds of Examples 1-132, or pharmaceutically acceptable salts thereof.
  • the compounds of Formula I include the hydrochloride salts of compounds of Examples 1-132.
  • the compounds of Formula I include the trifluoroacetate salts of compounds of Examples 1-132.
  • composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the present invention also provides a process for the preparation of a compound of Formula I or a salt thereof as defined herein, which comprises: [00498] (a) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
  • L 1 is a leaving group, in the presence of a base
  • the base may be an amine base, such as triethylamine or diisopropylethylamine.
  • Suitable solvents include dichloromethane, dichloroethane, THF,
  • the base may be an amine base, such as triethylamine or diisopropylethylamine.
  • Suitable solvents include dichloromethane, dichloroethane, THF,
  • the leaving group may be, for example, phenoxy or 4- nitrophenoxy.
  • the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DMA, DMF and DCE. The reaction is conveniently performed at ambient temperature.
  • the leaving group may be, for example, phenoxy or 4- nitrophenoxy.
  • the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DCE, DMA and DMF. The reaction is conveniently performed at ambient temperature.
  • the base may be an amine base, such as triethylamine or diisopropylethylamine.
  • Suitable solvents include toluene and DMF.
  • the reaction is conveniently performed at elevated temperatures, for example the reflux temperature of the solvent.
  • the base may be an amine base, such as triethylamine or diisopropylethylamine.
  • Suitable solvents include DCM, DCE, DMF and THF. The reaction is conveniently performed at temperatures between about 0 °C and ambient temperature.
  • 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.
  • Compounds of Formula I are useful in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.
  • compounds of Formula I are useful for treating pain, including chronic and acute pain.
  • compounds of Formula I are useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery or bone fracture.
  • compounds of Formula I are useful for treating acute pain.
  • 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, and is confined to a given period of time and severity. In some instances, it can become chronic.
  • compounds of Formula I are useful for treating chronic pain.
  • Chronic pain as defined by the International Association for the Study of Pain, is widely believed to represent a disease in 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.
  • Particular examples include neuroblastoma, ovarian, pancreatic, colorectal and prostate cancer.
  • Compounds of Formula I are also useful for treating inflammation and certain infectious diseases.
  • compounds of Formula I may be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, atopic dermatitis, and psoriasis.
  • IC interstitial cystitis
  • PBS painful bladder syndrome
  • urinary incontinence asthma
  • asthma atopic dermatitis
  • psoriasis psoriasis
  • Compounds of Formula I are also useful for treating 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 said neurodegenerative disease.
  • compounds of Formula I may also be used to treat demyelination and dysmyelination by promoting myelination, neuronal survival, and oligodendrocyte differentiation via blocking Sp35-TrkA interaction.
  • the neurodegenerative disease is multiple sclerosis.
  • the neurodegenerative disease is Parkinson's disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • Compounds of Formula I are also useful for treating certain infectious diseases such as Trypanosoma cruzi infection in a mammal. [00537] Compounds of Formula I are also useful for treating Sjogren's syndrome in a mammal.
  • Compounds of Formula I are also useful for treating endometriosis in a mammal.
  • Compounds of Formula I are also useful for treating diabetic peripheral neuropathy in a mammal.
  • Compounds of Formula I are also useful for treating prostatitis in a mammal.
  • Compounds of Formula I are also useful for treating pelvic pain syndrome in a mammal.
  • Compounds of Formula I are also useful in treating diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disorder or condition, 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.
  • compounds of Formula I are useful for preventing diseases and disorders as defined herein.
  • 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, or a symptom thereof, and includes to the administration of a compound of Formula I prior to the onset of symptoms.
  • one embodiment of this invention provides a method of treating pain in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said pain.
  • the pain is chronic pain.
  • the pain is acute pain.
  • the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.
  • Another embodiment of this invention provides a method of preventing pain in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to prevent said pain.
  • the pain is chronic pain.
  • the pain is acute pain.
  • the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.
  • Another embodiment of this invention provides a method of treating cancer in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said cancer.
  • a method for treating a patient diagnosed with a cancer having a dysregulation of TrkA comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the dysregulation of TrkA comprises overexpression of wild-type TrkA (autocrine activation).
  • the dysregulation of TrkA comprises one or more chromosome translocations or inversions resulting in TrkA gene fusions.
  • the dysregulation is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from non-TrkA and TrkA proteins, and at a minimum the TrkA kinase domain.
  • the TrkA fusion protein is LMNA- TrkA, TFG-TrkA, TPM3-TrkA, CD74-TrkA, NFASC-TrkA, MPRIP-TrkA, BCAN-TrkA, or TPR-TrkA, where:
  • LMNA Prelamin-A/C
  • NFASC Neurofascin
  • MPRIP MPRIP protein
  • the dysregulation of TrkA comprises one or more deletions, insertions or mutations in the TrkA protein. In one embodiment, the dysregulation comprises a deletion of one or more residues from the TrkA protein, resulting in constitutive activity of TrkA kinase. In one embodiment the deletion includes deletion of residues 303- 377 in TrkA Isoform 2. [00552] In one embodiment, the dysregulation of TrkA comprises a splice variation in which the expressed protein is an alternatively spliced variant of TrkA having one or more residues deleted resulting in constitutive activity of TrkA kinase. In one embodiment, an alternatively spliced form of TrkA with constitutive activity has deletions of exons 8, 9, and 1 1 resulting in an expressed protein missing residues 192-284 and 393-398 relative to TrkA Isoform 2.
  • TrkA comprises one or more deletions, insertions or mutations in the TrkA protein, including:
  • chemotherapeutics 314 e.g. abiraterone, cabazitaxel,
  • fluorouracil gemcitabine, mitomycin C
  • combinations e.g. gemcitabine-oxaliplatin
  • a method for treating a patient diagnosed with a cancer having a dysregulation of TrkA comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.
  • the compounds of the present invention are useful for treating cancer in combination with one or more additional therapeutic agents or therapies that work by the same or a different mechanism of action.
  • the additional therapeutic agent(s) is selected from receptor tyrosine kinase-targeted therapeutic agents, including cabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, and trastuzumab.
  • receptor tyrosine kinase-targeted therapeutic agents including cabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, and trastuzumab.
  • the additional therapeutic agent(s) is selected from signal transduction pathway inhibitors, including Ras-Raf-MEK-ERK pathway inhibitors (e.g. sorafenib, trametinib, vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g. everolimus, rapamycin, perifosine, temsirolimus) and modulators of the apoptosis pathway (e.g. obataclax).
  • Ras-Raf-MEK-ERK pathway inhibitors e.g. sorafenib, trametinib, vemurafenib
  • PI3K-Akt-mTOR-S6K pathway inhibitors e.g. everolimus, rapamycin, perifosine, temsirolimus
  • modulators of the apoptosis pathway e.g. obataclax
  • the additional therapeutic agent(s) is selected from cytotoxic chemotherapeutics, including arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.
  • cytotoxic chemotherapeutics including arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel,
  • the additional therapeutic agent(s) is selected from angiogenesis-targeted therapies, including aflibercept and bevacizumab.
  • the additional therapeutic agent(s) is selected from immune-targeted agents, including aldesleukin, ipilimumab, lambrolizumab, nivolumab, sipuleucel-T.
  • the additional therapeutic agent(s) is selected from agents active against the TrkA pathway, including NGF-targeted biopharmaceuticals such as NGF antibodies, and panTrk inhibitors.
  • the additional therapeutic agent or therapy is radiotherapy, including radioiodide therapy, external-beam radiation and radium 223 therapy.
  • the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of TrkA.
  • a method of treating cancer in a patient comprising administering to said patient a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapy or therapeutic agent selected from radiotherapy (e.g. radioiodide therapy, external-beam radiation, radium 223 therapy), cytotoxic chemotherapeutics (e.g.
  • arsenic trioxide bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, vincristine), tyrosine kinase targeted-therapeutics (e.g.
  • aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, sipuleucel-T) and angiogenesis-targeted therapies e.g. aflibercept, bevacizumab
  • additional therapeutic agents may be administered with one or more compounds of the invention 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.
  • a pharmaceutical combination for treating cancer in a patient in need thereof which comprises (a) a compound of the invention or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of a tumor disease, wherein the amounts of the compound or salt thereof and of the additional therapeutic agent are together effective in treating said cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.
  • the combination therapy is for treating a cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.
  • Another embodiment of this invention provides a method of treating inflammation or an inflammatory disease or disorder in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said inflammation.
  • the inflammatory disease is inflammatory lung diseases (such as asthma), interstitial cystitis, bladder pain syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and inflammatory skin diseases such as atopic dermatitis.
  • the method of treating inflammation or an inflammatory disease or disorder comprises administering a compound of the invention in combination with one or more additional agents.
  • additional agents include anti-TNF treatments (for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or a circulating receptor fusion protein such as etanercept (Enbrel)), antimetabolite and antifolate drug (for example Methotrexate), or targeted kinase inhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritinib and TG101348).
  • anti-TNF treatments for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzi
  • Another embodiment of this invention provides a method of treating Trypanosoma cruzi infection in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said Trypanosoma cruzi infection.
  • Another embodiment of this invention provides a method of treating Sjogren's syndrome in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said syndrome.
  • Another embodiment of this invention provides a method of treating endometriosis in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said endometriosis.
  • Another embodiment of this invention provides a method of treating diabetic peripheral neuropathy in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said diabetic peripheral neuropathy.
  • Another embodiment of this invention provides a method of treating prostatitis in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said prostatitis.
  • Another embodiment of this invention provides a method of treating pelvic pain syndrome in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said pelvic pain syndrome.
  • Another embodiment of this invention provides a method of treating a neurodegenerative disease in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said neurodegenerative disease.
  • Another embodiment of this invention provides a method of treating diseases related to an imbalance of the regulation of bone remodeling in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said disease.
  • the disease is osteoporosis, rheumatoid arthritis, and bone metastases.
  • the method for treating diseases related to an imbalance of the regulation of bone remodeling in a mammal comprises administering a TrkA inhibitor of the invention in combination with one or more additional therapeutic agents or therapies.
  • additional therapeutic agents or therapies include anti-TNF treatments (for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or with a circulating receptor fusion protein such as etanercept (Enbrel)), antimetabolite and antifolate drug (for example Methotrexate), or targeted kinase inhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritinib and TGI 01348).
  • anti-TNF treatments for example monoclonal antibody such as infliximab (Remicade), adalim
  • an "effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat a particular disease, condition, or disorder which can be treated with a compound of Formula I, or (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder described herein.
  • the term "mammal” refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • the compounds of the present invention can be used in combination with one or more additional therapeutic agents that work by the same or a different mechanism of action.
  • additional therapeutic agents 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.
  • a pharmaceutical combination comprising an effective amount of: (a) at least one compound of Formula I; and (b) at least one additional therapeutic agent selected from 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), for use in the treatment of pain in a mammal, wherein (a) and (b) can be in separate dosage forms or in the same dosage form.
  • steroids e.g., dexamethasone, cortisone and fluticasone
  • analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen)
  • opioids such as morphine
  • the term "pharmaceutical combination” as used herein refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that at least one of the compounds of Formula I, and at least one additional therapeutic agent are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that at least one of the compounds of Formula I, and at least one additional therapeutic agent, are administered to a patient as separate entities either simultaneously or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • Also provided herein is a method of treating pain in a mammal, comprising co-administering to a mammal in need thereof an effective amount of: (a) at least one compound of Formula I; and (b) at least one additional therapeutic agent selected from antiinflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), opioids (such as morphine), calcitonin gene-related peptide receptor antagonists, subtype-selective ion channel modulators, anticonvulsants (for example Pregabalin and gabapentin), dual serotonin-norepinephrin reuptake inhibitors (for example duloxetine, venlafaxine and milnacipran), and tricyclic antidepressants (such as amitriptyline, nortrip
  • co-administering is meant to encompass administration of the selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • This term encompasses administration of two or more agents to a mammal so that both agents and/or their metabolites are present in the mammal at the same time. It includes simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compound(s) of the invention and the other therapeutic agent(s) are administered in a single composition.
  • compound(s) of the invention and the other agent(s) are admixed in the composition.
  • steroids e.g., dexamethasone, cortisone and fluticasone
  • analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen)
  • opioids such as morphine
  • steroids e.g., dexamethasone, cortisone and fluticasone
  • analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen)
  • opioids such as morphine
  • 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.
  • Another formulation may be prepared by mixing a compound described herein and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the
  • composition which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove, together with a pharmaceutically acceptable diluent or carrier.
  • the present 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, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a mammal.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation or an inflammatory disease or disorder in a mammal.
  • the inflammatory disease is inflammatory lung diseases (such as asthma), interstitial cystitis, bladder pain syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and inflammatory skin diseases such as atopic dermatitis.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of infectious diseases, for example Trypanosoma cruzi infection, in a mammal.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of Sjogren's syndrome in a mammal.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of endometriosis in a mammal.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic peripheral neuropathy in a mammal,
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of prostatitis in a mammal,
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pelvic pain syndrome 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 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 condition selected from pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection.
  • the condition is chronic pain.
  • the condition is acute pain.
  • the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.
  • the condition is cancer.
  • the condition is inflammation.
  • the condition is a neurodegenerative disease.
  • the condition is Trypanosoma cruzi infection.
  • the condition is Sjogren's syndrome.
  • the condition is endometriosis.
  • the condition is diabetic peripheral neuropathy.
  • the condition is prostatitis.
  • the condition is pelvic pain syndrome.
  • TrkA binding activity was determined in a TrkA LanthaScreenTM Eu Kinase Binding Assay. 5 nM His-tagged recombinant human TrkA (6HIS tagged cytoplasmic domain from Invitrogen, Catalog No. PV3144) was incubated with 4 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat. No.PV5592), 2 nM biotinylated anti-His (Invitrogen Cat. No. PV6090), and 2 nM europium-labeled Streptavidin (Invitrogen Cat. No.
  • Table A provides averaged IC 50 values for compounds of the invention when tested in the assay of Example A, where A represents an averaged IC 50 value ⁇ 100 nM; B represents an averaged IC 50 value from 100 to 1,000 nM; and C represents an average IC50 value above 1000 nM.
  • p38a binding activity was determined in a p38a LanthaScreenTM Eu Kinase Binding Assay. 5nM of inactive, GST-tagged recombinant human p38a (GST-tagged cytoplasmic domain from Invitrogen, Catalog No. PV3305) was incubated with 5 nM Alexa- Fluor® Tracer 199 (Invitrogen Cat. No. PV5830), and 2 nM europium labeled anti-GST antibody (Invitrogen Cat. No. PV5594), in buffer (25mM [Na + ] HEPES pH 7.3, 10 raM MgCl 2 , ⁇ NaVC ⁇ ).
  • Examples 33 and 10 Representative compounds of the invention (Examples 33 and 10) were tested for off-target kinase activity at a concentration of 10 ⁇ by Millipore, Inc. in their KinaseProfilerTM service against all the kinases available in their full kinase panel. Compounds were run in duplicate at a concentration of ATP near the Km for each individual kinase according to Millipore 's specifications. The results are shown in Table B. Data are reported as percent of control (POC) and are the average of the two replicates.
  • POC percent of control
  • the representative compounds showed remarkable and unexpected selectivity for inhibiting TrkA and TrkB versus other kinases in the panel.
  • the compounds were largely inactive against off-target kinases at a concentration of 10 ⁇ , and thus would not be expected to inhibit off-target kinases at therapeutic doses in mammals.
  • the ability of compounds of the invention to selectively inhibit the Trk pathway without inhibiting other off-target kinases could translate into drug profiles that are essentially free of side-effects related to inhibition of off-target kinases. Such a drug profile would represent a safer approach to treating pain, inflammation, cancer and certain skin diseases than has been previously reported.
  • Step A Preparation of 2-bromo-5 -formylbenzonitrile: To a 1 liter, 3-neck round bottom flask equipped with a condenser, and temperature probe was added 2-fluoro-5- formylbenzonitrile (20 g, 134 mmol) and 535 mL of NMP, and lithium bromide (116.5 g, 1341 mmol). A modest exotherm was observed. This mixture was warmed to 150 °C under a nitrogen atmosphere for 3.5 days. After cooling to ambient temperature, the mixture was diluted with 2 liters of ice water, and extracted two times with MTBE. The combined extracts were washed two times with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography, eluting with 100% DCM, to give 2-bromo-5-formylbenzonitrile as a white solid (5 g, 18% yield).
  • Step B Preparation of 2-cyclopropyl-5-formylbenzonitrile: A heavy walled pressure tube was charged with 2-bromo-5-formylbenzonitrile (500 mg, 2.38 mmol) and 8 mL of toluene.
  • Step C Preparation of 2-cyclopropyl-5-(hydroxymethyl)benzonitrile: To a round bottom flask containing 2-cyclopropyl-5-formylbenzonitrile (260 mg, 1.52 mmol) was added dry methanol (5 mL). A solution formed and was chilled to 0°C. Sodium borohydride (115 mg, 3.04 mmol) was then added in one portion and the mixture was then allowed to warm to ambient temperature.
  • Step D Preparation of 2-cvclopropyl-5-(methoxymethyl)benzonitrile: A round bottom flask and nitrogen inlet was charged with 2-cyclopropyl-5-
  • Step E Preparation of . (2-cyclopropyl-5-
  • Step A Preparation of 2-cyclobutyl-5-formylbenzonitrile: To a heavy walled pressure tube was added 2-bromo-5-formylbenzonitrile (250 mg, 1.19 mmol) and 5 mL of dry THF. To this was added palladium acetate (26.7 mg, 0.119 mmol), S-Phos (73.3 mg, 0.179 mmol), and cyclobutylzinc bromide 5.95 mL, 2.98 mmol, 0.5 M in THF), the tube was sealed and and stirred under a nitrogen atmosphere for one hour. The mixture was then diluted with EtO Ac/water and filtered through GF/F filter paper. The organics were isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography to give 2-cyclobutyl-5- formylbenzonitrile (110 mg, 50% yield) as an oil.
  • Step B Preparation of 2-cyclobutyl-5-(methoxymethyl)phenyl)methanamine: Prepared by the methods described in Preparation A, Steps C through E, replacing 2- cyclopropyl-5-formylbenzonitrile with 2-cyclobutyl-5-formylbenzonitrile, to give the title compound.
  • Preparation C Preparation of 2-cyclobutyl-5-(methoxymethyl)phenyl)methanamine: Prepared by the methods described in Preparation A, Steps C through E, replacing 2- cyclopropyl-5-formylbenzonitrile with 2-cyclobutyl-5-formylbenzonitrile, to give the title compound.
  • Step A Preparation of 2-bromo-5-ethoxybenzonitrile: A round bottom flask and nitrogen inlet was charged with 2-bromo-5-hydroxybenzonitrile (1.50 g, 7.58 mmol) and dry DMF (30 mL). To this was added cesium carbonate (4.94 g, 15.2 mmol) followed by ethyl iodide (1.77 g, 11.4 mmol) and the mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with water and extracted two times with diethyl ether. The extracts were washed two times with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-bromo-5-ethoxybenzonitrile (1.72 g, 100%) as a white solid.
  • Step B Preparation of 2-cvclopropyl-5-ethoxybenzonitrile: A heavy walled pressure tube was charged with 2-bromo-5-ethoxybenzonitrile (0.750 g, 3.32 mmol) and 8 mL of toluene.
  • potassium cyclopropyltrifluoroborate (1.96 g, 13.3 mmol)
  • palladium acetate (0.111 g, 0.498 mmol)
  • dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2- yl)phosphine (0.464 g, 0.995 mmol)
  • potassium phosphate (2.11 g, 9.95 mmol) and 2 mL of water.
  • the mixture was purged with nitrogen for 5 minutes, tube sealed and heated to 1 10 °C for 3 hours.
  • the reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc and water.
  • Step C Preparation of (2-cyclopropyl-5-ethoxyphenyl)methanamine: Prepared by the methods described in Preparation A, Step E, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 2-cyclopropyl-5-ethoxybenzonitrile, to give the title compound (0.424 g, 94% yield).
  • Step A Preparation of 5-bromo-2-ethoxybenzonitrile: To a round bottom flask and nitrogen inlet was added 5-bromo2-hydroxybenzonitrile (2.00 g, 10.1 mmol) and 40 mL of dry DMF. To this mixture was added powdered potassium carbonate (2.79 g, 20.2 mmol) and ethyl iodide (4.73 g, 30.3 mmol), which was stirred at ambient temperature for 2 hours under a nitrogen atmosphere. The mixture was then diluted with water and extracted two times with MTBE. The extracts were washed two times with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 5-bromo-2- ethoxybenzonitrile (2.06 g, 90% yield).
  • Step B Preparation of 2-ethoxy-5-(methoxymethyl)benzonitrile: A heavy walled pressure tube was charged with 5-bromo-2-ethoxybenzonitrile (0.500 g, 2.21 mmol), 8mls of dioxane and 2mls of water. Potassium methoxymethyltrifluoroborate (0.672 g, 4.42 mmol), PdCl 2 (dppf) dichloromethane adduct (0.361 g, 0.442 mmol), and cesium carbonate (2.16 g, 6.64 mmol) were then added to the reaction mixture under a nitrogen atmosphere, the tube was sealed and heated to 100 °C for 16 hours.
  • Step C Preparation of (2-ethoxy-5-(methoxymethyl)phenyl)methanamine: Prepared by the methods described in Preparation A, Step E, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 2-ethoxy-5-(methoxymethyl)benzonitrile to give the title compound (66 mg, 65% yield).
  • Preparation F Preparation of (2-ethoxy-5-(methoxymethyl)phenyl)methanamine: Prepared by the methods described in Preparation A, Step E, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 2-ethoxy-5-(methoxymethyl)benzonitrile to give the title compound (66 mg, 65% yield).
  • Step A Preparation of 5-( , methoxymethylV2-
  • Step B Preparation of 5-(methoxymethyl)-2-(trifluoromethoxy)benzaldehyde oxime: To a round bottom flask equipped a stir bar was added 5-(methoxymethyl)-2- (trifluoromethoxy)benzaldehyde (0.230 g, 0.982 mmol), ethanol (10 mL) and water (1ml). Hydroxylamine hydrochloride (0.102 g, 1.47 mmol) was then added and the mixture was stirred at ambient temperature for 2 hrs.
  • Step A Preparation of 5-bromo-2-cvclobutoxybenzonitrile: A heavy walled pressure tube was charged with 5-bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), dry DMF (20 mL), powdered potassium carbonate (1.40 g, 10.1 mmol), and bromocyclobutane (2.05 g, 15.2 mmol). The tube was sealed and warmed to 80 °C for 16 hours, then allowed to cool to ambient temperature. The mixture was then diluted with water and extracted 2 times with MTBE. The extracts were washed 2 times with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2-cyclobutoxybenzonitrile (0.983 g, 77% yield) as an orange oil.
  • Step B Preparation of. (2-cvclobutoxy-5-
  • Step A Preparation of 5-bromo-2-(difluoromethoxy)benzonitrile: To walled pressure tube was added 5-bromohydroxybenzonitrile (5 g , 25.3 mmol), acetonitrile (250 mL) and 30% (w/w) of aqueous KOH (100 mL). This mixture was chilled to -78 °C and 2-chloro-2,2-difluoro-l-phenylethanone (9.62 g, 50.5 mmol) was then added. The tube was sealed, allowed to warm to ambient temperature, and heated to 80 °C for 4 hours.
  • Step B Preparation of . (2-(difluoromethoxy)-5-
  • Step B Preparation of 2-bromo-5-n-methoxyethyl)benzonitrile: Prepared by the method described in Preparation A, Step D, replacing 2-cyclopropyl-5- (hydroxymethyl)benzonitrile with 2-bromo-5-(l -hydroxy ethyl)benzonitrile and DMF with THF, to give 2-bromo-5-(l-methoxyethyl)benzonitrile (86 mg, 54%) as a solid.
  • Step C Preparation of 2-cvclobutyl-5-(l-methoxyethyl)benzonitrile: Prepared by the method described in Preparation B, Step A, replacing 2-bromo-5- formylbenzonitrile with 2-bromo-5-(l-methoxyethyl)benzonitrile to give 2-cyclobutyl-5-(l - methoxyethyl)benzonitrile (39 mg, 51% yield) as an oil.
  • Step D Preparation of i2-cyclobutyl-5-(T- methoxyethyPphenvDmethanamine: Prepared by the method described in Preparation A, Step E, replacing 2-cyclopropyl-5-(methoxymethyl)benzonitrile with 2-cyclobutyl-5-(l- methoxyethyl)benzonitrile to give the title compound (30 mg, 76% yield) as an oil.
  • Step A Preparation of (4-bromo-3-chlorophenyl)methanol: A round bottom flask equipped with a stirbar and nitrogen inlet was charged with dry THF (72 mL), and sodium borohydride (1.09 g, 28.9 mmol). This suspension was chilled to 0 °C and boron trifluoride etherate (8.20 g, 57.8 mmol) was then added and the mixture stirred at 0 °C for 15 minutes. To this was added 4-bromo-3-chlorobenzoic acid (3.40 g, 14.4 mmol) in one portion (gas evoluiton observed). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours.
  • Step B Preparation of l-bromo-2-chloro-4-(methoxymethyl)benzene: Prepared by the method described in Preparation J, Step B, replacing 2-bromo-5-(l- hydroxyethyl)benzonitrile with (4-bromo-3-chlorophenyl)methanol to give l-bromo-2- chloro-4-(methoxymethyl)benzene (1.72 g, 65% yield) as an oil.
  • Step C Preparation of 2-chloro-4-(methoxymethyl)-l-vinylbenzene: To a heavy walled pressure tube was added l-bromo-2-chloro-4-(methoxymethyl)benzene (1.72 g, 7.30 mmol), 35 mL of dioxane, and 4 mL of water. To this was added potassium vinyltrifluoroborate (1.96 g, 14.6 mmol), palladium chloride (0.0259 g, 0.146 mmol), triphenylphosphine (0.1 15 g, 0.438 mmol), and cesium carbonate (7.14 g, 21.9 mmol).
  • Step D Preparation of 2-chloro-l-(2,2-difluorocyclopropyl -4-
  • Step E Preparation of tert-butyl 2-(2,2-difluorocyclopropyl -5- (methoxymethyl)benzylcarbamate: To a microwave reaction tube was added 2-chloro-l-(2,2- difluorocyclopropyl)-4-(methoxymethyl)benzene (0.200 g, 0.860 mmol), potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (0.224 g, 0.946 mmol, Org. Lett., 2012, 14 (12), pp 3138-3141) toluene (6.5 mL) and water (1.5 mL).
  • Step F Preparation of (2-(2,2-difluorocyclopropyl -5-
  • Step A Preparation of 2-bromo-5-(hvdroxymethyl benzonitrile: Prepared by the method described in Preparation A, Step C, replacing 2-cyclopropyl-5-formylbenzonitrile with 2-bromo-5-formylbenzonitrile, to give 2-bromo-5-(hydroxymethyl)benzonitrile (2.02 g, 100% yield) as a white solid.
  • Step B Preparation of 2-bromo-5-(methoxymethyl)benzonitrile: Prepared by the method described in Preparation J, Step B, replacing 2-cyclopropyl-5- (hydroxymethyl)benzonitrile with 2-bromo-5-(hydroxymethyl)benzonitrile to give the title compound (1.35 g, 63%) as a waxy solid.
  • Step C Preparation of 2-( 1 -hydroxycyclobutyl)-5-
  • Step A Preparation of 3-(methoxymethyl)benzonitrile: Prepared by the method described in Preparation A, Step D, replacing 2-cyclopropyl-5- (hydroxymethyl)benzonitrile with 3-(hydroxymethyl)benzonitrile to give 3- (methoxymethyl)benzonitrile (2.21 g, 100%) as an oil.
  • Step B Preparation of cyclopropyl(3-(methoxymethyl)phenyl)methanamine: Prepared by the method described in Preparation M, Step A, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 3-(methoxymethyl)benzonitrile and methylmagnesium iodide with cyclopropylmagnesium bromide, to give the title compound (0.39 g, 100%) as an oil.
  • Step A Preparation of 3-(2-chloro-4-(methoxymethvDphenyl)oxetan-3-ol: A round bottom flask was charged with l-bromo-2-chloro-4-(methoxymethyl)benzene (1.00 g, 4.25 mmol) and dry THF (42 mL). This solution was chilled to -78 °C and n-BuLi (2.04 mL, 5.10 mmol, 2.5 M in hexanes) was added by syringe over a 5 minute period.
  • Step B Preparation of 3-(2-chloro-4-(methoxymethyl)phenyl)-3- fluorooxetane: A round bottom flask was charged with 3-(2-chloro-4- (methoxymethyl)phenyl)oxetan-3-ol (0.305 g, 1.33 mmol) and dry DCM (13 mL). This solution was chilled to 0 °C and Deoxofluor (0.384 g, 1.30 mmol) was added. This mixture was stirred at 0 °C for 1 hour, then quenched with 10% aqueous potassium carbonate. This was extracted with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC to give 3-(2-chloro- 4-(methoxymethyl)phenyl)-3-fluorooxetane (0.165 g, 54%) as an oil.
  • Step C Preparation tert-butyl 2-i3-fluorooxetan-3-yr)-5-

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of Formula I or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C, X, Ra, Rb, Rc, Rd and n are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.

Description

N-(ARYLALKYL)-N'-PYRAZOLYL-UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS
BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds in therapy. More particularly, it relates to arylalkyl and heteroarylalkyl urea, thiourea , guanidine and cyanoguanidine compounds which exhibit TrkA kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.
[0002] The current treatment regimens for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative respiratory effects, as well as the potential for addictions. Nonsteroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) also have drawbacks including insufficient efficacy in treating severe pain. In addition, COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.
[0003] Trk's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).
[0004] Inhibitors of the Trk/neurotrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain. For example, antagonistic NGF and TrkA antibodies such as RN-624 have been shown to be efficacious in inflammatory and neuropathic pain animal models (Woolf, C.J. et al. (1994) Neuroscience 62, 327-331; Zahn, P.K. et al. (2004) J Pain 5, 157-163; McMahon, S.B. et al., (1995) Nat. Med. 1, 774-780; Ma, Q. P. and Woolf, C. J. (1997) NeuroReport 8, 807-810; Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15, 355-361; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442- 448) and neuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999) Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Herzberg, U. et al., Pain 79, 265-274 (1997) Neuroreport 8, 1613-1618; Theodosiou, M. et al. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci. 23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 1 17— 120).
[0005] It has also been shown that NGF secreted by tumor cells and tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers. Using various tumor models in both mice and rats, it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine. Because TrkA kinase may serve as a mediator of NGF driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide an effective treatment for chronic pain states.
[0006] Recent literature has also shown that overexpression, activation, amplification and/or mutation of Trk kinases are associated with many cancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003, 3, 203-216), ovarian (Davidson. B., et al., Clin. Cancer Res. 2003, 9, 2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949), melanoma (Truzzi, F., et al., Dermato-Endocrinology 2008, 3 (1), pp. 32-36), head and neck cancer (Yilmaz, T., et al., Cancer Biology and Therapy 2010, 10 (6), pp. 644-653), gastric carcinoma (Du, J. et al., World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), lung carcinoma (Ricci A., et al., American Journal of Respiratory Cell and Molecular Biology 25 (4), pp. 439-446), breast cancer (Jin, W., et al., Carcinogenesis 2010, 31 (1 1), pp. 1939- 1947), Glioblastoma (Wadhwa, S., et al., Journal of Biosciences 2003, 28 (2), pp. 181-188), medulloblastoma (Gruber-Olipitz, M., et al., Journal of Proteome Research 2008, 7 (5), pp. 1932-1944), secratory breast cancer (Euthus, D.M., et al., Cancer Cell 2002, 2 (5), pp. 347- 348), salivary gland cancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention and Treatment 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma (Greco, A., et al., Molecular and Cellular Endocrinology 2010, 321 (1), pp. 44-49) and adult myeloid leukemia (Eguchi, M., et al., Blood 1999, 93 (4), pp. 1355-1363). In preclinical models of cancer, nonselective small molecule inhibitors of TrkA, B and C were efficacious in both inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169:107-1 14; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia, M.A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351).
[0007] In addition, inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of pre-clinical models of inflammatory diseases with NGF antibodies or non-selective small molecule inhibitors of TrkA. For example, inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma (Freund-Michel, V; Frossard, N., Pharmacology & Therapeutics (2008) 117(1), 52-76), interstitial cystitis (Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016-21), bladder pain syndrome (Liu, H.-T., et al, (2010) BJU International, 106 (11), pp. 1681-1685), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Di Mola, F. F, et. al., Gut (2000) 46(5), 670-678) and inflammatory skin diseases such as atopic dermatitis (Dou, Y.-C, et. al. Archives of Dermatological Research (2006) 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S. P., et al., J Investigative Dermatology (2004) 122(3), 812-819).
[0008] The TrkA receptor is also thought to be critical to the disease process 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).
[0009] Trk inhibitors may also find use in treating disease related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases. Bone metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer and in approximately 15 to 30 percent of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases can cause severe pain, pathologic fractures, life- threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. For these reasons, bone metastasis is a serious and costly complication of cancer. Therefore, agents that can induce apoptosis of proliferating osteoblasts would be highly advantageous. Expression of TrkA receptors has been observed in the bone-forming area in mouse models of bone fracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). In addition, localization of NGF was observed in almost all bone-forming cells (K. Asaumi, et al.). Recently, it was demonstrated that a Trk inhibitor inhibits the signaling activated by neurotrophins binding to all three of the Trk receptors in human hFOB osteoblasts (J. Pinski, et al., (2002) 62, 986-989). These data support the rationale for the use of Trk inhibitors for the treatment of bone remodeling diseases, such as bone metastases in cancer patients.
[0010] Trk inhibitors may also find use in treating diseases and disorders such as
Sjogren's syndrome (Fauchais, A.L., et al., (2009) Scandinavian Journal of Rheumatology, 38(1), pp. 50-57), endometriosis (Barcena De Arellano, M.L., et al., (2011) Reproductive Sciences, 18(12), pp. 1202-1210; Barcena De Arellano, et al., (2011) Fertility and Sterility, 95(3), pp. 1123-1126; Cattaneo, A., (2010) Current Opinion in Molecular Therapeutics, 12(1), pp. 94-106), diabetic peripheral neuropathy (Kim, H.C., et al., (2009) Diabetic Medicine, 26 (12), pp. 1228-1234; Siniscalco, D., et al., (2011) Current Neuropharmacology, 9(4), pp. 523-529; Ossipov, M.H., (2011) Current Pain and Headache Reports, 15(3), pp. 185-192), and prostatitis and pelvic pain syndrome (Watanabe, T., et al., (2011) BJU International, 108(2), pp. 248-251; and Miller, L.J., et al., (2002) Urology, 59(4), pp. 603- 608).
[0011] 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), 305-319).
SUMMARY OF THE INVENTION
[0012] It has now been found that pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds are inhibitors of TrkA, and useful for treating disorders and diseases such as pain, including chronic and acute pain. Compounds of the invention useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. In addition, compounds of the invention are useful for treating cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
[0013] More specifically, provided herein are compounds of Formula I:
Figure imgf000006_0001
[0014] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C, X, Ra, Rb, Rc, Rd and n are as defined herein. [0015] Another aspect of the present invention provides methods of treating a disease or disorder modulated by TrkA, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer, solvate or pharmaceutically acceptable salt thereof. In one embodiment, the disease and disorders include chronic and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. In another embodiment, the disease and disorders include, but are not limited to, cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases. In one embodiment, the treatment includes treating the mammal with a compound of this invention in combination with an additional therapeutic agent.
[0016] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.
[0017] Another aspect of the present invention provides the compounds of the present invention for use in therapy.
[0018] Another aspect of the present invention provides the compounds of the present invention for use in the treatment of disease and disorders such as chronic and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. Another aspect of the present invention provides the compounds of the present invention for use in the treatment of disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
[0019] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of disease and disorders such as chronic and acute pain including, but not limited to, inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.
[0020] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
[0021] Another aspect of the present invention provides intermediates for preparing compounds of Formula I.
[0022] Another aspect of the present invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Provided herein are compounds, and pharmaceutical formulations thereof, that are useful in the treatment of diseases, conditions and/or disorders modulated by TrkA.
[0024] A representative compound of the invention (See Table B below), was found to be highly selective for TrkA over a panel of about 230 other kinases at 10 μΜ concentration. In addition, compounds of the invention such as those shown in Table A below, were found to be at least 1000 fold more selective for TrkA versus p38a.
[0025] One embodiment provides a compound of Formula I:
Figure imgf000008_0001
I
[0026] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:
[0027] X is O, S, NH or N-CN;
[0028] Ring A is formula A- 1 or A-2
Figure imgf000009_0001
A-1 A-2
[0029] wherein the dashed lines are optional double bonds;
[0030] n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A is formula A-
2;
[0031] G1, G2 and G3 are independently CRX or N, wherein no more than 2 of G1, G2 and G can be N;
[0032] each Rx is independently H, halogen, ( 1 -4C)alkyl or ( 1 -4C)alkoxy;
[0033] R1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH3CH2NRy, CF3CH2NRy, HCF2CH2NRy, H2CFCH2NRy, CH3NRyCH2, RyRyNCH2CH2, RyRyNCH2CFH, or RyRyNCH2CF2;
[0034] each Ry is independently H or methyl;
[0035] when n is 0, R2 is selected from the group consisting of H, halogen, (1-
6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH20-, amino(l-3C)alkyl, CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyc3, hetCycaCH2, Cyca, hetAr1 and Ar1, and
[0036] when n is 1, R2 is selected from the group consisting of H, halogen, CF3,
F2CH, FCH2, methyl and methoxy.
[0037] hetCyca is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1 -3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
[0038] Cyca is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1-
4C)alkyl, F or OH; [0039] hetAr1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl;
[0040] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
[0041] Ra is H, (1 -3C)alkyl, cyclopropyl,cyclobutyl, or CF3, and
[0042] Rb is H, methyl or ethyl,
[0043] or Ra and Rb together with the carbon atom to which they are attached form a
3-6 membered cycloalkyl ring;
[0044] Rc is H, methyl or ethyl
[0045] Rd is CF3CH2CH2, phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl;
[0046] Ring C is formula C- 1 or C-2
Figure imgf000010_0001
C-l C-2
[0047] R3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl, a C5-
C8 bridged cycloalkyl, or hetAr2;
[0048] Ar2 is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
[0049] hetCyc1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
[0050] hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[0051] R4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafiuoro(2- 6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l- 6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro( 1 -6C)alkoxy, ( 1 -3C)alkylsulfonamido( 1 -6C)alkoxy, ( 1 -3 C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1- 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr5, Ar4-0-, hetCyc4-0-, Cyc^O-, or aminohydroxy(l-6C)alkoxy;
[0052] hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo;
[0053] hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
[0054] hetCyc4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[0055] Cyc1 is a 3-6 membered carbocycle optionally substituted with an amino group;
[0056] hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
[0057] Ar3 is phenyl optionally substituted with (l-4C)alkoxy;
[0058] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino;
[0059] hetAr5 is a group selected from the structures:
Figure imgf000012_0001
[0060] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
[0061] Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)0C(O)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1- 3C alkoxy)(l-3C alkyl)OC(=0)-;
[0062] R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-
6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy); or
[0063] R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
[0064] R4 and R5 together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=0)0-, (l-6C)acyl, (l-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(=0) or S02;
[0065] R3a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[0066] R4a is hydrogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1- 6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl; and
[0067] R5a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
[0068] In one embodiment, compounds of Formula I include compounds of Formula
I-A
Figure imgf000014_0001
I-A
[0069] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:
[0070] X is O, S, NH or N-CN;
[0071] Rin A is formula A-l or A-2
Figure imgf000014_0002
A-1 A-2
[0072] wherein the dashed lines are optional double bonds;
[0073] n is 0 or 1 when Ring A is formula A-l, and n is 0 when Ring A is formula A-
2;
[0074] G1, G2 and G3 are independently CRX or N, wherein no more than 2 of G1, G2 and G can be N;
[0075] each Rx is independently H, halogen, ( 1 -4C)alkyl or ( 1 -4C)alkoxy;
[0076] R1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH3CH2NRy, CF3CH2NRy, HCF2CH2NRy, H2CFCH2NRy, CH3NRyCH2, RyRyNCH2CH2, RyRyNCH2CFH, or R^^CHzCFz;
[0077] each Ry is independently H or methyl;
[0078] when n is 0, R2 is selected from the group consisting of H, halogen, (1-
6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH20-, amino(l-3C)alkyl, CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyc3, hetCycaCH2, Cyca, hetAr1 and Ar1, and
[0079] when n is 1, R is selected from the group consisting of H, halogen, CF3,
F2CH, FCH2, methyl and methoxy.
[0080] hetCyc3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
[0081] Cyca is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1-
4C)alkyl, F or OH;
[0082] hetAr1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl;
[0083] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
[0084] Ra is H, (l-3C)alkyl, cyclopropyl or cyclobutyl, and
[0085] Rb is H, methyl or ethyl,
[0086] or Ra and Rb together with the carbon atom to which they are attached form a
3-6 membered cycloalkyl ring;
[0087] R° is H, methyl or ethyl
[0088] Rd is CF3CH2CH2, phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen and methoxy;
[0089] Ring C is formula C- 1 or C-2
Figure imgf000016_0001
C-l C-2
[0090] R3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl, a C5-
C8 bridged cycloalkyl, or hetAr ;
[0091] Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
[0092] hetCyc1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
[0093] hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[0094] R4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, (1-3 C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafluoro(2- 6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l- 6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro( 1 -6C)alkoxy, ( 1 -3C)alkylsulfonamido( 1 -6C)alkoxy, ( 1 -3 C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1- 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr5; [0095] hetCyc2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkylcarboxy)(l-6C)alkyl, and (l-6C)acyl;
[0096] hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
[0097] hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
[0098] Ar is phenyl optionally substituted with (l-4C)alkoxy;
[0099] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino ;
[00100] hetAr5 is a group selected from the structures:
Figure imgf000017_0001
[00101] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
[00102] Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=O)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and CI SC alkoxy)(l-3C alkyl)OC(=0)-;
[00103] R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifiuoro(l- 6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy); or
[00104] R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
[00105] R4 and R5 together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=0)0-, (l-6C)acyl, (l-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(=0) or S02;
[00106] R3a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[00107] R4a is hydrogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1- 6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl; and
[00108] R5a is hydrogen, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
[00109] In one embodiment, compounds of Formula I include compounds of Formula I-B
Figure imgf000019_0001
I-B
[00110] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:
[00111] X is O, S, NH or N-CN;
[00112] Rin A is formula A-l or A-2
Figure imgf000019_0002
A-1 A-2
[00113] wherein the dashed lines are optional double bonds;
[00114] n is 0 or 1 when Ring A is formula A-l, and n is 0 when Ring A is formula A-
2;
[00115] G1, G2 and G3 are independently CRX or N, wherein no more than 2 of G1, G2 and G can be N;
[00116] each Rx is independently H, halogen, (l-4C)alkyl or (l-4C)alkoxy; [00117] R1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH3CH2NRy, CF3CH2NRy, HCF2CH2NRy, H2CFCH2NRy, CH3NRyCH2, RyRyNCH2CH2, RyRyNCH2CFH, or RyRyNCH2CF2;
[00118] each Ry is independently H or methyl;
[00119] when n is 0, R is selected from the group consisting of H, halogen, (1- 6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH20-, amino(l-3C)alkyl, CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyc3, hetCycaCH2, Cyca, hetAr1 and Ar1, and
[00120] when n is 1, R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, methyl and methoxy.
[00121] hetCyc3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
[00122] Cyca is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1- 4C)alkyl, F or OH;
[00123] hetAr1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl;
[00124] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
[00125] Ra is H, (l-3C)alkyl, cyclopropyl or cyclobutyl, and
[00126] Rb is H, methyl or ethyl,
[00127] or Ra and Rb together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl ring;
[00128] Rc is H, methyl or ethyl [00129] Rd is CF3CH2CH2, phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen and methoxy;
[00130] Ring C is formula C-1 or C-2
Figure imgf000021_0001
C-1 C-2
[00131] R3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl, a C5- C8 bridged cycloalkyl, or hetAr2;
[00132] Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
[00133] hetCyc1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
[00134] hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[00135] R4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafluoro(2- 6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l- 6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro( 1 -6C)alkoxy, ( 1 -3 C)alkylsulfonamido( 1 -6C)alkoxy, ( 1 -3 C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1- 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc3, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr5;
[00136] hetCyc2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkylcarboxy)(l-6C)alkyl, and (l-6C)acyl;
[00137] hetCyc3 is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
[00138] hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
[00139] Ar is phenyl optionally substituted with (l-4C)alkoxy;
[00140] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino;
[00141] hetAr5 is a group selected from the structures:
Figure imgf000022_0001
[00142] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros; [00143] AT4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and CISC alkoxy)(l-3C alkyl)OC(=0)-;
[00144] R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l- 6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy); or
[00145] R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
[00146] R4 and R5 together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=0)0-, (l-6C)acyl, (l-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(=0) or S02;
[00147] R3a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[00148] R4a is hydrogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1- 6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl; and [00149] R5a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
[00150] In one embodiment, compounds of Formula I include compounds of Formula I-C
Figure imgf000024_0001
I-C
[00151] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:
[00152] X is O, S, NH or N-CN;
[00153] Rin A is formula A-1 or A-2
Figure imgf000024_0002
A-1 A-2
[00154] wherein the dashed lines are optional double bonds;
[00155] n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A is formula A-
2; [00156] G1, G2 and G3 are independently CRX or N, wherein no more than 2 of G1, G2 and G can be N;
[00157] each Rx is independently H, halogen, ( 1 -4C)alkyl or ( 1 -4C)alkoxy;
[00158] R1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1- 3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH3CH2NRy, CF3CH2NRy, HCF2CH2NRy, H2CFCH2NRy, CH3NRyCH2, RyRyNCH2CH2, RyRyNCH2CFH, or RyRyNCH2CF2;
[00159] each Ry is independently H or methyl;
[00160] when n is 0, R2 is selected from the group consisting of H, halogen, (1- 6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH20-, amino(l-3C)alkyl, CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyc3, hetCycaCH2, Cyca, hetAr1 and Ar1, and
[00161] when n is 1, R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, methyl and methoxy.
[00162] hetCyc3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
[00163] Cyca is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (1- 4C)alkyl, F or OH;
[00164] hetAr1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl;
[00165] Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l- 4C)alkyl, (l-6C)alkyl and CN;
[00166] Ra is H, (1 -3C)alkyl, cyclopropyl, cyclobutyl, or CF3, and
[00167] Rb is H, methyl or ethyl,
[00168] or Ra and Rb together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl ring; [00169] Rc is H, methyl or ethyl
[00170] Rd is CF3CH2CH2, phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl;
[00171] Ring C is formula C-1 or C-2
Figure imgf000026_0001
C-1 C-2
[00172] R3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl, a C5- C8 bridged cycloalkyl, or hetAr2;
[00173] Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
[00174] hetCyc1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
[00175] hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[00176] R4 is OH, (l-6C)alk l, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, (1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafluoro(2- 6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l- 6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro( 1 -6C)alkoxy, (1-3 C)alkylsulfonamido( 1 -6C)alkoxy, (1-3 C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1- 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr5, Ar4-0-, hetCyc4-0-, Cyc^O-, or aminohydroxy(l-6C)alkoxy;
[00177] hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo;
[00178] hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;
[00179] hetCyc4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[00180] Cyc1 is a 3-6 membered carbocycle optionally substituted with an amino group;
[00181] hetAr is a 5 -membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
[00182] Ar is phenyl optionally substituted with (l-4C)alkoxy;
[00183] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino ;
[00184] hetAr is a group selected from the structures:
Figure imgf000027_0001
Figure imgf000028_0001
[00185] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
[00186] Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1- 3C alkoxy)(l-3C alkyl)OC(=0)-;
[00187] R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l- 6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy); or
[00188] R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
[00189] R4 and R5 together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=0)0-, (l-6C)acyl, (l-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(=0) or S02;
[00190] R3a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
[00191] R4a is hydrogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-], or a 5-6 membered heteroaryl ring having 1 -3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1- 6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-5 (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl; and
[00192] R5a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
[00193] It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, the radical "alkoxyalkyl" is attached to the structure in question by the alkyl group.
[00194] The terms M(l-6C)alkyl", "(l-4C)alkyl" and "(l-3C)alkyl" as used herein refer to saturated linear monovalent hydrocarbon radicals of one to six carbon atoms, one to four carbon atoms, and one to three carbon atoms, respectively, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, three to four carbon atoms, or three carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1- propyl, 2-propyl, 1 -butyl, 2-methyl-l -propyl, 2-butyl, 2-methyl-2 -propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l -butyl, 2-methyl- 1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.
[00195] "(l-4C)Alkoxy", "(l-3C)alkoxy", "(l-6C)alkoxy" and "(2-6C)alkoxy" refer to an -OR radical where R is (l-4C)alkyl, (l-3C)alkyl, (l-6C)alkyl, or (2-6C)alkyl, respectively, as defined above. Examples include methoxy, ethoxy, and the like.
[00196] "(l-6)Acyl" means a RC(=0)- radical where R is a linear saturated monovalent hydrocarbon radical of one to five carbon atoms or a branched saturated monovalent hydrocarbon radical of three to five carbon atoms, e.g., methylcarbonyl, and the like. [00197] "(1-3C Alkoxy)(l-6C)alkyl" and "(1-3C alkoxy)(l-4C)alkyl" mean a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms or three to four carbon atoms, respectively, wherein one of the carbon atoms is substituted with one (l-3C)alkoxy group as defined herein.
[00198] "(1-3C Alkoxy)(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a (l-3C)alkoxy group as defined herein. Examples include methoxymethoxy, methoxyethoxy, and the like.
[00199] "(1-3C Alkoxy)aminocarbonyl" means a (1-3C alkyl)-0-NH-C(=0)- group.
[00200] "(l-6C)Alkoxycarbonyl" and "(l-4C)alkoxycarbonyl" mean a (l-6C)-0- C(=0)- and (l-4C)-0-C(=0)- group, respectively.
[00201] "(1-4C Alkoxycarbonyl)(l-6C alkoxy)" means a (1-6C) alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1-4C alkoxycarbonyl group, i.e., an alkyl-0-C(=0)- group.
[00202] "(1-3C Alkoxy)hydroxycarbonylalkyl" means a hydroxycarbonylalkyl group as defined herein wherein one of the carbon atoms is substituted with one (1-3C alkoxy) group.
[00203] "Amino" means a -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein. Examples include H2N-, CH3NH-, (CH3)2N, and the like."Amino(l-6C)alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, wherein one of the carbon atoms is substituted with one -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein. Examples include aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, and the like.
[00204] "Amino(2-6C)alkoxy" means a (2-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with one -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein.
[00205] "Aminocarbonyl" means a RR"NCO- radical where R and R' are independently hydrogen or (l-6C)alkyl as defined herein. Examples include H2NCO-, dimethylaminocarbonyl, and the like.
[00206] "Aminocarbonyl(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons wherein one of the carbon atoms is substituted with one aminocarbonyl group as defined herein, e.g., 2-aminocarbonylethyl, 1-, 2-, or 3-dimethylaminocarbonylpropyl, and the like.
[00207] "Aminocarbonyl(l-6C)alkoxy" means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one aminocarbonyl group as defined herein.
[00208] "Aminohydroxy(l-6C)alkoxy" means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one amino group as defined herein, and one of the carbon atoms (other than the carbon atom substituted with the amino group) is substituted with one OH group.
[00209] "(l-3C)Alkylamido(l-6C)alkoxy" means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one alkylamido group, i.e., substituted with a (1-3C)C(=0)NH- group.
[00210] "(1 -4C alkyl)carboxy" means a R'-C(=0)0- group where R' is (1 -4C)alkyl.
[00211] "(1-4C alkylsiloxy)(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1-4C alkyl)siloxy group, e.g., a (1-4C alkyl)Si-0- group such as a tert-butylsiloxy group.
[00212] "(l-3C)Alkylsulfonamido" means a (l-3C)alkylS02NH- radical where (1- 3C)alkyl is as defined herein
[00213] "(1-3C Alkylsulfonamido)(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one (l-3C)alkylsulfonamido group as defined herein.
[00214] "(l-3C)Alkylsulfonamido(l-6C)alkoxy" means a (l -6C)alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1- 3C)alkylsulfonamido group as defined herein.
[00215] "(l-3C)Alkylsulfonyl" means a -S02R radical where R is (l-3C)alkyl as defined above, e.g., methylsulfonyl, and the like.
[00216] "(1-3C Alkylsulfonyl)(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a (l-3C)alkylsulfonyl group.
[00217] "Hydroxycarbonyl" means HOC(=0)-.
[00218] "(1-4C alkyl)carboxy(l-6C)alkyl" means a (l-6C)alkyl group as defined herein wherein one of the carbon atoms is substituted with a (1-4C alkyl)carboxy group as defined herein. [00219] "Cyano(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with a cyano (CN) group.
[00220] "(3-6C)Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[00221] "Dihydroxy(2-6C)alkyl" means a linear saturated hydrocarbon radical of two to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with two hydroxy (OH) groups, provided that two hydroxy groups are not both on the same carbon atom.
[00222] "Dihydroxy(2-6C)alkoxy" means a (2-6C)alkoxy group as defined herein, wherein two of the carbon atoms are substituted with a hydroxy group.
[00223] "Halogen" as used herein means F, CI, Br or I.
[00224] "Heterocycle" refers to a saturated or partially unsaturated ring system having one or more ring heteroatoms as recited for the specific heterocyclic group, wherein the heterocycle is optionally substituted with substituents as defined for that particular heterocyclic group.
[00225] "Heteroaryl" refers to a 5-6 membered unsaturated ringsystem having one or more ring heteroatoms as recited for the specific heteroaryl group, wherein the heteroaryl is optionally substituted with substituents as defined for that particular heteroaryl group.
[00226] "hetCyc2C(=0)(l-6C)alkoxy" means means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with a hetCyc2C(=0) group, wherein hetCyc2 is as defined herein.
[00227] "Hydroxy(l-6C)alkyl" and "hydroxy(l-4C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, respectively, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms or three to four carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy (OH) group.
[00228] "Hydroxy(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
[00229] "Hydroxy(l-3C alkoxy)(l-6C)alkoxy" means a (1-3C alkoxy)(l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
[00230] "Hydroxydifluoro(l-6C)alkyl" means a difluoro(l-6C)alkyl group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group. [00231] "Hydroxytrifluoro(l-6C)alkoxy" means a trifluoro(l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.
[00232] "Hydroxycarbonylalkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one -COOH group. Examples include 2-hydroxycarbonylethyl, 1-, 2-, or 3-hydroxycarbonylpropyl, and the like.
[00233] "Isoindoline-l,3-dionyl(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with an isoindoline-l,3-dionyl group.
[00234] "Monofluoro(l-6C)alkyl", "difluoro(l-6C)alkyl" and "trifluoro(l-6C)alkyl" refer to a (l-6C)alkyl group as defined herein wherein one to three hydrogen atoms, respectively, is replaced by a fluoro group.
[00235] "Tetrafluoro(2-6C)alkyl" and "pentafluoro(2-6C)alkyl" refer to a linear saturated monovalent hydrocarbon radical of two to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms wherein four to five hydrogen atoms, respectively, is replaced by a fluoro group.
[00236] "Trifluoro(l-3C alkyl)amido" means a (1-3C alkyl)C(=0)NH- group wherein one of the carbons is substituted with three fluoros.
[00237] "Trifluoro(l-6C)alkoxy" means a (l-6C)aIkoxy group as defined herein, wherein one of the carbon atoms is substituted with three fluoros.
[00238] "Sulfamido(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one sulfamido (H2NS02NH-) group.
[00239] It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as heteroatom substituted heteroaryl or heterocyclic groups and the like, which are illustrated in the following general and specific examples:
Figure imgf000033_0001
G' G'H
Figure imgf000033_0002
Figure imgf000034_0001
[00240] where G' = O, S, or NR, and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.
[00241] In one embodiment of Formula I, X is O.
[00242] In one embodiment of Formula I, X is S.
[00243] In one embodiment of Formula I, X is NH.
[00244] In one embodiment of Formula I, X is N-CN.
[00245] In one embodiment of Formula I Ring A is Formula A-l :
Figure imgf000034_0002
A-1
[00246] where G1, G2 and G3 are independently CRX or N, wherein no more than 2 of G1, G2 and G3 can be N; and R1 and R2 are as defined for Formula I.
[00247] In one embodiment of Formula I, G1, G2 and G3 are CRX and Formula A-l has the structure:
Figure imgf000034_0003
[00248] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, each Rx is hydrogen.
[00249] In one embodiment of Formula I, G1 is N and G2 and G3 are CRX, and Formula A-l has the structure:
Figure imgf000034_0004
[00250] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, each Rx is hydrogen.
[00251] In one embodiment of Formula I, G2 is N and G1 and G3 are CRX, and Formula A-l has the structure:
Figure imgf000035_0001
[00252] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, each Rx is hydrogen.
[00253] In one embodiment of Formula I, G3 is N and G1 and G2 are CRX, and Formula A-l has the structure:
Figure imgf000035_0002
[00254] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, each Rx is hydrogen.
[00255] In one embodiment of Formula I, G1 and G2 are N and G3 is CRX, and Formula A-l has the structure:
Figure imgf000035_0003
[00256] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, Rx is hydrogen.
[00257] In one embodiment of Formula I, G1 and G3 are N and G2 is CRX, and Formula A-l has the structure:
Figure imgf000035_0004
[00258] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, Rx is hydrogen. [00259] In one embodiment of Formula I, G1 is CRxand G2 and G3 are N, and Formula A-l has the structure:
Figure imgf000036_0001
[00260] where Rx, R1 and R2 are as defined for Formula I. In one embodiment, each Rx is independently H or F. In one embodiment, Rx is hydrogen.
[00261] In one embodiment of F A is Formula A-2:
Figure imgf000036_0002
A-2
[00262] wherein the dashed lines are optional double bonds.
[00263] In one embodiment of F a A-2 has the structure:
Figure imgf000036_0003
[00264] In one embodiment of Formula I, Formula A-2 has the structure:
Figure imgf000036_0004
[00265] In one embodiment of Formula I, R is H.
[00266] In one embodiment of Formula I, R1 is halogen. In one embodiment of Formula I, R1 is Br.
[00267] In one embodiment of Formula I, R1 is (l-3C)alkoxy(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R1 is (l-3C)alkoxy(l-3C)alkyl. In one embodiment, R1 is (l-3C)alkoxy(l-3C)alkyl which is substituted with 1-5 fluoros. In one embodiment, R1 is CH3OCH2-, CF3OCH2-, or CH3OCF2-. In one embodiment, R1 is CH3OCH2-.
[00268] In one embodiment of Formula I, R1 is (1-3C alkyl)sulfanyl(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R1 is (1-3C alkyl)sulfanyl(l- 3C)alkyl. In one embodiment, R1 is (1-3C alkyl)sulfanyl(l-3C)alkyl substituted with 1-5 fluoros In one embodiment, R1 is CH3SCH2 or CF3SCH2. [00269] In one embodiment of Formula I, R1 is (l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment of Formula I, R1 is (l-3C)alkyl. In one embodiment, R1 is (l-3C)alkyl substituted with 1-3 fluoros. In one embodiment, R1 is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or 2,2,2-trifluoroethyl.
[00270] In one embodiment of Formula I, R1 is (l-3C)alkoxy optionally substituted with 1-5 fluoros. In one embodiment, R1 is (l-3C)alkoxy. In one embodiment, R1 is (1- 3C)alkoxy substituted with 1-5 fluoros. In one embodiment, R1 is CH30-, CH3CH20-, or CF30-.
[00271] In one embodiment of Formula I, R1 is (1-3C alkyl)sulfanyl optionally substituted with 1-5 fluoros. In one embodiment R1 is (1-3C alkyl)sulfanyl. In one embodiment, R1 is (1-3C alkyl)sulfanyl substituted with 1-5 fluoros. In one embodiment, R1 is CH3S, CF3S or CH3CH2S.
[00272] In one embodiment of Formula I, R1 is cyano(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R1 is CNCH2CH2CH2.
[00273] In one embodiment of Formula I, R1 is hydroxy(l-3C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R1 is HOCH2CH2CH2.
[00274] In one embodiment of Formula I, R1 is (l-4C)alkyl optionally substituted with
1-5 fluoros. In one embodiment of Formula I, R1 is CF3CH2CH2CH2.
[00275] In one embodiment of Formula I, R1 is CH3CH2NRy, CF3CH2NRy, HCF2CH2NRy, H2FCH2NRy, CH3NRyCH2, RyRyNCH2CH2 or RyRyNCH2CF2, where each Ry is independently H or methyl.
[00276] In one embodiment of Formula I, n is 0; R2 is selected from the group consisting of H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)0-, (3- 6C cycloalkyl)CH20-, amino(l-3C)alkyl, CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyc3, hetCycaCH2, Cyca, hetAr1 and Ar1; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00277] In one embodiment of Formula I, n is 0; R2 is H; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00278] In one embodiment of Formula I, n is 0; R2 is halogen; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment, R2 is F or CI.
[00279] In one embodiment of Formula I, n is 0; R2 is (l-6C)alkyl [optionally substituted with 1-5 fluoros]; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment of Formula I, R is methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl.
[00280] In one embodiment of Formula I, n is 0; R is (l-6C)alkoxy [optionally substituted with 1-5 fluoros]; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment of Formula I, R is methoxy, ethoxy, fiuoromethoxy, trifluoromethoxy, difluoromethoxy, or 2,2,2-trifluoroethoxy; and Ra and Rb are as defined for Formula I.
[00281] In one embodiment of Formula I, n is 0; R2 is (1-3C alkoxy)(l-4C)alkyl; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment, R2 is CH3OCH2-.
[00282] In one embodiment of Formula I, n is 0; R2 is (3-6C cycloalkyl)0-; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment, R2 has the structure:
Figure imgf000039_0001
[00283] In one embodiment of Formula I, n is 0; R is (3-6C cycloalkyl)CH20-; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment, R2 is cyclopropylmethoxy.
[00284] In one embodiment of Formula I, n is 0; R is amino(l-3C)alkyl; and R , X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, R2 is NH2CH2- . In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00285] In one embodiment of Formula I, n is 0; R2 is CF3CH2NHCH2; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00286] In one embodiment of Formula I, n is 0; R2 is HCF2CH2NHCH2; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl; Rb is H; and Ra and Rb are as defined for Formula I. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00287] In one embodiment of Formula I, n is 0; R2 is HCF2CH2NHCH2; and R1, X,
Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00288] In one embodiment of Formula I, n is is a C5-C8 bridged cycloalkyl; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, R2 has the structure:
Figure imgf000040_0001
[00289] In one embodiment of Formula I, n is 0; R2 is hetCyca, where hetCyc3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (l-6C)alkoxy and (l-6C)alkyl [optionally substituted with 1-3 fluoros]; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment, R2 is hetCyc3, where hetCyc3 is a 4-6 membered heterocyclic ring having a ring oxygen atom and optionally substituted with OH, F, (l-6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros]. In one embodiment of Formula I, n is 0 and R has the structure:
Figure imgf000040_0002
[00290] In one embodiment of Formula I, n is 0; R2 is hetCycaCH2; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00291] In one embodiment of Formula I, n is 0; R2 is Cyca, where Cyca is a (3- 6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (l-4C)alkyl, F or OH; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H. In one embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl, 2,2-difluorocyclopropyl, 3,3-diflorocyclobutyl, or 1- methoxycyclobutyl. [00292] In one embodiment of Formula I, n is 0; R is hetAr , where hetAr is a 5-6 membered heteroaryl having 1 -3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and Rb is H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00293] In one embodiment of Formula I, n is 0; R2 is Ar1, where Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN; and R1, X, Ring C, Ra and Rb are as defined for Formula I. In one embodiment, Ar1 is phenyl. In one embodiment, Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl. In one embodiment, Ra and Rb are both H. In one embodiment, Ra is cyclopropyl and R s H. In one embodiment, Ra is methyl and Rb is H. In one embodiment, Ra is CF3 and Rb is H.
[00294] In one embodiment, the portion of Formula I which has the structure
Figure imgf000041_0001
[00295] when n is 0 is selected from the structures:
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000043_0003
Figure imgf000043_0004
[00296] where X and Ring C are as defined for Formula I. In one embodiment of the above structures, X is O and Ring C is as defined for Formula I. In one embodiment of the above structures, X is O and Ring C is formula C-l.
[00297] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; and Ra, Rb, Rc, Rd, X, R1 and Ring C are as defined for Formula I. In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; Ra and Rb are hydrogen; and Rc, Rd, X, R1 and Ring C are as defined for Formula I.
[00298] In one embodiment of Formula I, n is 1; Ring A is A-l; R2 is H; and Ra, Rb, Rc, Rd, X, R1, and Ring C are as defined for Formula I. In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is H; Ra and Rb are hydrogen; and Rc, Rd, X, R1, and Ring C are as defined for Formula I.
[00299] In one embodiment of Formula I, n is 1; Ring A is A-l ; R2 is halogen; and Ra, Rb, Rc, Rd, X, R1, and Ring C are as defined for Formula I. In one embodiment of Formula I, n is 1 ; Ring A is A-l; R2 is halogen; Ra and Rb are hydrogen; and Rc, Rd, X, R1, and Ring C are as defined for Formula I.
[00300] In one embodiment of Formula I, n is 1 ; Ring A is A-l; R is CF3, F2CH, FCH2 or methyl; and Ra, Rb, Rc, Rd, X, R1, and Ring C are as defined for Formula I. In one embodiment of Formula I, n is 1 ; Ring A is A-l; R2 is CF3, F2CH, FCH2 or methyl; Ra and Rb are hydrogen; and Rc, Rd, X, R1, and Ring C are as defined for Formula I.
[00301] In one embodiment of Formula I, n is 1; Ring A is A-l; R is methoxy; and
Ra, Rb, Rc, Rd, X, R1, and Ring C are as defined for Formula I. In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is methoxy; Ra and Rb are hydrogen; and Rc, Rd, X, R1, and Ring C are as defined for Formula I.
[00302] In one embodiment, the portion of Formula I which has the structure
Figure imgf000044_0001
[00303] when n is 1 is selected from the structures:
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000045_0002
[00304] where X and Ring C are as defined for Formula I. In one embodiment, X is O and Ring C is as defined for Formula I. In one embodiment, X is O and Ring C is formula C- 1.
[00305] Reference will now be made to Ring C.
[00306] In one embodiment, Ring C is formula C-l:
Figure imgf000045_0003
C-l
[00307] where R3, R4 and R5 are as defined for Formula I.
[00308] In one embodiment, R3 is (l-6C)alkyl. In one embodiment, R3 is methyl or ethyl.
[00309] In one embodiment, R3 is hydroxy(l-6C)alkyl. An example of R3 is 2- hydroxyethyl.
[00310] In one embodiment, R is Ar , where Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl. [00311] In one embodiment, R when represented by Ar is phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3- chlorophenyl, 3-chloro-4-fluorophenyl or 3-chloro-2-fluorophenyl. In one embodiment, R when represented by Ar2 is phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2- methylphenyl, 3-methylphenyl or 4-methylphenyl. In one embodiment, R is phenyl.
[00312] In one embodiment, R is hetCyc , where hetCyc is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1 -2 ring heteroatoms independently selected from N and O. In one embodiment, R3 is a pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl ring. In one embodiment, R3 is tetrahydro-2H-pyran-4-yl .
[00313] In one embodiment, R3 is (3-7C)cycloalkyl. In one embodiment R3 is cyclohexyl.
[00314] In one embodiment, R3 is hetAr2, where hetAr2 is 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (l-6C)alkyl and halogen. In one embodiment, R3 is thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl and halogen. In one embodiment, R3 is pyrazolyl, pyridyl or pyridazinyl optionally substituted with one or more groups independently selected from (1- 6C)alkyl and halogen. In one embodiment, R is pyrazolyl, pyridyl or pyridazinyl optionally substituted with (l-6C)alkyl or halogen. In one embodiment, R when represented by hetAr is 1 -methyl- 1 H-pyrazol-4-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyridazinyl or 3-chloropyrid- 5-yl.
[00315] In one embodiment, R3 is selected from Ar2 and hetAr2.
[00316] In one embodiment, R is Ar . In one embodiment, R is phenyl.
[00317] In one embodiment, R4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino( 1 -6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido(l-6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (1- 6C)alkoxy, monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l- 6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l-6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1- 3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro( 1 -6C)alkoxy, (1-3 C)alkylsulfonamido( 1 -6C)alkoxy, (1-3 C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1- 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr5, Ar4-0-, hetCyc4-0-, Cyc'-Ο-, or aminohydroxy(l-6C)alkoxy; and
[00318] R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l- 6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy).
[00319] In one embodiment, R4 is OH. In one embodiment, R4 is OH and R3 is H. Examples of C-l rings when R4 is OH and R3 is H include the following tautomeric structures:
Figure imgf000047_0001
[00320] In one embodiment, R4 is (l-6C)alkyl. In one embodiment, R4 is methyl, ethyl, isopropyl or tert-butyl.
[00321] In one embodiment, R4 is monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl. In one embodiment, R4 is fluoromethyl, 2-fluoroethyl, difluoromethyl and 2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl or 2,2,3,3,3- pentafluoropropyl
[00322] In one embodiment, R4 is trifluoro(l-6C)alkyl. In one embodiment, R4 is CF3. [00323] In one embodiment, R4 is cyano(l-6C)alkyl. In one embodiment, R4 is cyanomethyl or 2-cyanopropan-2-yl.
[00324] In one embodiment, R4 is hydroxy(l-6C)alkyl. In one embodiment, R4 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl or 1-hydroxy- 2-methylpropan-2-yl.
[00325] In one embodiment, R4 is dihydroxy(2-6C)alkyl. In one embodiment, R4 is 2,3-dihydroxypropyl.
[00326] In one embodiment, R4 is (1-3C alkoxy)(l-6C)alkyl. In one embodiment, R4 is methoxymethyl, 2-methoxyethyl or 3-methoxypropyl.
[00327] In one embodiment, R4 is amino(l-6C)alkyl. In one embodiment, R4 is aminomethyl, 2-aminoethyl or 3-aminopropyl.
[00328] In one embodiment, R4 is aminocarbonyl(l-6C)alkyl. In one embodiment, R4 is aminocarbonylmethyl and 2-(aminocarbonyl)ethyl.
[00329] In one embodiment, R4 is (l-3C)alkylsulfonamido(l-6C)alkyl. In one embodiment, R4 is CH3S02NHCH2- or CH3S02NHCH2CH2-.
[00330] In one embodiment, R4 is hydroxycarbonyl(l-6C)alkyl. In one embodiment, R4 is HOC(=0)CH2- and HOC(=0)CH2CH2-.
[00331] In one embodiment, R4 is hetAr3(l-6C)alkyl, where hetAr3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, S and O and optionally substituted with (l-6C)alkyl. In one embodiment, hetAr3 is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (l-6C)alkyl. In one embodiment, R4 when represented by hetAr3(l-6C)alkyl is (l-methyl-lH-l,2,4-triazol-3-yl)methyl or (5-methyl-l,3,4-oxadiazol-2- yl)methyl.
[00332] In one embodiment, R4 is Ar3(l-6C)alkyl, where phenyl optionally substituted with (l-4C)alkoxy or hydroxy(l-4C)alkyl. In one embodiment, Ar (l-6C)alkyl is benzyl.
[00333] In one embodiment, R4 is (l-6C)alkoxy. Examples include methoxy and ethoxy.
[00334] In one embodiment, R4 is monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifiuoro(l-6C)alkoxy, tetrafluoro(2-6C)alkoxy or pentafluoro(2-6C)alkoxy. In one embodiment, R4 is fluoromethoxy, 2-fluoroethoxy, 2,2-difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or 2,2-difluoroethoxy. In one embodiment, R4 is 2-fluoroethoxy.
[00335] In one embodiment, R4 is cyano(l-6C)alkoxy. In one embodiment, R4 is cyanomethoxy or 2-cyanoethoxy. [00336] In one embodiment, R4 is hydroxy(l-6C)alkoxy. In one embodiment, R4 is 2- hydroxy-2-methylpropoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2- methylpropoxy or 2-hydroxybutoxy.
[00337] In one embodiment, R4 is dihydroxy(2-6C)alkoxy. In one embodiment, R4 is
2,3-dihydroxypropoxy or 3-hydroxy-2-(hydroxymethyl)propoxy.
[00338] In one embodiment, R4 is amino(2-6C)alkoxy. In one embodiment, R4 is H2NCH2CH20- or H2NCH(CH3)CH20-.
[00339] In one embodiment, R is hetCyc (l-6C)alkoxy, where hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc is optionally substituted with 1-2 groups independently selected from (1- 6C)alkyl, (1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo. In one embodiment, hetCyc is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or and 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo.
4 2 2
[00340] In one embodiment, R is hetCyc (l-6C)alkoxy, where hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc2 is optionally substituted with 1-2 groups independently selected from (1- 6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl. In one embodiment, hetCyc2 is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or and 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, R4 when represented by hetCyc2(l-6C)alkoxy is oxetan-2-ylmethoxy, 2- (oxetan-2-yl)propoxy, 2-morpholinoethoxy, piperazinylethyoxy or piperidinylethoxy optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl.
[00341] In one embodiment, R4 is represented by the structures:
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000050_0004
Figure imgf000050_0005
Figure imgf000050_0006
Figure imgf000050_0007
[00342] In one embodiment, R4 is hetAr3(l-6C)alkoxy, where hetAr3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, S and O and optionally substituted with (l-6C)alkyl. In one embodiment, hetAr3 is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (l-6C)alkyl. In one embodiment, hetAr3 is triazolyl or oxadiazolyl ring optionally substituted with a (l-6C)alkyl group such as a methyl group. In one embodiment, R4 when represented by hetAr3(l-6C)alkoxy is (1 -methyl- lH-l,2,4-triazol- 3-yl)methoxy or (5-methyl-l,3,4-oxadiazol-2-yl)methoxy, which can be represented by the structures:
Figure imgf000051_0001
[00343] In one embodiment, R4 is Ar3(l-6C)alkoxy, where Ar3 is phenyl optionally substituted with (l-4C)alkoxy. In one embodiment, R4 is phenylmethoxy or (4- methoxyphenyl)methoxy having the structures:
Figure imgf000051_0002
[00344] In one embodiment, R4 is (1-4C alkoxy)(l-6C)alkoxy. In one embodiment, R4 is(2-methoxy)ethoxy having the structure:
Figure imgf000051_0003
[00345] In one embodiment, R4 is (l-3Calkylsulfonyl)(l-6C)alkoxy. In one embodiment, 4 is (2-methylsulfonyl)ethoxy having the structure:
Figure imgf000051_0004
[00346] In one embodiment, R4 is (3-6C)cycloalkyl optionally substituted with F, OH,
(1-6C alkyl), (l-6C)alkoxy or (1-3C alkoxy)(l -6C)alkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-hydroxycyclobutyl. In one embodiment, R4 is cyclopropyl or 2-hydroxycyclobutyl. In one embodiment, R4 is cyclopropyl.
[00347] In one embodiment, R4 is hetAr4, where hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3- 6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino.
[00348] In one embodiment, R4 is hetAr4 where hetAr4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1 ,2,4-oxadiazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l- 6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino.
[00349] In one embodiment, R4 is hetAr4 where hetAr4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1 ,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1 ,2,4-oxadiazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3- 6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl and cyclopropylNH-.
[00350] In one embodiment, R4 is hetAr4, where hetAr4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1 ,2,4-oxadiazolyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H2N-, (CH3)2N-, 2- hydroxyethyl, 2-methoxyethyl, 1 -(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl, cyclopropylcarbonyl, methylsulfonyl and cyclopropylNH-.
[00351] In one embodiment, R4 is hetAr4, where hetAr4 is pyridyl, pyrimidinyl or pyridazinyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2- trifluoroethyl, methoxy, ethoxy, CN, H2N-, CH3NH-, (CH3)2N-, and cyclopropylNH-.
[00352] In one embodiment, R4 when represented by hetAr4 is selected from the structures:
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
[00353] In one embodiment, R4 is hetAr4-0-. In one embodiment, R4 is hetAr4-0-, where hetAr4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4- triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1,2,4-oxadiazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1- 6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl and cyclopropylNH-.
[00354] In one embodiment, R4 is hetAr4-0-, where hetAr4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1,2,4-oxadiazolyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H2N-, (CH3)2N-, 2- hydroxyethyl, 2-methoxyethyl, 1 -(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl, cyclopropylcarbonyl, methylsulfonyl and cyclopropylNH-.
[00355] In one embodiment, R4 is hetAr4-0-, where hetAr4 is pyridyl, pyrimidinyl or pyridazinyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2- trifluoroethyl, methoxy, ethoxy, CN, H2N-, CH3NH-, (CH3)2N-, and cyclopropylNH-.
[00356] In one embodiment, R4 when represented by hetAr4-0- is a group having the structure:
Figure imgf000054_0002
[00357] In one embodiment, R4 is Ar4, where Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (1- 6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-. In one embodiment, Ar4 is phenyl optionally substituted with one or more groups independently selected from methyl, F, CI, CN, methoxy, CH3OC(=0)-, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylthio, CH3S02-, HOC(=0)- and CH3OCH2CH2OC(=0)-. In one embodiment, Ar4 is phenyl optionally substituted with one or two of said substituents. In one embodiment, Ar4 is selected from the structures:
Figure imgf000055_0001
[00358] In one embodiment, R4 is hetCyc2(0)CH2, where hetCyc2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc is optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl. Examples of hetCyc2 include oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, R4 when represented by hetCyc (0)CH2, is selected from the structures:
Figure imgf000056_0001
[00359] In one embodiment, R4 is (1-4C alkoxycarbonyl)(l-6C)alkoxy. In one embodiment, R4 is methoxycarbonyl(l-6C)alkoxy or ethylcarbonyl(l-6C)alkoxy. A particular example is ethoxycarbonylmethoxy.
[00360] In one embodiment, R4 is hydroxycarbonyl(l-6C)alkoxy. In one embodiment, R4 is hydroxycarbonylmethoxy.
[00361] In one embodiment, R4 is aminocarbonyl(l-6C)alkoxy. In one embodiment, R4 is H2NC(=0)(l-6C)alkoxy, (1-6C alkyl)NHC(=0)(l-6C)alkoxy, or di(l- 6Calkyl)NC(=0)(l-6C)alkoxy. In one embodiment, R4 is H2NC(=0)CH20-,
H2NC(=0)CH2CH20- or CH3CH2NC(=0)CH20-.
[00362] In one embodiment, R4 is hetCyc2C(=0)(l-6C)alkoxy, where hetCyc2 is a 4-6 membered heterocyclic ring having 1 -2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl. In one embodiment, hetCyc2 is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, hetCyc2 is morpholinyl. In one embodiment, R4 when represented by hetCyc2C(=0)(l-6C)alkoxy is the structure:
Figure imgf000056_0002
[00363] In one embodiment, R4 is hydroxy(l-3C alkoxy)(l-6C)alkoxy.
embodiment, R4 is 2-hydroxy-3-methoxypropoxy, having the structure:
Figure imgf000056_0003
[00364] In one embodiment, R4 is hydroxytrifluoro(l-6C)alkoxy. In one embodiment, R4 is 3,3,3-difluoro-2-hydroxypropoxy having the structure:
Figure imgf000057_0001
[00365] In one embodiment, R4 is (l-3C)alkylsulfonamido(l-6C)alkoxy. In one embodiment, R4 is methanesulfonamido(l-6C)alkoxy. In one embodiment, R4 is 2- methanesulfonamidoethoxy having the structure:
Me02S 0
[00366] In one embodiment, R4 is (l-3C)alkylamido(l-6C)alkoxy. In one embodiment, R4 is 2-(methylamido)ethox having the structure:
Figure imgf000057_0002
[00367] In one embodiment, R4 is di(l-3C alkyl)aminocarboxy. In one embodiment, R4 is dimethylaminocarboxy having the structure:
Figure imgf000057_0003
[00368] In one embodiment, R4 is hetCyc2C(=0)0-, where hetCyc2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, hetCyc is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, hetCyc is morpholinyl. In one embodiment, R4 when represented by hetCyc2C(=0)0- is the structure:
Figure imgf000057_0004
[00369] In one embodiment, R4 is hydroxydifluoro(l-6C)alkyl. In one embodiment, R4 is 2,2-difluro-2-hydroxyethyl. [00370] In one embodiment, R4 is (1-4C alkylcarboxy)(l-6C)alkyl. In one embodiment, R4 is methylcarboxy(l-6C)alkyl. In one embodiment, R4 is 2- (methylcarboxy)ethyl .
[00371] In one embodiment, R4 is (l-6C)alkoxycarbonyl. In one embodiment, R4 is methoxycarbonyl or ethoxycarbonyl.
[00372] In one embodiment, R4 is hydroxycarbonyl.
[00373] In one embodiment, R4 is aminocarbonyl, that is, a RR'NCO- radical where R and R' are independently hydrogen or (l-6C)alkyl as defined herein. In one embodiment, R4 is aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylcarbonyl or isopropylaminocarbonyl.
[00374] In one embodiment, R4 is (1-3C alkoxy)aminocarbonyl. In one embodiment, R4 is methoxyaminocarbonyl.
[00375] In one embodiment, R4 is hetCyc3, where is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, CF3, (l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc is optionally substituted with one or two of said substituents. In one embodiment, hetCyc is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl optionally substituted with CN, Me, CH3C(=0)-, MeS02-, or CF3S02-. In one embodiment, R4 when represented by hetCyc3 is selected from the structures:
Figure imgf000058_0001
[00376] In one embodiment, R4 is halogen. In one embodiment, R4 is Br.
[00377] In one embodiment, R4 is CN.
[00378] In one embodiment, R4 is trifluoromethylsulfonyl.
[00379] In one embodiment, R4 is hetAr5, where hetAr5 is a group selected from the structures:
Figure imgf000059_0001
[00380] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros.
[00381] In one embodiment, R4 when represented by hetAr5 is selected from the structures:
Figure imgf000059_0002
Figure imgf000059_0003
[00382] In one embodiment, R4 is N-(1-3C alkyl)oxadiazolonyl. In one embodiment, R4 is represented by the structures:
Figure imgf000060_0001
[00383] In one embodiment, R4 is Ar4-0-, where Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF3O-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1- 6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-. In one embodiment, R4 is phenoxy.
[00384] In one embodiment, R4 is hetCyc4-0-, where hetCyc4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
[00385] In one embodiment, R4 is hetCyc4-0-, where hetCyc4 is pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, l-azaspiro[3.3]heptane or quinuclidinyl, optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
[00386] In one embodiment, R4 when represented by hetCyc4-0- is selected from the strutures:
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000060_0004
Figure imgf000060_0005
[00387] In one embodiment, R4 is Cyc'-O, where Cyc1 is a 3-6 membered carbocycle optionally substituted with an amino group. In one embodiment, R4 is Cyc'-O, where Cyc1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with NH2, NHCH3 or N(C¾)2. In one embodiment, R4 is cyclobutyl optionally substituted with an amino group. In one embodiment, R4 is cyclobutyl optionally substituted with NH2, NHCH3 or N(CH3)2. In one embodiment, R4 when represented by Cyc'-O- is selected from the structures:
Figure imgf000061_0001
[00388] In one embodiment, R4 is aminohydroxy(l-6C)alkoxy. In one embodiment,
R4 is 2-amino-3-hydroxypropoxy.
[00389] In one embodiment, R4 is selected from H, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, cyano(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2- 6C)alkoxy, hetCyc2(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1 -4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl, hetAr4, hetAr4-0-, Ar4, and hetAr5.
[00390] In one embodiment, R4 is hetAr4, Ar4, or hetAr5.
[00391] In one embodiment, R4 is hetAr4 or hetAr5.
[00392] In one embodiment, R4 is pyrazolyl optionally substituted with one or more groups independently selected from (l-6C alkyl, or a hetAr5 group having the structure:
Figure imgf000061_0002
[00393] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein said hetAr5 group is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros.
[00394] In one embodiment, R5 is (l-6C)alkyl. In one embodiment, R5 is methyl, ethyl, propyl, isopropyl or butyl.
[00395] In one embodiment, R5 is monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluro(2-6C)alkyl or pentafluro(2-6C)alkyl. In one embodiment, R5 is fluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, l,3-difluoroprop-2-yl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1,1,2,2-tetrafluoropropane or 2,2,3,3,3-pentafluoropropyl.
[00396] In one embodiment, R5 is halogen. In one embodiment, R5 is F. In one embodiment, R5 is CI. In one embodiment, R5 is Br.
[00397] In one embodiment, R5 is CN.
[00398] In one embodiment, R5 is (l-4C)alkoxy. In one embodiment, R5 is methoxy or ethoxy.
[00399] In one embodiment, R5 is hydroxy(l-4C)alkyl. In one embodiment, R5 is hydroxymethyl or 3-hydroxypropyl.
[00400] In one embodiment, R5 is (1-4C alkyl)OC(=0)-. In one embodiment, R5 is CH3CH2OC(=0)-.
[00401] In one embodiment, R5 is (l-6C)alkylthio. In one embodiment, R5 is methylthio (MeS-).
[00402] In one embodiment, R5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy. In one embodiment, R5 is phenyl optionally substituted with one or more groups independently selected from F, CI, methyl, ethyl, methoxy and ethoxy. In one embodiment, R5 is phenyl.
[00403] In one embodiment, R5 is (3-4C)cycloalkyl. In one embodiment, R5 is cyclopropyl. In one embodiment, R5 is cyclobutyl.
[00404] In one embodiment, R5 is amino. In one embodiment, R5 is NH2.
[00405] In one embodiment, R5 is aminocarbonyl. In one embodiment, R5 is
H2NC(=0)-.
[00406] In one embodiment, R5 is trifluoro(l-3C alkyl)amido. In one embodiment, R5 is CF3C(=0)NH-.
[00407] In one embodiment, R5 is halogen, CN, ( 1 -6C)alkyl, ( 1 -4C)alkoxy, hydroxy( 1 - 4C)alkyl, or phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy.
[00408] In one embodiment, R5 is selected from halogen, and (l-6C)alkyl.
[00409] In one embodiment, R5 is selected from methyl, CI and Br.
[00410] In one embodiment of Formula I, R4 is selected from H, (l-6C)alkyl, trifluoro(l-6C)alkyI, cyano(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, cyano(l-
6C)alkoxy, hydroxy(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (3-6C)cycloalkyl, hetAr4, Ar4, and hetAr5; and R5 is selected from halogen, CN, (l-6C)alkyl, (l-4C)alkoxy, hydroxy(l- 4C)alkyl, (l-6C)alkylthio, and phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy.
[00411] In one embodiment, R4 is selected from (l-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, hetAr4, hetAr5, Ar4-0-, hetCyc4-0-, Cyc'-Ο-, or aminohydroxy(l-6C)alkoxy.
[00412] In one embodiment, R4 is selected from (l-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, hetAr4 and hetAr5.
[00413] In one embodiment of Formula I, R4 is selected from hetAr4, Ar4, and hetAr5; and R5 is selected from (l-6C)alkyl.
[00414] In one embodiment of Formula I, R4 is selected from hetAr4 and hetAr5; and R5 is selected from (l-6C)alkyl.
[00415] In one embodiment of Formula I, R4 is hetAr4 and R5 is selected from (1-
6C)alkyl.
[00416] In one embodiment of Formula I, R4 is pyrazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl; and R5 is selected from (l-6C)alkyl.
[00417] In one embodiment of Formula I, R4 is hetAr5; and R5 is selected from (1- 6C)alkyl.
[00418] In one embodiment of Formula I R4 is a hetAr5 group having the structure:
Figure imgf000063_0001
[00419] where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein said hetAr5 group is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros; and R5 is selected from (l-6C)alkyl.
[00420] In one embodiment, R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl; or R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=0)0-, (l-6C)acyl, (l-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(=0) or S02.
[00421] In one embodiment, R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl. In one embodiment, Ring C when R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated or unsaturated carbocyclic ring is selected from the structures:
Figure imgf000064_0001
[00422] where R is as defined for Formula I. In one embodiment of the above structures, R is phenyl.
[00423] In one embodiment, R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said ring nitrogen atom is optionally substituted with (1-6C alkyl)C(=0)0- or (l-6C)acyl, and said sulfur ring atom is optionally oxidized to S(=0) or S02.
[00424] In one embodiment, R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl. In one embodiment, Ring C when R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated carbocyclic ring is selected from the structures:
Figure imgf000064_0002
[00425] where R3 is as defined for Formula I. In one embodiment of the above structures, R3 is phenyl.
[00426] In one embodiment, R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said ring N atom is optionally substituted with (1-6C alkyl)C(=0)0-, (1-6C alkyl)C(=0)-, (l-6C)alkyl or oxo, and said S ring atom is optionally oxidized to S(=0) or S02. In one embodiment, Ring C when R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring is selected from the structures:
Figure imgf000065_0001
[00427] where R3 is as defined for Formula I. In one embodiment of the above structures, R3 is phenyl.
[00428] In one embodiment, R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said ring N atom is optionally substituted with (1-6C alkyl)C(=0)0- or (1-6C alkyl)C(=0)-, and said S ring atom is optionally oxidized to S(=0) or S02. In one embodiment, Ring C when R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring is selected from the structures:
Figure imgf000065_0002
Figure imgf000066_0001
[00429] where R3 is as defined for Formula I. In one embodiment of the above structures, R is phenyl.
[00430] In one embodiment, R -2
Figure imgf000066_0002
[00431] where R3a, R4a and R5a are as defined for Formula I.
[00432] In one embodiment, R3a is hydrogen.
[00433] In one embodiment, R3a is halogen.
[00434] In one embodiment, R3a is (l-6C)alkyl. In one embodiment, R3a is methyl.
[00435] In one embodiment, R3a is trifluoro(l-6C)alkyl. In one embodiment, R3a is
CF3.
[00436] In one embodiment, R3a is (3-6C)cycloalkyl. In one embodiment, R3a is cyclopropyl.
[00437] In one embodiment, R3a is phenyl optionally substituted with one or more substituents independently selected from halogen and (l-6C)alkyl. In one embodiment, R3a is phenyl, fluorophenyl or methylphenyl, for example include phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3 -methylphenyl, 4-methylphenyl, 3- chlorophenyl, 3-chloro-4-fluorophenyl or 3-chloro-2-fluorophenyl. In one embedment, R3a is phenyl.
[00438] In one embodiment, R3a is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen. In one embodiment, R3a is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl ring optionally substituted with (l-6C)alkyl or halogen. In one embodiment, R3a is pyrazolyl, pyridyl or pyridazinyl optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen. In one embodiment, R3a is pyrazolyl, pyridyl or pyridazinyl optionally substituted with (l-6C)alkyl or halogen. [00439] In one embodiment, R4a is hydrogen.
[00440] In one embodiment, R4a is (l-6C)alkyl. In one embodiment, R4a is methyl, ethyl or isopropyl.
[00441] In one embodiment, R4a is trifluoro(l-6C)alkyl. In one embodiment, R4a is 2,2,2-trifluoroethyl.
[00442] In one embodiment, R4a is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (1- 6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-. In one embodiment, R4a is phenyl optionally substituted with one or more groups independently selected from methyl, F, CI, CN, methoxy, CH3OC(=0)-, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylthio, CH3S02-, HOC(=0)- or CH3OCH2CH2OC(=0)-. In certain embodiments, R4a is phenyl optionally substituted with one or two of said substituents. In one embodiment, R4a is phenyl.
[00443] In one embodiment, R4a is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l- 6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl. In one embodiment, R4a is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3- triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl or imidazo[l,2-a]pyridinyl optionally substituted with 1-2 substituents independently selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1- 6C alkyl)amino, di(l-6C alkyl)amino, and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl. In one embodiment, R4a is pyrazinyl.
[00444] In one embodiment, R5a is as defined for Formula I.
[00445] In one embodiment, R5a is selected from hydrogen, halogen, (l-6C)alkyl and phenyl.
[00446] In one embodiment, R5a is hydrogen.
[00447] In one embodiment, R5a is halogen.
[00448] In one embodiment, R5a is (l-6C)alkyl. In one embodiment, R5a is methyl.
[00449] In one embodiment, R5a is phenyl. [00450] In one embodiment, Ring C is formula C-2, in which R3a is (l-6C)alkyl, trifluoro(l-6C)alkyl or phenyl; R4a is (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl or pyrazinyl; and R5a is hydrogen, (l-6C)alkyl or phenyl.
[00451] In one embodiment of Formula I, Ring A is A- 1 , and R1, R2, Ra, Rb, n, Rc, Rd,
G1, G2, G3, X, Ring C, R3, R4, R5, R3a, R4a and R5a are as defined for Formula I.
[00452] In one embodiment of Formula I, Ring A is A-1 ; n is 0; and G1, G2, G3, R1, R2,
Ra, Rb, X, Ring C, R3, R4, R5, R3a, R4a and R5a are as defined for Formula I.
[00453] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; and G\ G
G3, R1, R2, Ra, Rb, Ring C, R3, R4 and R5 are as defined for Formula I.
[00454] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; and G1, G2, G3, R1, R2, Ra, Rb, R3, R4 and R5 are as defined for Formula I.
[00455] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ;
R4 is hetAr4 or hetAr5; and G1, G2, G3, R1, R2, Ra, Rb, R3, and R5 are as defined for Formula
I.
[00456] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; and G1, G2, G3, R1, R2, Ra, Rb, and R5 are as defined for Formula I.
[00457] In one embodiment of Formula I, Ring A is A-1 ; n is 0; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; and G1, G2, G3, R1, R2, Ra, and Rb are as defined for Formula I.
[00458] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; and G1, G2, G3, R1, R2, and Ra are as defined for Formula I.
[00459] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; and G1, G2, G3, R1, and R2 are as defined for Formula I.
[00460] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; and G1, G2, G3, and R2 are as defined for Formula I.
[00461] In one embodiment of Formula I, Ring A is A-1 ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; and G1, G2, and G3 are as defined for Formula I. [00462] In one embodiment of Formula I, Ring A is A-l ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alk l; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; and G1, G2 and G3 are CRX.
[00463] In one embodiment of Formula I, Ring A is A- 1 ; n is 0; X is O; Ring C is C- 1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; G1 and G3 are CRX; and G2 is N.
[00464] In one embodiment of Formula I, Ring A is A-l ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; G1 and G2 are CRX; and G3 is N.
[00465] In one embodiment of Formula I, Ring A is A-l ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; G1 and G2 are N; and G3 is CRX.
[00466] In one embodiment of Formula I, Ring A is A-l ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; G2 and G3 are N; and G1 is CRX.
[00467] In one embodiment of Formula I, Ring A is A-l ; n is 0; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Rb is H; Ra is H; R1 is (l-3C)alkoxy(l- 3C)alkyl; R2 is H, halogen, CF3, F2CH, FCH2 or methoxy; G1 and G3 are N; and G2 is CRX.
[00468] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; and G1, G2, G3, Ra, Rb, Rc, Rd, X, R1, Ring C, R3, R4, R5, R3a, R4a and R5aare as defined for Formula I.
[00469] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; and G , G , G , Ra, Rb, Rc, Rd, R1, Ring C, R3, R4, R5, R3a, R4a and R5aare as defined for Formula I.
[00470] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; and G1, G2, G3, Ra, Rb, Rc, Rd, X, R1, R3, R4, and R5 are as defined for Formula I. In one embodiment, G1, G2, G3, Ra, Rb, Rc, Rd, X, R1, R3, R4, and R5 are as defined for Formula I-C.
[00471] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; and G1, G2, G3, Ra, Rb, Rc, Rd, X, R1, R3, and R5 are as defined for Formula I.
[00472] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; and G1, G2, G3, Ra, Rb, Rc, Rd, X, R1, and R5 are as defined for Formula I. In one embodiment, G1, G2, G3, Ra, Rb, R°, Rd, X, R1, and R5 are as defined for Formula I-C.
[00473] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; and G1, G2, G3, Ra, Rb, Rc, Rd, and R1 are as defined for Formula I. In one embodiment, G1, G2, G3, Ra, Rb, Rc, Rd, and R1 are as defined for Formula I-C.
[00474] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; and G1, G2, G3, Rc, Rd, and R1 are as defined for Formula I. In one embodiment, G1, G2, G3, R°, Rd, and R1 are as defined for Formula I-C.
[00475] In one embodiment of Formula I, n is 1 ; Ring A is A- 1 ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; and G1, G2, G3, Rd, and R1 are as defined for Formula I. In one embodiment, G1, G2, G3, Rd, and R1 are as defined for Formula I-C.
[00476] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; and G1, G2, G3, and Rd are as defined for Formula I. In one embodiment, G1, G2, G3, and Rd are as defined for Formula I-C.
[00477] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; G1, G2 and G3 are CRX; and Rd is as defined for Formula I. In one embodiment, Rd is as defined for Formula I-C.
[00478] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; G1 and G3 are CRX; G2 is N; and Rd is as defined for Formula I. In one embodiment, Rd is as defined for Formula I-C. [00479] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; G1 and G2 are CRX; G3 is N; and Rd is as defined for Formula I. In one embodiment, Rd is as defined for Formula I-C.
[00480] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; G1 and G2 are N; G3 is CRX; and Rd is as defined for Formula I. In one embodiment, Rd is as defined for Formula I-C.
[00481] In one embodiment of Formula I, n is 1 ; Ring A is A- 1 ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; G2 and G3 are N; G1 is CRX; and Rd is as defined for Formula I. In one embodiment, Rd is as defined for Formula I-C.
[00482] In one embodiment of Formula I, n is 1 ; Ring A is A-l ; R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, MeO and methyl; X is O; Ring C is C-1; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; Ra and Rb are H; Rc is H; R1 is (1- 3C)alkoxy(l-3C)alkyl; G1 and G3 are N; G2 is CRX; and Rd is as defined for Formula I. In one embodiment, Rd is as defined for Formula I-C.
[00483] In one embodiment of Formula I, Ring A is A-2, and Ra, Rb, X, Ring C, R3, R4, R5, R3a, R4a and R5a are as defined for Formula I. In one embodiment, Ra, Rb, X, Ring C, R3, R4, R5, R3a, R4a and RSa are as defined for Formula I-C.
[00484] In one embodiment of Formula I, Ring A is A-2; X is O; and Ra, Rb, Ring C, R3, R4, R5, R3a, R4a and R5a are as defined for Formula I. In one embodiment, Ra, Rb, Ring C, R3, R4, R5, R3a, R4a and R5a are as defined for Formula I-C.
[00485] In one embodiment of Formula I, Ring A is A-2; X is O; Ring C is C-1 ; and Ra, Rb, R3, R4, and R5 are as defined for Formula I. In one embodiment, Ra, Rb, R3, R4, and R5 are as defined for Formula I-C.
[00486] In one embodiment of Formula I, Ring A is A-2; X is O; Ring C is C-1 ; R4 is hetAr4 or hetAr5; and Ra, Rb, R3 and R5 are as defined for Formula I. In one embodiment, Ra, Rb, R3 and R5 are as defined for Formula I-C. [00487] In one embodiment of Formula I, Ring A is A-2; X is O; Ring C is C-l ; R4 is hetAr4 or hetAr5; R3 is Ar2; and Ra, Rb and R5 are as defined for Formula I. In one embodiment, Ra, Rb and R5 are as defined for Formula I-C.
[00488] In one embodiment of Formula I, Ring A is A-2; X is O; Ring C is C-l ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; and Ra and Rb are as defined for Formula I. In one embodiment, Ra and Rb are as defined for Formula I-C.
[00489] In one embodiment of Formula I, Ring A is A-2; X is O; Ring C is C-l ; R4 is hetAr4 or hetAr5; R3 is Ar2; R5 is (l-6C)alkyl; and Ra and R are H.
[00490] It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
[00491] It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of Formula I can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
[00492] The compounds of Formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which are useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I. Particular examples of salts include hydrochloride salts and trifluoroacetate salts.
[00493] In one embodiment, the compounds of Formula I include the free base form of compounds of Examples 1-132, or pharmaceutically acceptable salts thereof.
[00494] In one embodiment, the compounds of Formula I include the hydrochloride salts of compounds of Examples 1-132.
[00495] In one embodiment, the compounds of Formula I include the trifluoroacetate salts of compounds of Examples 1-132.
[00496] The term "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[00497] The present invention also provides a process for the preparation of a compound of Formula I or a salt thereof as defined herein, which comprises: [00498] (a) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
Figure imgf000073_0001
II
[00499] with a corresponding compound having the formula HI
Figure imgf000073_0002
III
[00500] in the presence carbonyldiimidazole or triphosgene and a base; or
[00501] (b) for a compound of Formula I where X is S, coupling a corresponding compound having the formula II
Figure imgf000073_0003
II
[00502] with a corresponding compound having the formula III
Figure imgf000073_0004
III
[00503] in the presence di(lH-imidazol-2-yl)methanethione and a base; or
[00504] (c) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
Figure imgf000074_0001
II
[00505] with a corresponding compound having the formula IV
Figure imgf000074_0002
IV
[00506] where L1 is a leaving group, in the presence of a base; or
[00507] (d) for a compound of Formula I where X is O, coupling a corresponding compound having the formula V
Figure imgf000074_0003
[00508] where L is a leaving group, with a corresponding compound having the formula III
Figure imgf000074_0004
III
[00509] in the presence of a base; or [00510] (e) for a compound of Formula I where X is O, activating a corresponding compound having the formula VI
Figure imgf000075_0001
VI
[00511] with diphenylphosphoryl azide followed by coupling the activated intermediate with a corresponding compound having the formula III
Figure imgf000075_0002
III
[00512] in the presence a base; or
[00513] (f) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
Figure imgf000075_0003
II
[00514] with a corresponding com ound havin the formula VII
Figure imgf000075_0004
vn [00515] in the presence of a base; or
[00516] (g) for a compound of Formula I where X is O, coupling a corresponding compound having the formula VIII
Figure imgf000076_0001
VIII
[00517] a corresponding com ound having the formula III
Figure imgf000076_0002
III
[00518] in the presence of a base; and
[00519] optionally removing protecting groups and optionally preparing a pharmaceutically acceptable salt thereof.
[00520] In the above methods, the term "corresponding" means that the definitions for the "corresponding compound" are as defined for Formula I unless stated otherwise.
[00521] Referring to method (a), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include dichloromethane, dichloroethane, THF,
DMA and DMF. The reaction is conveniently performed at ambient temperature.
[00522] Referring to method (b), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include dichloromethane, dichloroethane, THF,
DMA and DMF. The reaction is conveniently performed at ambient temperature.
[00523] Referring to method (c), the leaving group may be, for example, phenoxy or 4- nitrophenoxy. The base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DMA, DMF and DCE. The reaction is conveniently performed at ambient temperature. [00524] Referring to method (d), the leaving group may be, for example, phenoxy or 4- nitrophenoxy. The base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DCE, DMA and DMF. The reaction is conveniently performed at ambient temperature.
[00525] Referring to method (e), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include toluene and DMF. The reaction is conveniently performed at elevated temperatures, for example the reflux temperature of the solvent.
[00526] Referring to methods (f) and (g), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DCM, DCE, DMF and THF. The reaction is conveniently performed at temperatures between about 0 °C and ambient temperature.
[00527] Amine groups in compounds described in any of the above methods may be protected with any convenient amine protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC) and [2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groups may be protected with any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groups may be protected with any convenient alcohol protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.
[00528] The compounds of the formulas II, IV, V, VI, VII and VIII are also provided as further aspects of the invention. In one embodiment, the compounds of the formulas II, IV, V, VI, VII and VIII are useful as intermediates for the preparation of compounds of Formula I.
[00529] Compounds of Formula I are useful in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome. [00530] In one embodiment, compounds of Formula I are useful for treating pain, including chronic and acute pain. For example, compounds of Formula I are useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery or bone fracture.
[00531] In one embodiment, compounds of Formula I are useful for treating acute pain. 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, and is confined to a given period of time and severity. In some instances, it can become chronic.
[00532] In one embodiment, compounds of Formula I are useful for treating chronic pain. Chronic pain, as defined by the International Association for the Study of Pain, is widely believed to represent a disease in 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.
[00533] Compounds of Formula I are also useful for treating cancer. Particular examples include neuroblastoma, ovarian, pancreatic, colorectal and prostate cancer.
[00534] Compounds of Formula I are also useful for treating inflammation and certain infectious diseases. For example, compounds of Formula I may be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, atopic dermatitis, and psoriasis.
[00535] Compounds of Formula I are also useful for treating 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 said neurodegenerative disease. In one embodiment, compounds of Formula I may also be used to treat demyelination and dysmyelination by promoting myelination, neuronal survival, and oligodendrocyte differentiation via blocking Sp35-TrkA interaction. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease.
[00536] Compounds of Formula I are also useful for treating certain infectious diseases such as Trypanosoma cruzi infection in a mammal. [00537] Compounds of Formula I are also useful for treating Sjogren's syndrome in a mammal.
[00538] Compounds of Formula I are also useful for treating endometriosis in a mammal.
[00539] Compounds of Formula I are also useful for treating diabetic peripheral neuropathy in a mammal.
[00540] Compounds of Formula I are also useful for treating prostatitis in a mammal.
[00541] Compounds of Formula I are also useful for treating pelvic pain syndrome in a mammal.
[00542] Compounds of Formula I are also useful in treating diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
[00543] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disorder or condition, 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.
[00544] In certain embodiments, compounds of Formula I are useful for preventing diseases and disorders as defined herein. 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, or a symptom thereof, and includes to the administration of a compound of Formula I prior to the onset of symptoms.
[00545] Accordingly, one embodiment of this invention provides a method of treating pain in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said pain. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.
[00546] Another embodiment of this invention provides a method of preventing pain in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to prevent said pain. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.
[00547] Another embodiment of this invention provides a method of treating cancer in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said cancer.
[00548] In one embodiment, provided herein is a method for treating a patient diagnosed with a cancer having a dysregulation of TrkA, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
[00549] In one embodiment, the dysregulation of TrkA comprises overexpression of wild-type TrkA (autocrine activation).
[00550] In one embodiment, the dysregulation of TrkA comprises one or more chromosome translocations or inversions resulting in TrkA gene fusions. In one embodiment, the dysregulation is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from non-TrkA and TrkA proteins, and at a minimum the TrkA kinase domain. In one embodiment, the TrkA fusion protein is LMNA- TrkA, TFG-TrkA, TPM3-TrkA, CD74-TrkA, NFASC-TrkA, MPRIP-TrkA, BCAN-TrkA, or TPR-TrkA, where:
LMNA = Prelamin-A/C;
TFG TRK-fused gene protein;
TPM3 Tropomysin alpha-3;
CD74 HLA class II histocompatibility antigen gamma chain;
NFASC = Neurofascin;
MPRIP = MPRIP protein;
BCAN Brevican core protein; and
TPR Nucleoprotein TPR
[00551] In one embodiment, the dysregulation of TrkA comprises one or more deletions, insertions or mutations in the TrkA protein. In one embodiment, the dysregulation comprises a deletion of one or more residues from the TrkA protein, resulting in constitutive activity of TrkA kinase. In one embodiment the deletion includes deletion of residues 303- 377 in TrkA Isoform 2. [00552] In one embodiment, the dysregulation of TrkA comprises a splice variation in which the expressed protein is an alternatively spliced variant of TrkA having one or more residues deleted resulting in constitutive activity of TrkA kinase. In one embodiment, an alternatively spliced form of TrkA with constitutive activity has deletions of exons 8, 9, and 1 1 resulting in an expressed protein missing residues 192-284 and 393-398 relative to TrkA Isoform 2.
[00553] Cancers identified as having dysregulation of TrkA (see literature references below; also see www.cancer. gov and www.nccn.org) include:
[00554] (A) Cancers wherein the dysregulation of TrkA comprises one or more chromosome translocations or inversions resulting in TrkA gene fusions, including:
Figure imgf000081_0001
[00555] (B) Cancers wherein the dysregulation of TrkA comprises one or more deletions, insertions or mutations in the TrkA protein, including:
Figure imgf000082_0001
[00556] (C) Cancers driven by overexpression of wild-type TrkA (autocrine activation), including:
Cancer Literature Reference(s) Standard of care
Prostate Carcinoma Walch et al: Clinical & Radiotherapy (e.g. radium 223
Experimental Metastasis 17: 307- therapy) or chemotherapeutics 314 (e.g. abiraterone, cabazitaxel,
Papatsoris et al 2007: Expert degarelix, denosumab, docetaxel, Opinion on Investigational Drugs enzalutamide, leuprolide, 16(3): 303-309 prednisone, sipuleucel-T)
Neuroblastoma Van Noesel et al 2004: Gene 325: Chemotherapeutics (e.g.
1-15 cyclophosphamide, doxorubicin, vincristine)
Pancreatic Zhang et al 2005: Oncology Chemotherapeutics as single Carcinoma Reports 14: 161-171 agents (e.g. erlotinib,
fluorouracil, gemcitabine, mitomycin C) or combinations (e.g. gemcitabine-oxaliplatin)
Melanoma Truzzi et al 2008: Journal of Chemotherapeutics (e.g.
Investigative Dermatology aldesleukin, dabrafenib,
128(8): 2031 dacarbazine, interferon alfa-2b, ipilimumab, peginterferon alfa- 2b, trametinib, vemurafenib)
Head and Neck Kolokythas et al 2010: Journal of Radiotherapy and/or
Squamous Cell Oral and Maxillofacial Surgery chemotherapeutics (e.g.
Carcinoma 68(6): 1290-1295 bleomycin, cetuximab, cisplatin, docetaxel, fluorouracil, Cancer Literature Reference(s) Standard of care methotrexate)
Gastric Carcinoma Ni et al 2012: Asian Pacific Chemotherapeutics (e.g.
Journal of Cancer Prevention 13: docetaxel, doxorubucin,
151 1 fluorouracil, mitomycin C,
trastuzumab)
[00557] In one embodiment, provided herein is a method for treating a patient diagnosed with a cancer having a dysregulation of TrkA, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.
[00558] In one embodiment, the compounds of the present invention are useful for treating cancer in combination with one or more additional therapeutic agents or therapies that work by the same or a different mechanism of action.
[00559] In one embodiment, the additional therapeutic agent(s) is selected from receptor tyrosine kinase-targeted therapeutic agents, including cabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, and trastuzumab.
[00560] In one embodiment, the additional therapeutic agent(s) is selected from signal transduction pathway inhibitors, including Ras-Raf-MEK-ERK pathway inhibitors (e.g. sorafenib, trametinib, vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g. everolimus, rapamycin, perifosine, temsirolimus) and modulators of the apoptosis pathway (e.g. obataclax).
[00561] In one embodiment, the additional therapeutic agent(s) is selected from cytotoxic chemotherapeutics, including arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.
[00562] In one embodiment, the additional therapeutic agent(s) is selected from angiogenesis-targeted therapies, including aflibercept and bevacizumab. [00563] In one embodiment, the additional therapeutic agent(s) is selected from immune-targeted agents, including aldesleukin, ipilimumab, lambrolizumab, nivolumab, sipuleucel-T.
[00564] In one embodiment, the additional therapeutic agent(s) is selected from agents active against the TrkA pathway, including NGF-targeted biopharmaceuticals such as NGF antibodies, and panTrk inhibitors.
[00565] In one embodiment, the additional therapeutic agent or therapy is radiotherapy, including radioiodide therapy, external-beam radiation and radium 223 therapy.
[00566] In one embodiment, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of TrkA.
[00567] In one embodiment, provided herein is a method of treating cancer in a patient, comprising administering to said patient a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapy or therapeutic agent selected from radiotherapy (e.g. radioiodide therapy, external-beam radiation, radium 223 therapy), cytotoxic chemotherapeutics (e.g. arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, vincristine), tyrosine kinase targeted-therapeutics (e.g. afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, panitumumab, pertuzumab, regorafenib, sunitinib, trastuzumab), apoptosis modulators and signal transduction inhibitors (e.g. everolimus, perifosine, rapamycin, sorafenib, temsirolimus, trametinib, vemurafenib), immune-targeted therapies (e.g. aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, sipuleucel-T) and angiogenesis-targeted therapies (e.g. aflibercept, bevacizumab), wherein the amount of the compound of the invention or a pharmaceutically acceptable salt thereof is, in combination with the additional therapy or therapeutic agent, is effective in treating said cancer. These additional therapeutic agents may be administered with one or more compounds of the invention 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.
[00568] Also provided herein is (i) a pharmaceutical combination for treating cancer in a patient in need thereof, which comprises (a) a compound of the invention or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of a tumor disease, wherein the amounts of the compound or salt thereof and of the additional therapeutic agent are together effective in treating said cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.
[00569] In one embodiment, the combination therapy is for treating a cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.
[00570] Another embodiment of this invention provides a method of treating inflammation or an inflammatory disease or disorder in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said inflammation. In one embodiment, the inflammatory disease is inflammatory lung diseases (such as asthma), interstitial cystitis, bladder pain syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and inflammatory skin diseases such as atopic dermatitis.
[00571] In one embodiment, the method of treating inflammation or an inflammatory disease or disorder comprises administering a compound of the invention in combination with one or more additional agents. Examples of additional agents include anti-TNF treatments (for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or a circulating receptor fusion protein such as etanercept (Enbrel)), antimetabolite and antifolate drug (for example Methotrexate), or targeted kinase inhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritinib and TG101348).
[00572] Another embodiment of this invention provides a method of treating Trypanosoma cruzi infection in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said Trypanosoma cruzi infection. [00573] Another embodiment of this invention provides a method of treating Sjogren's syndrome in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said syndrome.
[00574] Another embodiment of this invention provides a method of treating endometriosis in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said endometriosis.
[00575] Another embodiment of this invention provides a method of treating diabetic peripheral neuropathy in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said diabetic peripheral neuropathy.
[00576] Another embodiment of this invention provides a method of treating prostatitis in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said prostatitis.
[00577] Another embodiment of this invention provides a method of treating pelvic pain syndrome in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said pelvic pain syndrome.
[00578] Another embodiment of this invention provides a method of treating a neurodegenerative disease in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said neurodegenerative disease.
[00579] Another embodiment of this invention provides a method of treating diseases related to an imbalance of the regulation of bone remodeling in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said disease. In one embodiment, the disease is osteoporosis, rheumatoid arthritis, and bone metastases.
[00580] In one embodiment, the method for treating diseases related to an imbalance of the regulation of bone remodeling in a mammal comprises administering a TrkA inhibitor of the invention in combination with one or more additional therapeutic agents or therapies. Examples of additional therapeutic agents or therapies include anti-TNF treatments (for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or with a circulating receptor fusion protein such as etanercept (Enbrel)), antimetabolite and antifolate drug (for example Methotrexate), or targeted kinase inhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritinib and TGI 01348).
[00581] As used herein, an "effective amount" means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat a particular disease, condition, or disorder which can be treated with a compound of Formula I, or (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder described herein.
[00582J 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.
[00583] As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
[00584] The compounds of the present invention can be used in combination with one or more additional therapeutic agents that work by the same or a different mechanism of action. Examples of additional therapeutic agents 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.
[00585] Also provided herein is a pharmaceutical combination comprising an effective amount of: (a) at least one compound of Formula I; and (b) at least one additional therapeutic agent selected from 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), for use in the treatment of pain in a mammal, wherein (a) and (b) can be in separate dosage forms or in the same dosage form.
[00586] The term "pharmaceutical combination" as used herein refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one of the compounds of Formula I, and at least one additional therapeutic agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that at least one of the compounds of Formula I, and at least one additional therapeutic agent, are administered to a patient as separate entities either simultaneously or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.
[00587] Also provided herein is a method of treating pain in a mammal, comprising co-administering to a mammal in need thereof an effective amount of: (a) at least one compound of Formula I; and (b) at least one additional therapeutic agent selected from antiinflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), opioids (such as morphine), calcitonin gene-related peptide receptor antagonists, subtype-selective ion channel modulators, anticonvulsants (for example Pregabalin and gabapentin), dual serotonin-norepinephrin reuptake inhibitors (for example duloxetine, venlafaxine and milnacipran), and tricyclic antidepressants (such as amitriptyline, nortriptyline and desipramine).
[00588] The term "co-administering" is meant to encompass administration of the selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. This term encompasses administration of two or more agents to a mammal so that both agents and/or their metabolites are present in the mammal at the same time. It includes simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. In some embodiments, the compound(s) of the invention and the other therapeutic agent(s) are administered in a single composition. In some embodiments, compound(s) of the invention and the other agent(s) are admixed in the composition.
[00589] Also provided herein is a medicament containing a compound of Formula I for treatment of pain in a mammal in combination with an additional therapeutic agent selected from 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).
[00590] Also provided herein is a medicament containing a therapeutic agent selected from 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) for treatment of pain in a mammal in combination with a compound of Formula I.
[00591] 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.
[00592] Another formulation may be prepared by mixing a compound described herein and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[00593] Accordingly, another aspect of the present invention provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove, together with a pharmaceutically acceptable diluent or carrier.
[00594] According to another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pain in a mammal. In one embodiment, the pain is chronic pain. In one embodiment the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture. [00595] According to another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a mammal.
[00596] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation or an inflammatory disease or disorder in a mammal. In one embodiment, the inflammatory disease is inflammatory lung diseases (such as asthma), interstitial cystitis, bladder pain syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and inflammatory skin diseases such as atopic dermatitis.
[00597] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of infectious diseases, for example Trypanosoma cruzi infection, in a mammal.
[00598] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of Sjogren's syndrome in a mammal.
[00599] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of endometriosis in a mammal.
[00600] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic peripheral neuropathy in a mammal,
[00601] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of prostatitis in a mammal,
[00602] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pelvic pain syndrome in a mammal,
[00603] In another embodiment, 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.
[00604] According to a further aspect, 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 condition selected from pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection. In one embodiment, the condition is chronic pain. In one embodiment, the condition is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture. In one embodiment, the condition is cancer. In one embodiment, the condition is inflammation. In one embodiment, the condition is a neurodegenerative disease. In one embodiment, the condition is Trypanosoma cruzi infection. In one embodiment, the condition is Sjogren's syndrome. In one embodiment, the condition is endometriosis. In one embodiment, the condition is diabetic peripheral neuropathy. In one embodiment, the condition is prostatitis. In one embodiment, the condition is pelvic pain syndrome.
Examples
[00605] The following examples illustrate the invention. In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated.
[00606] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
[00607] Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel or C-l 8 reverse phase column, or on a silica SepPak cartridge (Waters).
Biological assays
Example A-l
TrkA Kinase Binding Assay
[00608] TrkA binding activity was determined in a TrkA LanthaScreen™ Eu Kinase Binding Assay. 5 nM His-tagged recombinant human TrkA (6HIS tagged cytoplasmic domain from Invitrogen, Catalog No. PV3144) was incubated with 4 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat. No.PV5592), 2 nM biotinylated anti-His (Invitrogen Cat. No. PV6090), and 2 nM europium-labeled Streptavidin (Invitrogen Cat. No. PV5899), in buffer (25 mM MOPS, pH 7.5, 5 mM MgCl2, 0.005% Triton X-100). Three fold serial dilutions of compounds of the invention in DMSO were added to a final percentage of 2% DMSO. After 60-minute incubation at 22 °C, the reaction was measured using the EnVision mutlimode plate reader (PerkinElmer) via TR-FRET dual wavelength detection at 615 nM and 665 nM. The percent of control was calculated using a ratiometric emission factor. The IC50 values were determined by fitting a four parameter model to the percent of control data.
[00609] Table A provides averaged IC50 values for compounds of the invention when tested in the assay of Example A, where A represents an averaged IC50 value <100 nM; B represents an averaged IC50 value from 100 to 1,000 nM; and C represents an average IC50 value above 1000 nM.
Table A
Example # TrkA Enzyme IC50
(nM)
1 A
2 A
3 A
4 A
5 A
6 A
7 A
8 A
9 A
10 A
11 A
12 A
13 A
14 A
15 A
16 B
17 A
18 B
19 A
20 A
21 A
22 B
23 A Example # TrkA Enzyme IC50 (nM)
24 B
25 A
26 B
27 B
28 B
29 B
30 B
31 A
32 B
33 A
34 A
35 A
36 A
37 B
38 A
39 B
40 B
41 B
42 A
43 B
44 A
45 B
46 A
47 A
48 B
49 B
50 B
51 A
52 A
53 A
54 A Example # TrkA Enzyme IC50 (nM)
55 A
56 A
57 A
58 A
59 A
60 A
61 A
62 A
63 A
64 A
65 A
66 A
67 A
68 B
69 A
70 A
71 A
72 A
73 A
74 A
75 A
76 A
77 B
78 A
79 A
80 A
81 A
82 A
83 A
84 A
85 A Example # TrkA Enzyme IC50 (nM)
86 A
87 A
88 A
89 A
90 A
91 A
92 A
93 A
94 A
95 A
96 A
97 A
98 A
99 A
100 A
101 A
102 A
103 A
104 A
105 A
106 A
107 A
108 A
109 A
110 A
111 A
112 A
113 A
114 A
115 A
116 A Example # TrkA Enzyme IC50
(nM)
117 A
118 B
119 B
120 A
121 A
122 A
123 A
124 A
125 A
126 A
127 B
128 B
129 A
130 A
131 A
132 C
Example A-2
p38 Kinase Binding Assay
[00610] p38a binding activity was determined in a p38a LanthaScreen™ Eu Kinase Binding Assay. 5nM of inactive, GST-tagged recombinant human p38a (GST-tagged cytoplasmic domain from Invitrogen, Catalog No. PV3305) was incubated with 5 nM Alexa- Fluor® Tracer 199 (Invitrogen Cat. No. PV5830), and 2 nM europium labeled anti-GST antibody (Invitrogen Cat. No. PV5594), in buffer (25mM [Na+] HEPES pH 7.3, 10 raM MgCl2, ΙΟΟμΜ NaVC^). Three fold serial dilutions of compounds of the invention in DMSO were added to a final percentage of 2% DMSO. After 60-minute incubation at 22 °C, the reaction was measured using the EnVision multimode plate reader (PerkinElmer) via TR- FRET dual wavelength detection at 615 nM and 665 nM. The percent of control was calculated using a ratiometric emission factor. The IC50 values were determined by fitting a four parameter model to the percent of control data. The compounds of Examples 1-132 were tested in this assay, and all compounds were found to be 1000 fold more potent against TrkA than p38a.
Example B
Off-Target Kinase Profiling
[00611] Representative compounds of the invention (Examples 33 and 10) were tested for off-target kinase activity at a concentration of 10 μΜ by Millipore, Inc. in their KinaseProfiler™ service against all the kinases available in their full kinase panel. Compounds were run in duplicate at a concentration of ATP near the Km for each individual kinase according to Millipore 's specifications. The results are shown in Table B. Data are reported as percent of control (POC) and are the average of the two replicates.
[00612] In the KinaseProfiler™ the representative compounds showed remarkable and unexpected selectivity for inhibiting TrkA and TrkB versus other kinases in the panel. In fact, the compounds were largely inactive against off-target kinases at a concentration of 10 μΜ, and thus would not be expected to inhibit off-target kinases at therapeutic doses in mammals. The ability of compounds of the invention to selectively inhibit the Trk pathway without inhibiting other off-target kinases could translate into drug profiles that are essentially free of side-effects related to inhibition of off-target kinases. Such a drug profile would represent a safer approach to treating pain, inflammation, cancer and certain skin diseases than has been previously reported.
Table B
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Preparation of intermediates
Preparation A
Figure imgf000102_0002
(2-cvclopropyl-5-(methoxymethyl)phenvnmethanamine
[00613] Step A: Preparation of 2-bromo-5 -formylbenzonitrile: To a 1 liter, 3-neck round bottom flask equipped with a condenser, and temperature probe was added 2-fluoro-5- formylbenzonitrile (20 g, 134 mmol) and 535 mL of NMP, and lithium bromide (116.5 g, 1341 mmol). A modest exotherm was observed. This mixture was warmed to 150 °C under a nitrogen atmosphere for 3.5 days. After cooling to ambient temperature, the mixture was diluted with 2 liters of ice water, and extracted two times with MTBE. The combined extracts were washed two times with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography, eluting with 100% DCM, to give 2-bromo-5-formylbenzonitrile as a white solid (5 g, 18% yield).
[00614] Step B: Preparation of 2-cyclopropyl-5-formylbenzonitrile: A heavy walled pressure tube was charged with 2-bromo-5-formylbenzonitrile (500 mg, 2.38 mmol) and 8 mL of toluene. To this mixture was added potassium cyclopropyltrifluoroborate (1.41 g, 9.52 mmol), palladium acetate (80 mg, 0.36 mmol), dicyclohexyl(2',6'-diisopropoxy-[l,l'- biphenyl]-2-yl)phosphine (333 mg, 0.71 mmol), K3PO4 (1.52 g, 7.14 mmol), and 2 mL of water. The mixture was purged with nitrogen for 5 minutes, tube sealed, and heated to 1 10°C for 16 hours, then allowed to cool to ambient temperature. The mixture was then diluted with EtOAc/brine and filtered through GF/F filter paper. The organics were isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography, eluting with 15% ethyl acetate/hexane to 25% ethyl acetate/Hex, to give 2-cyclopropyl-5-formylbenzonitrile (260 mg, 64% yield).
[00615] Step C: Preparation of 2-cyclopropyl-5-(hydroxymethyl)benzonitrile: To a round bottom flask containing 2-cyclopropyl-5-formylbenzonitrile (260 mg, 1.52 mmol) was added dry methanol (5 mL). A solution formed and was chilled to 0°C. Sodium borohydride (115 mg, 3.04 mmol) was then added in one portion and the mixture was then allowed to warm to ambient temperature. After about one hour, the mixture was then concentrated under reduced pressure and the crude was taken up in saturated ammonium chloride solution, diluted with water, extracted with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure to give 2-cyclopropyl-5-(hydroxymethyl)benzonitrile (228 mg, 87%) as a white solid.
[00616] Step D: Preparation of 2-cvclopropyl-5-(methoxymethyl)benzonitrile: A round bottom flask and nitrogen inlet was charged with 2-cyclopropyl-5-
(hydroxymethyl)benzonitrile (228 mg, 1.32 mmol) and dry DMF (13 mL). This solution was chilled to 0°C and sodium hydride (105 mg, 2.63 mmol, 60% dispersion in mineral oil) was added in one portion. The cooling bath was removed and the mixutre stirred for 45 minutes. To this was then added methyl iodide (247 μί, 3.95 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then quenched with brine and extracted with EtOAc. The extracts were washed with brine, dried over sdoium sulfate and concentrated under reduced pressure to give 2-cyclopropyl-5-(methoxymethyl)benzonitrile (248 mg, 100%) as an oil.
[00617] Step E: Preparation of. (2-cyclopropyl-5-
(methoxymethvDphenvDmethanamine: To a round bottom flask containing 2-cyclopropyl-5- (methoxymethyl)benzonitrile (245 mg, 1.31 mmol) was added dry THF (13 mL) and LAH (3.93 mL, 3.93 mmol, 1M in THF). This was refluxed for 5 hours, then allowed to cool to ambient temperature. The mixture was chilled to 0 °C and quenched (Fieser) with 0.149 mL of water, 0.149 mL of 15% NaOH, and 0.447 mL of water. The mixture was vigorously stirred for 15 minutes, diluted with MTBE and sodium sulfate added. The mixture was then filtered through GF/F paper and the filtrate was concentrated under reduced pressure to give (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine (230 mg, 92%) as an oil.
Preparation B
Figure imgf000104_0001
(2-cyclobutyl-5-(methoxymethyl phenyl)methanamine
[00618] Step A: Preparation of 2-cyclobutyl-5-formylbenzonitrile: To a heavy walled pressure tube was added 2-bromo-5-formylbenzonitrile (250 mg, 1.19 mmol) and 5 mL of dry THF. To this was added palladium acetate (26.7 mg, 0.119 mmol), S-Phos (73.3 mg, 0.179 mmol), and cyclobutylzinc bromide 5.95 mL, 2.98 mmol, 0.5 M in THF), the tube was sealed and and stirred under a nitrogen atmosphere for one hour. The mixture was then diluted with EtO Ac/water and filtered through GF/F filter paper. The organics were isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography to give 2-cyclobutyl-5- formylbenzonitrile (110 mg, 50% yield) as an oil.
[00619] Step B: Preparation of 2-cyclobutyl-5-(methoxymethyl)phenyl)methanamine: Prepared by the methods described in Preparation A, Steps C through E, replacing 2- cyclopropyl-5-formylbenzonitrile with 2-cyclobutyl-5-formylbenzonitrile, to give the title compound. Preparation C
Figure imgf000105_0001
(2-cvclopentyl-5-(methoxymethyl)phenyl)methanamine
Prepared by the methods described in Preparation B, Steps A through B, replacing cyclobutylzinc bromide with cyclopentylzinc bromide, to give the title compound.
Preparation D
Figure imgf000105_0002
(2-cvclopropyl-5-ethoxyphenyl)methanamine
[00620] Step A: Preparation of 2-bromo-5-ethoxybenzonitrile: A round bottom flask and nitrogen inlet was charged with 2-bromo-5-hydroxybenzonitrile (1.50 g, 7.58 mmol) and dry DMF (30 mL). To this was added cesium carbonate (4.94 g, 15.2 mmol) followed by ethyl iodide (1.77 g, 11.4 mmol) and the mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with water and extracted two times with diethyl ether. The extracts were washed two times with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-bromo-5-ethoxybenzonitrile (1.72 g, 100%) as a white solid.
[00621] Step B: Preparation of 2-cvclopropyl-5-ethoxybenzonitrile: A heavy walled pressure tube was charged with 2-bromo-5-ethoxybenzonitrile (0.750 g, 3.32 mmol) and 8 mL of toluene. To this was added potassium cyclopropyltrifluoroborate (1.96 g, 13.3 mmol), palladium acetate (0.111 g, 0.498 mmol), dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2- yl)phosphine (0.464 g, 0.995 mmol), followed by potassium phosphate (2.11 g, 9.95 mmol) and 2 mL of water. The mixture was purged with nitrogen for 5 minutes, tube sealed and heated to 1 10 °C for 3 hours. The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc and water. This was filtered through GF/F filter paper and the organics were isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography to give 2- cyclopropyl-5-ethoxybenzonitrile (0.446 g, 72% yield) as a light yellow oil. [00622] Step C: Preparation of (2-cyclopropyl-5-ethoxyphenyl)methanamine: Prepared by the methods described in Preparation A, Step E, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 2-cyclopropyl-5-ethoxybenzonitrile, to give the title compound (0.424 g, 94% yield).
Preparation E
Figure imgf000106_0001
(2-ethoxy-5-(methoxymethyl)phenyl)methanamine
[00623] Step A: Preparation of 5-bromo-2-ethoxybenzonitrile: To a round bottom flask and nitrogen inlet was added 5-bromo2-hydroxybenzonitrile (2.00 g, 10.1 mmol) and 40 mL of dry DMF. To this mixture was added powdered potassium carbonate (2.79 g, 20.2 mmol) and ethyl iodide (4.73 g, 30.3 mmol), which was stirred at ambient temperature for 2 hours under a nitrogen atmosphere. The mixture was then diluted with water and extracted two times with MTBE. The extracts were washed two times with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 5-bromo-2- ethoxybenzonitrile (2.06 g, 90% yield).
[00624] Step B: Preparation of 2-ethoxy-5-(methoxymethyl)benzonitrile: A heavy walled pressure tube was charged with 5-bromo-2-ethoxybenzonitrile (0.500 g, 2.21 mmol), 8mls of dioxane and 2mls of water. Potassium methoxymethyltrifluoroborate (0.672 g, 4.42 mmol), PdCl2(dppf) dichloromethane adduct (0.361 g, 0.442 mmol), and cesium carbonate (2.16 g, 6.64 mmol) were then added to the reaction mixture under a nitrogen atmosphere, the tube was sealed and heated to 100 °C for 16 hours. After allowing to cool to ambient temperature, the mixture was diluted with EtOAc/water and filtered through GF/F filter paper. The organic layer was isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography to give 2-ethoxy-5-(methoxymethyl)benzonitrile (0.100 g, 24% yield).
[00625] Step C: Preparation of (2-ethoxy-5-(methoxymethyl)phenyl)methanamine: Prepared by the methods described in Preparation A, Step E, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 2-ethoxy-5-(methoxymethyl)benzonitrile to give the title compound (66 mg, 65% yield). Preparation F
Figure imgf000107_0001
(2-(cyclopropylmethoxy)-5-(methoxymethyl')phenvnmethanamine
[00626] Prepared by the methods described in Preparation E, Steps A through C, replacing ethyl iodide with (bromomethyl)cyclopropane in step A, to give the title compound (0.576 g, 27% overall yield).
Preparation G
Figure imgf000107_0002
(5-(methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine
[00627] Step A: Preparation of 5-(,methoxymethylV2-
(trifluoromethoxy)benzaldehyde: A heavy walled pressure tube was charged with 5-bromo- 2-(trifluoromethoxy)benzaldehyde (1.00 g, 3.72 mmol), 37 mL of dioxane and 4 mL of water. Potassium methoxymethyltrifluoroborate (1.13 g, 7.43 mmol), palladium acetate (0.083 g, 0.372 mmol) S-Phos (0.305 g, 0.743 mmol), and cesium carbonate (4.84 g, 14.9 mmol) were then added, the tube was sealed and the mixture heated to 100°C for 16 hours. After allowing to cool to ambient temperature, the mixture was diluted with EtO Ac/water and filtered through GF/F filter paper. The organic layer was isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography to give 5-(methoxymethyl)-2- (trifluoromethoxy)benzaldehyde as an oil (0.240 g, 28%).
[00628] Step B: Preparation of 5-(methoxymethyl)-2-(trifluoromethoxy)benzaldehyde oxime: To a round bottom flask equipped a stir bar was added 5-(methoxymethyl)-2- (trifluoromethoxy)benzaldehyde (0.230 g, 0.982 mmol), ethanol (10 mL) and water (1ml). Hydroxylamine hydrochloride (0.102 g, 1.47 mmol) was then added and the mixture was stirred at ambient temperature for 2 hrs. The mixture was then concentrated under reduced pressure and the crude was taken up in 10% aqueous potassium carbonate/EtOAc, organics isolated, dried over sodium sulfate and concentrated under reduced pressure to give 5- (methoxymethyl)-2-(trifluoromethoxy)benzaldehyde oxime (0.185 g, 76% yield) as an oil.
[00629] Step C: Preparation of 5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine: To a round bottom flask containing 5- (methoxymethyl)-2-(trifluoromethoxy)benzaldehyde oxime (0.180 g, 0.722 mmol) was added acetic acid (7 mL) and zinc powder 0.189 g, 2.89 mmol). This was warmed to 70 °C for 16 hours. The mixture was filtered and the filtrate concentrated under reduced pressure. The resulting crude material was taken up in EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated to give the title compound (75 mg, 47% yield) of an oil.
Preparation H
Figure imgf000108_0001
(2-cvclobutoxy-5-(methoxymethyl)phenyf)methanamine 2,2,2-trifluoroacetate
[00630] Step A: Preparation of 5-bromo-2-cvclobutoxybenzonitrile: A heavy walled pressure tube was charged with 5-bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), dry DMF (20 mL), powdered potassium carbonate (1.40 g, 10.1 mmol), and bromocyclobutane (2.05 g, 15.2 mmol). The tube was sealed and warmed to 80 °C for 16 hours, then allowed to cool to ambient temperature. The mixture was then diluted with water and extracted 2 times with MTBE. The extracts were washed 2 times with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2-cyclobutoxybenzonitrile (0.983 g, 77% yield) as an orange oil.
[00631] Step B: Preparation of. (2-cvclobutoxy-5-
(methoxymethvDphenyDmethanamine 2,2,2-trifluoroacetate: Prepared by the methods described in Preparation E, Steps B and C, replacing 5-bromo-2-ethoxybenzonitrile with 5- bromo-2-cyclobutoxybenzonitrile. The crude product in the reduction step was purified by reverse phase prep HPLC, to give the title compound (61 mg, 26% yield). Preparation I
Figure imgf000109_0001
(2-(difluoromethoxy -5-(methoxymethyl)phenynmethananiine
[00632] Step A: Preparation of 5-bromo-2-(difluoromethoxy)benzonitrile: To walled pressure tube was added 5-bromohydroxybenzonitrile (5 g , 25.3 mmol), acetonitrile (250 mL) and 30% (w/w) of aqueous KOH (100 mL). This mixture was chilled to -78 °C and 2-chloro-2,2-difluoro-l-phenylethanone (9.62 g, 50.5 mmol) was then added. The tube was sealed, allowed to warm to ambient temperature, and heated to 80 °C for 4 hours. After cooling to ambient temperature, water was added and the mixture extracted 2 times with EtOAc, extracts dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was taken up in DCM and filtered. The filtrate was purified by flash chromatography to give 5-bromo-2-(difluoromethoxy)benzonitrile (1.84 g, 29% yield) as a white solid.
[00633] Step B: Preparation of. (2-(difluoromethoxy)-5-
(methoxymethyl)phenvDmethanamine: Prepared by the methods described in Preparation E, Steps B and C, replacing 5-bromo-2-ethoxybenzonitrile with 5-bromo-2- (difluoromethoxy)benzonitrile, to give the title compound (70 mg, 11% yield).
Preparation J
Figure imgf000109_0002
(2-cyclobutyl-5-( 1 -methoxyethvDphenvPmethanamine
[00634] P A: Preparation of 2-bromo-5-(l-hydroxyethyl)benzonitrile:
bottom flask and nitrogen inlet was charged with 2-bromo-5-formylbenzonitrile (0.300 g, 1.43 mmol) and dry THF (14 mL). This solution was chilled to 0 °C and MeMgl (0.952 mL, 2.86 mmol, 3M in ether) was then added by syringe, resulting in a cloudy mixture. This mixture was stirred at 0°C for 30 minutes, then quenched with saturated ammonium chloride solution. Water was added and the mixture was extracted 2 times with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure to give 2-bromo-5-(l- hydroxyethyl)benzonitrile (0.295 mg, 91%) as an orange oil. [00635] Step B: Preparation of 2-bromo-5-n-methoxyethyl)benzonitrile: Prepared by the method described in Preparation A, Step D, replacing 2-cyclopropyl-5- (hydroxymethyl)benzonitrile with 2-bromo-5-(l -hydroxy ethyl)benzonitrile and DMF with THF, to give 2-bromo-5-(l-methoxyethyl)benzonitrile (86 mg, 54%) as a solid.
[00636] Step C: Preparation of 2-cvclobutyl-5-(l-methoxyethyl)benzonitrile: Prepared by the method described in Preparation B, Step A, replacing 2-bromo-5- formylbenzonitrile with 2-bromo-5-(l-methoxyethyl)benzonitrile to give 2-cyclobutyl-5-(l - methoxyethyl)benzonitrile (39 mg, 51% yield) as an oil.
[00637] Step D: Preparation of i2-cyclobutyl-5-(T- methoxyethyPphenvDmethanamine: Prepared by the method described in Preparation A, Step E, replacing 2-cyclopropyl-5-(methoxymethyl)benzonitrile with 2-cyclobutyl-5-(l- methoxyethyl)benzonitrile to give the title compound (30 mg, 76% yield) as an oil.
Preparation K
Figure imgf000110_0001
(2-(2,2-difluorocyclopropyl)-5-(methoxymethyl)phenyl)methanamine 2,2,2-trifluoroacetate
[00638] Step A: Preparation of (4-bromo-3-chlorophenyl)methanol: A round bottom flask equipped with a stirbar and nitrogen inlet was charged with dry THF (72 mL), and sodium borohydride (1.09 g, 28.9 mmol). This suspension was chilled to 0 °C and boron trifluoride etherate (8.20 g, 57.8 mmol) was then added and the mixture stirred at 0 °C for 15 minutes. To this was added 4-bromo-3-chlorobenzoic acid (3.40 g, 14.4 mmol) in one portion (gas evoluiton observed). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was then carefully quenched with methanol until gas evolution had ceased. The mixture was concentrated under reduced pressure and the resulting crude material was taken up in 100 mL of 20% aqueous NaOH and stirred at ambient temperature for 1 hour. The mixture was extracted 2 times with DCM, extracts dried over sodium sulfate and concentrated under reduced pressure to give (4-bromo- 3-chlorophenyl)methanol (2.59 g, 81%) as an oil.
[00639] Step B: Preparation of l-bromo-2-chloro-4-(methoxymethyl)benzene: Prepared by the method described in Preparation J, Step B, replacing 2-bromo-5-(l- hydroxyethyl)benzonitrile with (4-bromo-3-chlorophenyl)methanol to give l-bromo-2- chloro-4-(methoxymethyl)benzene (1.72 g, 65% yield) as an oil.
[00640] Step C: Preparation of 2-chloro-4-(methoxymethyl)-l-vinylbenzene: To a heavy walled pressure tube was added l-bromo-2-chloro-4-(methoxymethyl)benzene (1.72 g, 7.30 mmol), 35 mL of dioxane, and 4 mL of water. To this was added potassium vinyltrifluoroborate (1.96 g, 14.6 mmol), palladium chloride (0.0259 g, 0.146 mmol), triphenylphosphine (0.1 15 g, 0.438 mmol), and cesium carbonate (7.14 g, 21.9 mmol). The tube was sealed and warmed to 90°C for 16 hours, then allowed to cool to ambient temperature. Ethyl acetate and water were added and the mixture filtered through GF/F filter paper. The organics were isolated from the filtrate, dired over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography to afford 2-chloro-4-(methoxymethyl)-l-vinylbenzene (790 mg, 59% yield) as an oil.
[00641] Step D: Preparation of 2-chloro-l-(2,2-difluorocyclopropyl -4-
(methoxymethy Dbenzene : To a microwave reaction tube was added the 2-chloro-4- (methoxymethyl)-l-vinylbenzene (0.732 g, 4.01 mmol), dry toluene (2.5 mL) and NaF (0.0168 g, 0.401 mmol). The tube was capped and warmed to 100 °C under a nitrogen atmosphere. Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.01 g, 8.02 mmol) was added by syringe, very slowly, over a 4 hour period, as vigorous gas evolution is observed. After the addition was complete, the mixture was stirred at 100 °C overnight, then allowed to cool to ambient temperature. The mixture was diluted with EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to an oil. This oil was purified by flash chromatography to give 2-chloro-l-(2,2- difluorocyclopropyl)-4-(methoxymethyl)benzene (0.419 g, 45% yield) as an oil.
[00642] Step E: Preparation of tert-butyl 2-(2,2-difluorocyclopropyl -5- (methoxymethyl)benzylcarbamate: To a microwave reaction tube was added 2-chloro-l-(2,2- difluorocyclopropyl)-4-(methoxymethyl)benzene (0.200 g, 0.860 mmol), potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (0.224 g, 0.946 mmol, Org. Lett., 2012, 14 (12), pp 3138-3141) toluene (6.5 mL) and water (1.5 mL). To this was added palladium acetate (0.00965 g, 0.0430 mmol), S-Phos (0.0353 g, 0.0860 mmol), and potassium carbonate (0.356 g, 2.58 mmol). The tube was sealed and heated to 90 °C for 24 hours, then allowed to cool to ambient temperature. EtOAc and water were added and the mixture filtered through GF/F filter paper. The organic layer was isolated from the filtrate, dried over sodium sulfate and concentrated under reduced pressure. Prep plate purification afforded tert-butyl 2-(2,2- difluorocyclopropyl)-5-(methoxymethyl)benzylcarbamate (15 mg, 5% yield) as a film.
[00643] Step F: Preparation of (2-(2,2-difluorocyclopropyl -5-
(methoxymethvDphenvPmethanamine 2,2,2-trifluoroacetate: To a flask containing tert-butyl 2-(2,2-difluorocyclopropyl)-5-(methoxymethyl)benzylcarbamate (15 mg, 0.046 mmol) was added TFA (1 mL) and the mixture stirred at ambient temperature for one hour and then concentrated under reduced pressure to give (2-(2,2-difiuorocyclopropyl)-5- (methoxymethyl)phenyl)methanamine 2,2,2-trifluoroacetate (0.016 mg, 100% yield).
Preparation L
Figure imgf000112_0001
(2-( 1 -methoxycyclobutyl)-5-(methoxymethyl)phenyl)methanamine
[00644] Step A: Preparation of 2-bromo-5-(hvdroxymethyl benzonitrile: Prepared by the method described in Preparation A, Step C, replacing 2-cyclopropyl-5-formylbenzonitrile with 2-bromo-5-formylbenzonitrile, to give 2-bromo-5-(hydroxymethyl)benzonitrile (2.02 g, 100% yield) as a white solid.
[00645] Step B: Preparation of 2-bromo-5-(methoxymethyl)benzonitrile: Prepared by the method described in Preparation J, Step B, replacing 2-cyclopropyl-5- (hydroxymethyl)benzonitrile with 2-bromo-5-(hydroxymethyl)benzonitrile to give the title compound (1.35 g, 63%) as a waxy solid.
[00646] Step C: Preparation of 2-( 1 -hydroxycyclobutyl)-5-
(methoxymethyl)benzonitrile : A flame dried round bottom flask and nitrogen inlet was charged with 2-bromo-5-(methoxymethyl)benzonitrile (0.205 g, 0.907 mmol) and dry THF (9 mL). This solution was chilled to -78 °C and n-BuLi (0.399 mL, 0.997 mmol, 2.5 M in hexanes) was then added dropwise by syringe. Once the addtion was complete, the mixture was stirred at -78 °C for 10 minutes, and cyclobutanone (0.127 g, 1.81 mmol) was added by syringe, and the mixture was allowed to warm to ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution. Water was added and the mixture was extracted with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography to give 2-(l- hydroxycyclobutyl)-5-(methoxymethyl)benzonitrile (100 mg, 50% yield). [00647] Step D: Preparation of 2-(l-methoxycyclobutyl)-5-
(methoxymethyl)benzonitri le : Prepared by the method described in Preparation J, Step B, replacing 2-cyclopropyl-5-(hydroxymethyl)benzonitrile with 2-(l-hydroxycyclobutyl)-5- (methoxymethyl)benzonitrile, to give the title compound (60 mg, 56% yield) as an oil.
[00648] Step E: Preparation of (2-(l-methoxycyclobutyl)-5-
(methoxymethyl)phenyl)methanamine: Prepared by the method described in Preparation A, Step E, replacing 2-cyclopropyl-5-(methoxymethyl)benzonitrile with 2-(l- methoxycyclobutyl)-5-(methoxymethyl)benzonitrile, to give the title compound (44 mg, 79%) as an oil.
Preparation M
Figure imgf000113_0001
l-(2-cyclopropyl-5-(methoxymethyl)phenyl)ethanamine
[00649] To a round bottom flask and nitrogen inlet was added 2-cyclopropyl-5- (methoxymethyl)benzonitrile (0.082 g, 0.438 mmol) and dry THF (4 mL). The mixture was chilled to 0 °C and MeMgl (0.292 mL, 0.876 mmol, 3M in ether) was added by syringe, resulting in a white mixture. The mixture was allowed to warm to and stir at ambient temperature for one hour, then warmed to 60 °C for one hour. Them mixture was chilled to 0 °C and LAH (0.876 mL, 0.876 mmol, 1M in THF) was then added. The mixture was allowed to warm to ambient temperature and then refluxed for one hour. After stirring at ambient temperature for 16 hours, the mixture chilled to 0 °C and was quenched with 33 μί of water, 33 of 15% aqueous NaOH, and 100 ih of water, and vigorously stirred for 30 minutes. This was then diluted with MTBE and filtered. The filtrate was concentrated under reduced pressure to give a mixture of the title compound and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine, which was used as is (90 mg, 100% yield).
Preparation N
Figure imgf000113_0002
Cyclopropyl(3-(methoxymethyl)phenyl)methanamine
[00650] Step A: Preparation of 3-(methoxymethyl)benzonitrile: Prepared by the method described in Preparation A, Step D, replacing 2-cyclopropyl-5- (hydroxymethyl)benzonitrile with 3-(hydroxymethyl)benzonitrile to give 3- (methoxymethyl)benzonitrile (2.21 g, 100%) as an oil.
[00651] Step B: Preparation of cyclopropyl(3-(methoxymethyl)phenyl)methanamine: Prepared by the method described in Preparation M, Step A, replacing 2-cyclopropyl-5- (methoxymethyl)benzonitrile with 3-(methoxymethyl)benzonitrile and methylmagnesium iodide with cyclopropylmagnesium bromide, to give the title compound (0.39 g, 100%) as an oil.
Preparation O
Figure imgf000114_0001
1 -(3 -(methoxymethyl)pheny Dethanamine
[00652] Prepared by the method described in Preparation M, Step A, replacing 2- cyclopropyl-5-(methoxymethyl)benzonitrile with 3-(methoxymethyl)benzonitrile to give the title compound (0.236 g, 84%) as an orange/brown oil.
Preparation P
Figure imgf000114_0002
(2-(3-fluorooxetan-3-yl -5-(methoxymethyl)phenyl)methanamine
[00653] Step A: Preparation of 3-(2-chloro-4-(methoxymethvDphenyl)oxetan-3-ol: A round bottom flask was charged with l-bromo-2-chloro-4-(methoxymethyl)benzene (1.00 g, 4.25 mmol) and dry THF (42 mL). This solution was chilled to -78 °C and n-BuLi (2.04 mL, 5.10 mmol, 2.5 M in hexanes) was added by syringe over a 5 minute period. This mixutre was stirred at -78 °C for 1 hour and a THF solution (10 mL) of oxetan-3-one (0.306 g, 4.25 mmol) was then added by syringe. After 15 minutes, the cooling bath was removed. After about 20 minutes, the mixture was quenched with saturated ammonium chloride solution, diluted with water and extracted with EtOAc. The extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography to give 3-(2-chloro-4-(methoxymethyl)phenyl)oxetan-3-ol (0.310 g, 32% yield) as an oil.
[00654] Step B: Preparation of 3-(2-chloro-4-(methoxymethyl)phenyl)-3- fluorooxetane: A round bottom flask was charged with 3-(2-chloro-4- (methoxymethyl)phenyl)oxetan-3-ol (0.305 g, 1.33 mmol) and dry DCM (13 mL). This solution was chilled to 0 °C and Deoxofluor (0.384 g, 1.30 mmol) was added. This mixture was stirred at 0 °C for 1 hour, then quenched with 10% aqueous potassium carbonate. This was extracted with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC to give 3-(2-chloro- 4-(methoxymethyl)phenyl)-3-fluorooxetane (0.165 g, 54%) as an oil.
[00655] Step C: Preparation tert-butyl 2-i3-fluorooxetan-3-yr)-5-
(methoxymethy Pbenzylcarbamate : Prepared as described in Preparation K, Step E, replacing 2-chloro- 1 -(2,2-difluorocyclopropyl)-4-(methoxymethyl)benzene with 3-(2-chloro-4- (methoxymethyl)phenyl)-3-fluorooxetane to give tert-butyl 2-(3-fluorooxetan-3-yl)-5- (methoxymethyl)benzylcarbamate (0.100 g, 44%) as a white solid.
[00656] Step D: Preparation of (2-i3-fluorooxetan-3-yr)-5-
(methoxymethvDphenyPmethanamine: A round bottom flask was charged with tert-butyl 2- (3-fluorooxetan-3-yl)-5-(methoxymethyl)benzylcarbamate (0.095 g, 0.292 mmol), dry DCM (3 mL) and TFA (0.322 g, 2.92 mmol). The mixture was stirred at ambient temperature for 3 hours, then diluted with EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.047 g, 72% yield) as an oil.
Intermediate 1
Figure imgf000115_0001
3 -ethoxy-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine
[00657] Step A: Preparation of 5-amino-4-methyl-l-phenyl-lH-pyrazol-3(2//)-one: A mixture of ethyl 2-cyanopropanoate (5.0 g, 46 mmol) and phenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 1 10 °C for 17 hours. The crude material was cooled to ambient temperature, concentrated, and triturated with cold EtOH and Et20. The resultant solid was filtered, washed with Et20, and dried under vacuum to give the product as a white solid (3.4 g, 39% yield). MS (apci) m/z = 190.0 (M-H).
[00658] Step B: Preparation of 3-ethoxy-4-methyl-l-phenyl-lH-pyrazol-5-amine: To a suspension of 5-amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one (10.0 g, 52.9 mmol) in DMF (100 mL) was added K2C03 (14.6 g, 106 mmol) and bromoethane (4.34 mL, 58.1) at ambient temperature. After stirring for 17 hours, the reaction mixture was treated with EtOAc and washed with water (to obtain the N-alkylation product) and brine, dried with MgS04, filtered, and concentrated to give the product (5.35 g, 47% yield). MS (apci) m/z 218.1 (M+H).
Intermediate 2
Figure imgf000116_0001
phenyl (3 -ethoxy-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)carbamate
[00659] To a suspension of 3 -ethoxy-4-methyl-l -phenyl- lH-pyrazol-5 -amine
[Intermediate 1] (138 mg, 0.57 mmol) in EtOAc (7 mL) at 0 °C was added NaOH (0.57 niL, 2M, 1.14 mmol) followed by phenyl chloro formate (0.12 mL, 0.97 mmol). The reaction was stirred at ambient temperature for 17 hours then treated with EtOAc, washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 6:1 hexanes / EtOAc to afford the title compound (139 mg, 72% yield). MS (apci) m/z = 338.0 (M+).
Figure imgf000116_0002
3 ,4-dimethyl- 1 -phenyl- 1 H-pyrazol-5 -amine
[00660] To a solution of 2-methyl-3-oxobutanenitrile (295 mg, 3.038 mmol) in EtOH
(40 mL) were added HC1 (5-6M in iPrOH, 0.6 mL) and phenylhydrazine (0.299 mL, 3.038 mmol). The reaction mixture was heated to reflux for 17 hours, then cooled to ambient temperature. The reaction mixture was diluted with saturated NaHC03 (20 mL), extracted with DCM (2 x 25 mL), and the combined organic phases were dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with 0-3% MeOH/DCM to yield the title compound (555 mg, 97% yield) as a tan solid. MS (apci) m/z = 188.2 (M+H). Intermediate 3
Figure imgf000117_0001
phenyl (3 ,4-dimethyl- 1 -phenyl- 1 H-pyrazol-5-yl)carbamate
[00661] To a solution of 3,4-dimethyl-l -phenyl- lH-pyrazol-5-amine (1.80 g, 9.6 mmol) in EtOAc (20 mL) was added 2N NaOH (9.6 mL, 19.2 mmol) followed by phenyl chloroformate (1.7 mL, 13.5 mmol). The mixture was stirred at ambient temperature for 16 hours then treated with phenyl chloroformate (500 μί) and stirred a further 4 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with saturated NaHC03 (50 mL) and brine (50 mL) then dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 4: 1 hexanes / EtOAc to afford the title compound (1.83 g, 62% yield) as a white powder.
Intermediate 4
Figure imgf000117_0002
1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-3 ,4'-bipyrazol-5-amine
[00662] Step A: ethyl 1 -methyl- lH-pyrazole-4-carboxylate: To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL). The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue dissolved in DCM and re-concentrated, then dried for 2 days to yield ethyl 1 -methyl- lH-pyrazole-4-carboxylate (106 g, 99% yield) as a tan orange oil. MS (apci) m/z = 155.1 (M+H).
[00663] Step B: 2-methyl-3-(l -methyl- lH-pyrazol-4-yl)-3-oxopropanenitrile: To a four-necked 5-liter round bottomed flask fitted with an overhead stirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.OM in THF). The solution was cooled in an acetone/dry ice bath first (internal temperature of -79 °C) under nitrogen, followed by slow addition of propiononitrile (103 mL, 1444 mmol) via dropping funnel. The mixture was stirred at -80 °C for 90 minutes. A solution of ethyl 1 -methyl- lH-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF (500 mL) was then introduced dropwise via an addition funnel (addition time: about 45 minutes; internal temperature during addition remained below -76 °C) . After the addition was complete, the reaction was allowed to slowly warm to ambient temperature and stirred overnight. An orange glass deposited on the bottom of the flask. The organics were decanted and the glass was dissolved in warm water. The mixture was washed with with ether (3 x 1000 mL). The aqueous phase was then pH-adjusted to 5 (pH paper) using concentrated HC1 and saturated bicarbarbonate solution The aqueous layer was extracted with DCM (3 x 1000 mL). The combined organic extracts were dried over MgS04 filtered and concentrated to yield 2-methyl-3-(l -methyl- lH-pyrazol-4-yl)-3- oxopropanenitrile as an amber oil (92 g, 82% yield). MS (apci) m/z = 162.1 (M-H).
[00664] Step C: 1 '.4-dimethyl- 1 -phenyl- 1 H.1 'H-3.4'-bipyrazol-5-amine: A 3L, 3 necked round bottomed flask was charged with 2-methyl-3-(l-methyl-lH-pyrazol-4-yl)-3- oxopropanenitrile (60 g, 368 mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazine hydrochloride (58 g, 404 mmol) at ambient temperature to form a yellowish suspension. The reaction vessel was equipped with a water condenser and refluxed (using a heating mantle) overnight. The reaction was concentrated and 1M NaOH (1L) was added and the solid was broken up and collected. The solid was washed with water and hexanes. A second crop crashed out in the filtrate and was collected. The combined solids were crushed and triturated with ether (500 mL). The solid was collected by filtration, washed with hexanes and dried in vacuo to provide the title compound (93 g, 100% yield) as a yellow solid. MS (apci) m/z = 254.1 (M+H).
Intermediate 5
Figure imgf000118_0001
phenyl 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 'H-3,4'-bipyrazol-5-ylcarbamate [00665] A 3 L, round bottomed flask was charged with 1',4-dimethyl-l-phenyl- lH,l'H-3,4'-bipyrazol-5-amine (50 g, 197.4 mmol) and EtOAc (1000 mL) to obtain a clear brownish solution. To this was added NaOH (2M aq) (500mL) in one portion to obtain a turbid mixture (the aqueous and organic layers were clear, but a precipitate was observed in between the two layers). After 3 minutes, phenyl carbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambient temperature (the temperature of the reaction mixture increased to 33 °C during the addition). The reaction stirred at ambient temperature for 2 hours. Additional phenyl carbonochloridate (10 mL) was added. After 30 minutes the organics layers were separated, washed with brine and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 75% EtOAc / hexanes to provide the title compound (60 g, 81% yield) as a cream foam. MS (apci) m/z = 374.1 (M+H).
Intermediate 6
Figure imgf000119_0001
5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl trifluoromethanesulfonate
[00666] Step A: Preparation of 5-amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one: A mixture of ethyl 2-cyanopropanoate (50.5 g, 397.2 mmol) and phenylhydrazine (39 mL, 397.2 mmol) in dioxane (100 mL) was heated at 110 °C for 5 days. The cooled mixture was concentrated to 1/2 volume then cooled in ice and triturated with cold Et20. Solids were filtered, washed extensively with Et20 and dried in vacuo to afford 5-amino-4-methyl-l- phenyl-lH-pyrazol-3(2H)-one (34.69 g, 46% yield) as a fluffy white powder. MS (apci) m/z = 190.1 (M+H).
[00667] Step B: Preparation of 5-amino-4-methyl-l -phenyl- lH-pyrazol-3-yl trifluoromethane sulfonate: A suspension of 5 -amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)- one (13.72 g, 72.5 mmol) and N-phenylbis(trifluoromethylsulfonamide) (27.2 g, 76.1 mmol) in DMF (100 mL) was treated with DIEA (37.9 mL, 217.5 mmol) and the mixture stirred at ambient temperature for 16 hours. The mixture was partitioned between saturated NaHC03 (400 mL) and EtOAc (200 mL) and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with water (5 x 50 mL) and brine (50 mL) then dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 4:1 hexanes/EtOAc, to afford the title compound (23.1 g, 99% yield) as a pale yellow solid. MS (apci) m/z = 322.0 (M+H). Intermediate 7
Figure imgf000120_0001
3-bromo-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine
[00668] To a suspension of 5-amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one
[Intermediate 6, step A] (1.60 g, 8.46 mmol) in acetonitrile (30 mL) was added phosphorus oxybromide (3.64 g, 12.7 mmol) in one portion. The mixture was stirred at reflux for 3 hours then cooled and concentrated in vacuo. The residue was treated with DCM (50 mL) then saturated NaHC03 (50 mL) was slowly added. The mixture was stirred for 30 minutes, and then the layers were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2:1 hexanes/EtOAc, to afford the title compound (273 mg, 13% yield) as a white solid. MS (apci) m/z = 254.0 (M+H).
Intermediate 8
Figure imgf000120_0002
5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)- 1 -methylpyridin-2( 1 H)-one
[00669] 3-Bromo-4-methyl-l-phenyl-lH-pyrazol-5-amine [Intermediate 7] (763 mg,
3.03 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (504 mg, 59% yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H). Intermediate 9
Figure imgf000121_0001
phenyl (4-methyl-3 -( 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3 -ylV 1 -phenyl- 1 H-pyrazol-5- yPcarbamate
[00670] To a suspension of 5-(5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)-l- methylpyridin-2(lH)-one [Intermediate 8] (2.80 g, 9.99 mmol) in EtOAc (120 mL) was added 2N NaOH (14.98 mL, 29.97 mmol) followed by phenyl chloroformate (2.5 mL, 19.98 mmol). The mixture was stirred at ambient temperature for 16 hours then partitioned between water (100 mL) and EtOAc (100 mL) and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaHC03 (50 mL) and brine (50 mL) then dried over Na2S04, filtered and concentrated to afford the title compound as a pale yellow syrup which was used directly without purification, assuming 100% yield. MS (apci) m/z = 401.2 (M+H).
Intermediate 10
Figure imgf000121_0002
4-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-νΠ- 1 -methylpyridin-2( 1 H)-one
[00671] Prepared according to the procedure of Intermediate 8, substituting 3-bromo- 4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine with 5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl trifluoromethanesulfonate and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2( 1 H)one with 1 -methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (160 mg, 37% yield) as a pink solid. MS (apci) m/z = 281.1 (M+H).
Figure imgf000122_0001
phenyl (4-methyl-3 -( 1 -methyl-2-oxo- 1 ,2-dihvdropyridin-4-yf)- 1 -phenyl- 1 H-pyrazol-5- vDcarbamate
[00672] Prepared according to the procedure of Intermediate 9, substituting 5-(5- amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)- 1 -methylpyridin-2( 1 H)-one with 4-(5-amino-4- methyl-1 -phenyl- lH-pyrazol-3-yl)-l-methylpyridin-2(lH)-one. MS (apci) m/z = 401.1 (M+H).
Intermediate 12
Figure imgf000122_0002
4-methyl-3-(2-methylpyrimidin-5-vD- 1 -phenyl- 1 H-pyrazol-5 -amine
[00673] 5-Amino-4-methyl-l -phenyl- lH-pyrazol-3-yl trifluoromethanesulfonate (900 mg, 2.8 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (925 mg, 4.2 mmol), K2C03 (1.55 g, 11.2 mmol) and Pd(PPh3)4 (324 mg, 0.28 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (533 mg, 72% yield) as a pink solid. MS (apci) m/z = 266.1 (M+H).
Intermediate 13
Figure imgf000122_0003
4-methyl-3 -(6-methylpyridin-3 -vP- 1 -phenyl- 1 H-pyrazol-5 -amine [00674] Prepared according to the procedure for Intermediate 12, replacing 2-methyl-
5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidine with (6-methylpyridin-3- yl)boronic acid, to afford the title compound (529 mg, 64% yield) as a red solid. MS (apci) m/z = 265.1 (M+H).
Intermediate 14
Figure imgf000123_0001
phenyl (2-phenyl-2,4,5,6-tetrahydrocyclopenta c1pyrazol-3-yl)carbamate
[00675] A suspension of 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Ryan Scientific, Inc., catalog # EN300- 14400) (6.0 g, 30.11 mmol) in EtOAc (250 mL) was cooled in ice bath and NaOH (2 N aq, 30.11 mL, 60.23 mmol) added in one portion. PhOCOCl (6.800 mL, 54.20 mmol) was added drop-wise and the reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (100 mL) and phase-separated. The organic layer was washed with water (2 x 150 mL) and brine (150 mL), dried (MgS04), filtered and concentrated. The crude product was taken up in DCM and concentrated to dryness. The crude solid was triturated with ether/hexanes (2:1, 2 x 100 mL), filtered and dried, giving the product as an off-white solid (7.4 g, 77%). MS (apci) m/z = 320.1 (M+H).
[00676] Table 1 provides a list of commercially available pyrazole intermediates can be used in the synthesis of compounds described in the Examples.
Table 1
Pyrazole Vendor/CataIog# CAS#
Oakwood, 021512 126208-61-5
Array BioPharma, Al 075-0 N/A
Figure imgf000123_0002
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
N/A = Not available Intermediate PI
Figure imgf000127_0001
Ethyl 3 -(5 -amino-3 -tert-butyl- 1 H-pyrazol- 1 - vDbenzoate
[00677] To a suspension of ethyl 3-hydrazinylbenzoate hydrochloride (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) m/z = 288.2 (M+H).
[00678] The compounds in Table 2 were prepared by the method as described for Intermediate PI , substituting 4,4-dimethyl-3-oxopentanenitrile with the appropriate cyanoketone and ethyl 3-hydrazinylbenzoate hydrochloride with the appropriate hydrazine.
Table 2
Figure imgf000127_0002
Figure imgf000128_0001
Figure imgf000129_0001
Intermediate P101
Figure imgf000129_0002
2-(l-methyl-lH-pyrazol-4-yn-2,4,5,6-tetrahvdrocvclopenta-fc]pyrazol-3-amine
[00679] Step A: Preparation of di-fert-butyl 1-(1 -methyl- lH-pyrazol-4-yl)hydrazine- 1,2-dicarboxylate: To a solution of 4-bromo-l -methyl- lH-pyrazole (1.93 mL, 18.6 mmol) in ether (37.3 mL) cooled to -78 °C was added nBuLi (23.3 mL, 37.3 mmol). After stirring at - 78 °C for 30 minutes, a solution of di-t-butyl azodicarboxylate (4.29 g, 18.6 mmol) in Et20 (37.3 mL, 18.6 mmol) was added dropwise. After 1 hour, the reaction mixture was warmed up to -20 °C and quenched with ice. After warming to ambient temperature, the mixture was filtered and rinsed with Et20. The resulting solid was taken up in a mixture of DCM and water, and the mixture was phase separated. The organic layer was dried with MgS04, filtered and concentrated in vacuo to afford the first batch of product as a white solid (1.64 g, 28% yield). A second batch of product was recovered from the filtrate by silica column chromatography, eluting with 40-60% hexanes/EtOAc (0.51 g, 8.8% yield). MS (apci) m/z - 313.0 (M+H).
[00680] Step B: Preparation of 2-(l-methyl-lH-pyrazol-4-vn-2.4.5.6- tetrahvdrocyclopenta-[clpyrazol-3-amine: To a solution of di-tert-butyl 1 -(1 -methyl- 1H- pyrazol-4-yl)hydrazine-l,2-dicarboxylate (103 mg, 0.330 mmol) in EtOH (1.65 mL, 0.330 mmol) was added concentrated HCl (137
Figure imgf000129_0003
1.65 mmol). The mixture was stirred at ambient temperature for 5 minutes, then cooled in an ice bath followed by addition of 2- oxocyclopentanecarbonitrile (36.0 mg, 0.330 mmol). After stirring for 5 minutes, the reaction mixture was warmed to ambient temperature overnight. The reaction mixture was concentrated and partitioned in water and DCM. After phase-separation, the aqueous layer was basified (pH 10) and then extracted with DCM (3 χ 10 mL). The combined organic extracts were dried with MgS04, filtered and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography, eluting with 0-100% acetonitrile/water to afford the product as a yellow solid (4.5 mg, 6.7% yield). MS (apci) m/z = 204.1 (M+H). Intermediate PI 02
Figure imgf000130_0001
3-tert-butyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-amine
[00681] Step A: Preparation of (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride: A suspension of dihydro-2H-pyran-4(3H)-one (2.00 g, 20.0 mmol) and tert-butyl hydrazinecarboxylate (2.64 g, 20.0 mmol) in hexanes (20.0 mL) was refluxed for 2 hours. After cooling, BH3-THF complex (20.0 mL, 20.0 mmol) was added and the reaction mixture was stirred for 1 hour. The mixture was then treated with 4 N HC1 in dioxane (20.0 mL, 79.9 mmol), followed by 3 drops of water. After stirring at ambient temperature for 1 hour, the reaction mixture was filtered and rinsed with EtOAc to afford the product as a solid (2.39 g, 78.4% yield). MS (apci) m/z = 1 17.0 (M+H).
[00682] Step B: Preparation of 3-fert-butyl-l -(tetrahydro-2H-pyran-4-yl)-lH-pyrazol- 5 -amine: Prepared by the method as described in for the preparation of Intermediate PI, substituting (tetrahydro-2H-pyran-4-yl)hydrazine dihydrochloride for ethyl 3- hydrazinylbenzoate hydrochloride to yield the product as a yellow oil (0.472 g, 99.9% yield). MS (apci) m/z = 224.1 (Μ+Η).
Intermediate PI 03
Figure imgf000130_0002
2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
[00683] Step A: Preparation of 2-(2-(pyridin-2-yl)hydrazono)cyclopentane- carbonitrile: A solution of 2-hydrazinylpyridine (0.200 g, 1.83 mmol) and 2- oxocyclopentanecarbonitrile (0.200 g, 1.83 mmol) in MeOH (9.16 mL) was treated with concentrated HC1 (0.764 mL, 9.16 mmol) and refluxed for 16 hours. The reaction mixture was concentrated in vacuo, and then partitioned in water and DCM. After phase-separation, the aqueous layer was washed with DCM, basified (saturated NaHC03; pH 10), and extracted with DCM. The combined organic layers were dried with MgS04, filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 100% EtOAc to afford the product (0.289 g, 78.6% yield). MS (apci) m/z = 201.2 (M+H). [00684] Step B: Preparation of. 2-(pyridin-2-yl)-2A5,6- tetrahydrocyclopenta[c]pyrazol-3-amine: A solution of 2-(2-(pyridin-2- yl)hydrazono)cyclopentanecarbonitrile (0.243 g, 1.21 mmol) in EtOH (6.06 mL, 1.21 mmol) was treated with 6 M HCl (0.202 mL, 1.21 mmol) and refluxed for 3 days. After removal of the solvent, the crude residue was diluted in water, basified (saturated NaHC03; pH 10) and extracted with DCM. The combined organic layers were dried with MgS04, filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 50% EtOAc/hexanes to afford the product (0.198 g, 81.6% yield). MS (apci) m/z = 201.2 (M+H).
Intermediate P104
Figure imgf000131_0001
2-(pyridin-3-yl)-2A5,6-tetrahvdrocvdopenta[c]pyrazol-3-amine
[00685] Prepared by the method described above for Intermediate PI 03, substituting 3- hydrazinylpyridine for 2-hydrazinyl pyridine to afford the title product. MS (apci) m/z = 201.1 (M+H).
Intermediate PI 05
Figure imgf000131_0002
6,6-dimethyl-2-phenyl-2,4,5,6-tetrahvdrocyclopenta[c]pyrazol-3-amine
[00686] Step A: Preparation of 5-chloro-2.2-dimethylpentanenitrile: Isobutyronitrile (1.38 g, 20.0 mmol) and l-bromo-3-chloropropane (3.46 g, 22.0 mmol) were sequentially added to a 1 M solution of lithium bis(trimethylsilyl)amide (20.0 mL, 20.0 mmol) while stirring. After stirring at 70 °C for 16 hours, the reaction mixture was quenched with water then extracted with DCM. The combined organic layers were dried with MgS04, filtered and concentrated in vacuo to afford 5-chloro-2,2-dimethylpentanenitrile (2.91 g, 100% yield). 1H NMR (CDC13) δ 3.57-3.61 (m, 2H), 1.94-2.02 (m, 2H), 1.67-1.72 (m, 2H), 1.37 (s, 6H).
[00687] Step B: Preparation of 2,2-dimethylhexanedinitrile: A suspension of 5-chloro- 2,2-dimethylpentanenitrile (2.91 g, 20.0 mmol) and NaCN (1.57 g, 32.0 mmol) in DMF (20.0 mL) and water (1 mL) was heated at 100 °C for 16 hours. After cooling, the reaction mixture was diluted with water and refluxed for 30 minutes, then cooled, poured into water and stirred for 3 hours. The solution was then extracted with Et20. The combined Et20 extracts were washed with H20, dried with MgS04, filtered and concentrated in vacuo to afford the product (2.20 g, 80.7% yield). 1H NMR (CDC13) δ 2.42-2.47 (m, 2H), 1.83-1.92 (m, 2H), 1.67-1.72 (m, 2H), 1.39 (s, 6H).
[00688] Step C: Preparation of 3,3-dimethyl-2-oxocyclopentanecarbonitrile: A suspension of KOtBu (0.511 g, 4.55 mmol) in toluene (18.4 mL) was treated a toluene (2.0 mL) solution of 2,2-dimethylhexanedinitrile (1.00 g, 7.34 mmol) and heated at 80 °C for 2 hours. The reaction mixture was then cooled to ambient temperature and quenched with water. The mixture was separated and the organic layer was stirred in 2 N HC1 (20 mL) for 16 hours. The mixture was separated and the organic layer dried with MgS04, filtered and concentrated in vacuo to a yellow-white solid. The crude solid was purified by silica column chromatography, eluting with 10-40% EtOAc/hexanes, to afford the product (0.250 g, 24.8% yield). 1H NMR (CDC13) δ 3.20-3.26 (m, 1H), 2.38-2.47 (m, 1H), 2.14-2.25 (m, 1H), 1.97- 2.05 (m, 1H), 1.74-1.83 (m, 1H), 1.14 (s, 6H).
[00689] Step D: Preparation of 6,6-dimethyl-2-phenyl-2A5,6-tetrahydrocyclopenta[c] pyrazol-3 -amine: Prepared by the method as described for Intermediate PI, substituting phenylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 3,3-dimethyl-2- oxocyclopentanecarbonitrile for 4,4-dimethyl-3-oxopentanenitrile to afford the product (0.192 g, 46.2% yield) as a yellow solid. MS (apci) m/z = 228.2 (M+H).
Intermediate PI 06
Figure imgf000132_0001
7.7-dimethyl-2-phenyl-4.5,6,7-tetrahydro-2H-indazol-3-amine
[00690] Step A: Preparation of 2,2-dimethylheptanedinitrile: Prepared by the method as described for Intermediate PI 05, Steps A and B, substituting l-bromo-4-chlorobutane for l-bromo-3-chloropropane to yield the product (2.21 g, 73.7% yield). 1H NMR (CDC13) δ 2.37-2.42 (m, 2H), 1.53-1.77 (m, 6H), 1.36 (s, 6H).
[00691] Step B: Preparation of 3.3-dimethyl-2-oxocvclohexanecarbonitrile: A suspension of KOtBu (0.463 g, 4.13 mmol) in toluene (16.6 mL) was treated with a solution of 2,2-dimethylheptanedinitrile (1.00 g, 6.66 mmol) in toluene (2.0 mL) and heated at 80 °C for 48 hours. After cooling to ambient temperature, the reaction mixture was quenched with water and phase-separated, and the organic layer was stirred with 2 N HC1 (20 mL) for 16 hours. After phase-separation, the organic layer was dried with MgS04, filtered and concentrated in vacuo. The crude material was purified by silica column chromatography, eluting with 10-20% EtOAc/hexanes to afford the product (0.374 g, 37.2% yield). 1H NMR (CDC13) δ 3.72-3.78 (m, 1H), 2.42-2.50 (m. 1H), 1.78-2.04 (m, 4H), 1.60-1.70 (m, 1H), 1.21 (s, 3H), 1.16 (s, 3H).
[00692] Step C: Preparation of 7,7-dimethyl-2-phenyl-4.5.6.7-tetrahvdro-2H-indazol- 3-amine: Prepared by the method as described for Intermediate PI, substituting phenylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 3,3-dimethyl-2- oxocyclohexanecarbonitrile for 4,4-dimethyl-3-oxopentanenitrile to yield the product as an off-white solid (0.490 g, 54.2% yield, 66% purity). MS (apci) m/z = 242.2 (M+H).
Intermediate P107
Figure imgf000133_0001
3-isopropyl-4-methyl-l-phenyl-lH-pyrazol-5-amine
[00693] Step A: Preparation of 2,4-dimethyl-3-oxopentanenitrile: To a solution of propiononitrile (518 mg, 9.40 mmol) in THF (50 mL, 7.83 mmol) at -78 °C under N2 was slowly added lithium bis(trimethylsilyl)amide (1M in THF) (7.83 mL, 7.83 mmol). After 30 minutes, methyl isobutyrate (0.898 mL, 7.83 mmol) was added dropwise, and the reaction mixture was warmed to 0 °C. A yellow precipitate formed, the reaction mixture was stirred for 1 hour, then diluted with H20 (50 mL) to dissolve the solids. The mixture was extracted with Et20 (25 mL), and the basic aqueous phase was acidified with 2M HC1 (5 mL) and extracted with Et20 (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried with MgS04, filtered, and concentrated to afford the product (421 mg, 42.9% yield)
[00694] Step B: Preparation of 3-isopropyl-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine: Prepared by the method as described for Intermediate PI, substituting phenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 4,4-dimethyl-3-oxopentanenitrile with 2,4- dimethyl-3-oxopentanenitrile to yield the product as a yellow syrup (0.587 g, 81.1% yield). MS (apci) m/z = 216.2 (M+H).
Intermediate P108
Figure imgf000133_0002
2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine
[00695] Step A: Preparation of 4-oxotetrahydrofuran-3-carbonitrile: To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 °C was added dropwise methyl 2-hydroxyacetate (675.7 μί, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 μΙ , 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HC1 (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgS04, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). 1H NMR (CDC13) δ 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
[00696] Step B: Preparation of 2-phenyl-4,6-dihydro-2H-furo[3,4-clpyrazol-3-amine: Prepared by the method as described for Intermediate PI, substituting phenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 4,4-dimethyl-3-oxopentanenitrile with 4- oxotetrahydrofuran-3-carbonitrile to yield the product as a reddish-brown syrup (182 mg, 22.5% yield). MS (apci) m/z = 202.1 (M+H).
Intermediate P109
Figure imgf000134_0001
3 -(methoxymethyl)- 1 -phenyl- 1H-pyrazol-5-amine
[00697] Step A: Preparation of 4-methoxy-3-oxobutanenitrile: To a solution of methyl 2-methoxyacetate (0.4753 mL, 4.803 mmol) in THF (20 mL, 4.803 mmol) at -78 °C under N2 was added acetonitrile (0.3033 mL, 5.763 mmol), followed by lithium bis(trimethylsilyl)amide (1M in THF) (4.803 mL, 4.803 mmol). After stirring 1 hour, the reaction mixture was warmed to 0 °C and stirred for 1 hour. The reaction mixture was then diluted with H20 (25 mL), washed with Et20 (25mL), then neutralized with 2 M HC1 (1.5 mL). This was extracted with Et20 (2 x 25 mL) and the combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to afford the product (169 mg, 31.1% yield). Ή NMR (CDC13) δ 4.09 (s, 2H), 3.66 (s, 2H), 3.46 (s, 3H)
[00698] Step B: Preparation of 3-(methoxymethyl -l-phenyl-lH-pyrazol-5-amine: Prepared by the method as described for Intermediate PI, substituting phenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 4,4-dimethyl-3-oxopentanenitrile with 4- methoxy-3-oxobutanenitrile to yield the product as a pale yellow residue (6.0 mg, 2.0% yield). MS (apci) m/z = 204.0 (M+H).
Intermediate PI 10
Figure imgf000135_0001
3-(methoxymethyl)-4-methyl- 1 -phenyl- 1 H-pyrazol-5 -amine
[00699] Prepared according to the method as described for Intermediate PI 09, replacing acetonitrile with propionitrile to afford the product as an orange residue. MS (apci) m/z = 218.0 (M+H).
Intermediate Pill
Figure imgf000135_0002
2-(5-amino- 1 -phenyl- lH-pyrazol-3-yP-2 -methylpropan- 1 -ol
[00700] Step A: Preparation of methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethyl- propanoate: Methyl 3-hydroxy-2,2-dimethylpropanoate (1.000 g, 7.567 mmol), TBDMS-C1 (1.140 g, 7.567 mmol) and imidazole (0.5666 g, 8.323 mmol) were dissolved in DMF (5 mL, 7.567 mmol) and stirred at ambient temperature overnight. The reaction mixture was diluted with H20 (25 mL) and extracted with EtOAc (2 x 25mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered and concentrated to afford the product (1.92 g, 103% yield). Ή NMR (CDC13) δ 3.66 (s, 3H), 3.57 (s, 2H), 1.15 (s, 6H), 0.87 (s, 9H), 0.02 (s, 6H).
[00701] Step B: Preparation of 5-(tert-butyldimethylsilyloxyV4.4-dimethyl-3- oxopentanenitrile: Prepared according to the method described for Intermediate PI 09, replacing methyl 2-methoxyacetate with methyl 3-(tert-butyldimethylsilyloxy)-2,2- dimethylpropanoate to afford the product as a pale yellow residue. lH NMR (CDC13) δ 3.70 (s, 2H), 3.55 (s, 2H), 1.15 (s, 6H), 0.89 (s, 9H), 0.06 (s, 6H).
[00702] Step C: Preparation of 2-(5-amino-l -phenyl- lH-pyrazol-3 -yl)-2- methylpropan- 1 -ol : Prepared by the method as described for Intermediate PI, substituting phenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 4,4-dimethyl-3- oxopentanenitrile with methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate to yield the product as yellow syrup (74 mg, 66% yield). MS (apci) m/z = 232.2 (M+H). Intermediate PI 12
Figure imgf000136_0001
2-(5-amino-4-methyl-l -phenyl- lH-pyrazol-3-yl)-2-methylpropan-l-ol
[00703] Prepared according to the method described for Intermediate Pi l l, replacing acetonitrile with propionitrile to afford the product as a yellow residue. MS (apci) m/z = 246.2 (Μ+Η).
Intermediate PI 13
Figure imgf000136_0002
3-(3-methoxypropyl)-4-methyl- 1 -phenyl- 1 H-pyrazol-5 -amine
[00704] Prepared according to the method described for Intermediate PI 09, replacing methyl 2-methoxyacetate with methyl 4-methoxybutanoate and replacing acetonitrile with propionitrile in Step A to afford the product as an orange-brown syrup. MS (apci) m/z = 246.1 (Μ+Η).
Intermediate PI 14
Figure imgf000136_0003
1 J'-dimethyl-lH,! 'H-3,4'-bipyrazol-5 -amine
[00705] Step A: Preparation of 3-(l-methyl-lH-pyrazol-4-yl)-3-oxopropanenitrile: A solution of ethyl 1 -methyl- lH-pyrazole-4-carboxylate (500 mg, 3.24 mmol), toluene (7.50 mL, 70.4 mmol), and acetonitrile (346 μί, 6.49 mmol) was treated in one portion with KOtBu (1092 mg, 9.73 mmol) to give a hazy solution. The reaction was allowed to stir at ambient temperature for one hour, and was determined to be complete by HPLC analysis. The mixture was treated with water (7.5 mL) and stirred for 1 minute, then acidified with 3M HCl (3027 μί, 9.08 mmol) to pH 5.5-6. The aqueous layer was extracted with ethyl acetate (3 x 5 mL) and the combined organic extracts were concentrated in vacuo to give a yellow viscous oil, which completely solidified upon placing under high vacuum to afford the product (102 mg, 21.1% yield). Ή NMR (CDC13) 5 8.02 (s, 1H), 7.94 (s, 1H), 3.98 (s, 3H), 3.82 (s, 2H) [00706] Step B: Preparation of 1.1 '-dimethyl- lH.l'H-3.4'-bipyrazol-5-amine: Prepared by the method as described for Intermediate PI, substituting methyl hydrazine for ethyl 3- hydrazinylbenzoate hydrochloride and replacing 4,4-dimethyl-3-oxopentanenitrile with 3-(l- methyl-lH-pyrazol-4-yl)-3-oxopropanenitrile to yield the product as an ivory white solid (45 mg, 44.6% yield). MS (apci) m/z = 178.1 (Μ+Η).
Intermediate PI 15
Figure imgf000137_0001
4-chloro- 1 -diphenyl- lH-pyrazol-5-amine
[00707] To a solution of l,3-diphenyl-lH-pyrazol-5-amine (Table 1; 0.100 g, 0.425 mmol) in acetonitrile (2 mL) was added N-chlorosuccinimide (0.0568 g, 0.425 mmol). The pale yellow solution was stirred at ambient temperature for 3 hours, then concentrated in vacuo and purified by silica column chromatography eluting with 20% EtOAc/Hexanes to afford the product as a light brown oil (0.10 g, 87% yield). MS (apci) m/z = 270.0 (M+H).
Intermediate PI 16
Figure imgf000137_0002
4-bromo- 1 ,3-diphenyl- 1 H-pyrazol-5-amine
[00708] Prepared according to the procedure described for Intermediate PI 15, substituting N-chloro succinimide with N-bromo-succinimide. MS (apci) m/z = 313.9 (M+H).
Intermediate PI 17
Figure imgf000137_0003
4-chloro-3 -methyl- 1 -phenyl- 1 H-pyrazol-5 -amine
[00709] Prepared according to the procedure described for Intermediate PI 15, substituting l,3-diphenyl-lH-pyrazol-5-amine with 3-methyl-l -phenyl- lH-pyrazol-5-amine. MS (apci) m/z = 207.9 (M+H). Intermediate PI 18
Figure imgf000138_0001
4-bromo-3 -methyl- 1 -phenyl- 1 H-pyrazol-5-amine
[00710] Prepared according to the procedure described for Intermediate PI 17, substituting N-chloro succinimide with N-bromo-succinimide. MS (apci) m/z = 251.9 (M+H).
Intermediate PI 19
Figure imgf000138_0002
4-chloro- 1 -methyl-3 -phenyl- 1 H-pyrazol-5-amine
[00711] Prepared according to the procedure described for Intermediate PI 15, substituting l,3-diphenyl-lH-pyrazol-5-amine with l -methyl-3-phenyl-lH-pyrazol-5-amine (Table 1). MS (apci) m/z = 208.0 (M+H).
Intermediate P120
Figure imgf000138_0003
4-bromo- 1 -methyl-3 -phenyl- 1 H-pyrazol-5 -amine
[00712] Prepared according to the procedure described for Intermediate PI 19, substituting N-chloro succinimide with N-bromo-succinimide. MS (apci) m/z = 251.9 (M+H).
Intermediate P121
Figure imgf000138_0004
1 -methyl-3 -(4-(methylthio)phenyl)- 1 H-pyrazol-5-amine
[00713] Step A: Preparation of 3-(4-(methylthio)phenyl)-3-oxopropanenitrile: To a suspension of NaH (60% in mineral oil) (154 mg, 3.84 mmol) in dioxane (25.0 mL, 2.74 mmol) was added acetonitrile (0.217 mL, 4.12 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes, then treated with methyl 4-(methylthio)benzoate (500 mg, 2.74 mmol) and heated to reflux for 15 hours. The suspension was cooled, then diluted with water (25 mL) and washed with Et20 (25 mL). The aqueous layer was neutralized with 2M HCl (1.8 mL) and extracted with Et20 (2 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered and concentrated in vacuo. The resultant residue was purified by silica column chromatography eluting with 0-5% MeOH/DCM to afford the product (317 mg, 60.4% yield). 1H NMR (CDC13) δ 7.82 (d, 2H), 7.30 (d, 2H), 4.02 (s, 2H), 2.54 (s, 3H).
[00714] Step B: Preparation of l-methyl-3-(4-(methylthio)phenyl -lH-pyrazol-5- amine: Prepared by the method as described in Intermediate PI, substituting methylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and substituting 3-(4-(methylthio)phenyl)-3- oxopropanenitrile for 4,4-dimethyl-3-oxopentanenitrile to yield the product as a yellow solid (0.307 g, 96.7% yield). MS (apci) m/z = 220.0 (M+H).
Intermediate P122
Figure imgf000139_0001
2-(5-amino- 1 -phenyl- lH-pyrazol-3-yl)-2-methylpropanenitrile
[00715] Prepared according to the procedure for Intermediate P121, substituting methyl 4-(methylthio)benzoate with ethyl 2-cyano-2-methylpropanoate in Step A and phenyl hydrazine hydrochloride for methyl hydrazine in Step B. MS (apci) m/z = 227.1 (M+H).
Intermediate P123
Figure imgf000139_0002
3-(4-(2-methoxyethoxy)phenyl)-l-methyl-lH-pyrazol-5-amine
[00716] Step A: Preparation of 3-(4-(benzyloxy')phenyl)-3-oxopropanenitrile: Prepared according to the procedure described for Intermediate PI 21, substituting methyl 4- (methylthio)benzoate with methyl 4-(benzyloxy)benzoate in Step A. 1H NMR (CDC13) δ 7.90 (d, 2H), 7.42 (m, 4H), 7.37 (m, 1H), 7.05 (d, 2H), 5.16 (s, 2H), 4.00 (s, 2H).
[00717] Step B: Preparation of 3-(4-(benzyloxy)phenylVl-methyl-lH-pyrazol-5- amine: Prepared by the method as described for Intermediate PI, substituting methylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and 3-(4-(benzyloxy)phenyl)- 3-oxopropanenitrile for 4,4-dimethyl-3-oxopentanenitrile to yield the product as a yellow solid. MS (apci) m/z = 280.1 (M+H).
[00718] Step C: Preparation of 4-(5-amino-l -methyl- lH-pyrazol-3-vDphenol: To a solution of 3 -(4-(benzyloxy)phenyl)-l -methyl- lH-pyrazol-5 -amine (47 mg, 0.17 mmol) in EtOH (5.0 mL) was added 5% Pd/C (9.0 mg, 0.0084 mmol) and stirred under a H2 balloon for 17 hours. The reaction mixture was filtered through Celite®, rinsed with EtOH and concentrated in vacuo to afford the product (28 mg, 88% yield). MS (apci) m/z - 190.1 (M+H).
[00719] Step D: Preparation of 3 -(4-(2-methoxyethoxy)phenyl)- 1 -methyl- 1 H-pyrazol- 5 -amine: To a solution of 4-(5-amino-l -methyl- lH-pyrazol-3-yl)phenol (14 mg, 0.074 mmol) in DMSO (0.50 mL, 7.0 mmol) was added Cs2C03 (48 mg, 0.15 mmol) and l-bromo-2- methoxyethane (9.7 μί, 0.10 mmol). The reaction mixture was stirred for 16 hours, then diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried with MgS04, filtered and concentrated to afford the crude product (22 mg, 120% yield). The crude product was used without purification in subsequent steps. MS (apci) m z = 248.0 (M+H).
Intermediate PI 24
Figure imgf000140_0001
1 '-methyl- 1 -phenyl- 1 H 1 'H-3 ,4'-bipyrazol-5-amine
[00720] Prepared according to the procedure described for Intermediate PI 14, substituting methylhydrazine with phenylhydrazine in Step B. MS (apci) m/z = 240.0 (Μ+Η).
Intermediate P125
Figure imgf000140_0002
4-methoxy-3 -methyl- 1 -phenyl- 1 H-pyrazol-5 -amine
[00721] Prepared according to the procedure for Intermediate PI 21, substituting methyl 4-(methylthio)benzoate with ethyl acetate and substituting acetonitrile with 2- methoxyacetonitrile in Step A and phenyl hydrazine hydrochloride for methyl hydrazine in Step B. MS (apci) m/z = 204.0 (M+H).
Intermediate P126
Figure imgf000141_0001
(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -vDmethanol
[00722] Prepared according to the procedure for Intermediate PI 12, substituting methyl 3-hydroxy-2,2-dimethylpropanoate with ethyl 2-hydroxyacetate in Step A. MS (apci) m/z = 204.1 (M+H).
Int rmediate P127
Figure imgf000141_0002
2-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yPethanol
[00723] Prepared according to the procedure for Intermediate PI 12, substituting methyl 3-hydroxy-2,2-dimethylpropanoate with methyl 3-hydroxypropanoate in Step A. MS (apci) m/z = 218.0 (Μ+Η).
Intermediate P128
Figure imgf000141_0003
3-(2-methoxyethyl)-4-methyl- 1 -phenyl- 1 H-pyrazol-5 -amine
[00724] Step A: Preparation of 5-methoxy-2-methyl-3-oxopentanenitrile: To a suspension of NaNH2 (50 wt% suspension in toluene) (330 mg, 4.23 mmol) in THF (25 mL, 4.23 mmol) under N2 at -78 °C was added propiononitrile (0.448 mL, 6.35 mmol), and the reaction mixture was stirred for 30 minutes. Methyl 3-methoxypropanoate (0.495 mL, 4.23 mmol) was added and the reaction mixture was stirred at -78 °C for 1 hour, then at 0 °C for 2.5 hours. The reaction mixture was diluted with H20 (25 mL) and washed with Et20 (25 mL). The basic aqueous phase was neutralized with 2M HC1 (1.6 mL), then extracted with Et20 (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to afford the crude product as a pale greenish oil (171 mg). The crude mixture was taken directly to the next step. [00725] Step B: Preparation of 3-(2-methoxyethyl)-4-methyl-l-phenyl-lH-pyrazol-5- amine: Prepared by the method as described for Intermediate PI, substituting 5-methoxy-2- methyl-3-oxopentanenitrile for 4,4-dimethyl-3-oxopentanenitrile and substituting phenylhydrazine hydrochloride for ethyl 3-hydrazinylbenzoate hydrochloride to yield the product as a yellow solid (56 mg, 20% yield). MS (apci) m/z = 232.0 (M+H).
Intermediate P129
Figure imgf000142_0001
Phenyl (5-oxido-2-phenyl-4,6-dihydro-2H-thieno[3.4-c]pyrazol-3-yncarbamate
[00726] A THF (4 mL) solution of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4- c]pyrazol-3-ylcarbamate (Intermediate PI 30, Step B; 50 mg, 0.15 mmol) was cooled to -50 °C with an external dry-ice/MeCN bath and treated with a THF (2 mL) solution of 3- chlorobenzoperoxoic acid (33 mg, 0.13 mmol). After stirring for 1 hour, the mixture was quenched with Na2S203 and water, extracted with EtOAc, washed with NaHC03 and brine, dried with MgS04, filtered, and concentrated to give the product which was directly used in next step without further purification. MS (apci) m/z = 354.1 (M+H).
Intermediate P130
Figure imgf000142_0002
Phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno 3,4-clpyrazol-3-yl)carbamate
[00727] Step A: Preparation of 2-phenyl-4.6-dihvdro-2H-thienor3.4-c1pyrazol-3- amine: A suspension of 4-oxotetrahydrothiophene-3-carbonitrile (1.00 g, 7.86 mmol) and phenylhydrazine hydrochloride (1.25 g, 8.65 mmol) in absolute EtOH (40 mL) was refluxed for 2 hours. After removal of solvent under reduced pressure, the white solid residue was triturated with 1 N NaOH (40 mL). The solid was collected by filtration, washed with 0.1 N NaOH, water, and hexanes (approx. 10 mL each) then dried on high vacuum to yield the product as white solid (1.6 g, 95% yield). MS (apci pos) m/z = 218.1 (M+H). [00728] Step B: Preparation of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol- 3-ylcarbamate. To a suspension of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine (500 mg, 2.30 mmol) in EtOAc (10 mL) was added NaOH (2M aq, 2.3 mL, 4.60 mmol), followed by dropwise addition of phenyl carbonochloridate (0.400 mL, 3.22 mmol). After stirring at ambient temperature for 2 hours, another portion of phenyl carbonochloridate (0.16 mL, 1.3 mmol) was added dropwise, and the reaction was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with EtOAc (20 mL) and phase-separated. The organic phase was washed with H20, brine (25 mL each), then dried with Na2S04, filtered and concentrated. The crude material was purified by reverse-phase column chromatography, eluting with 5-70% acetonitrile/water to yield the product as white solid (0.5 g, 64% yield). MS (apci pos) m/z = 338.1 (M+H).
[00729] Step C: Preparation of phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H- thieno [3 ,4-c] pyrazol-3 - vDcarbamate. To a turbid solution of phenyl 2-phenyl-4,6-dihydro- 2H-thieno[3,4-c]pyrazol-3-ylcarbamate (50 mg, 0.15 mmol) in DCM (1.5 mL) at 0 °C was added MCPBA (91 mg, 0.37 mmol, 70-75% water complex), and the mixture was stirred at ambient temperature for 10 min. The mixture was then diluted with DCM (3 mL) and washed with saturated aqueous NaHC03 (3 x 2 mL) and saturated aqueous Na2S203 (3 x 2 mL). The organic layer was dried with MgS04, filtered and concentrated under reduced pressure to yield the title product as light yellowish foamy solid (31 mg, 57% yield, 95% pure). MS (apci pos) m/z = 371.0 (M+H).
Intermediate P132
Figure imgf000143_0001
1 -methyl-3-(pyrazin-2-ylV lH-pyrazol-5-amine
[00730] Step A: Preparation of 3-oxo-3-(pyrazin-2-yl propanenitrile: To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.1 14 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with H20 (25 mL) and extracted with Et20 (25 mL). The aqueous phase was neutralized with 2M aqueous HC1 (0.7 mL), then extracted with 10% MeOH/DCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). 1H NMR (CDC13) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 1H), 4.34 (s, 2H).
[00731] Step B: Preparation of l-methyl-3-(pyrazin-2-yl)-lH-pyrazol-5-amine: To a suspension of 3-oxo-3-(pyrazin-2-yl)propanenitrile (67.0 mg, 0.455 mmol) in EtOH (5 mL) was added methylhydrazine (0.024 mL, 0.455 mmol). The reaction mixture was refluxed for 15 hours, then concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a brown residue (33 mg, 41% yield). MS (apci) m/z = 176.2 (M+H).
Intermediate P133
Figure imgf000144_0001
1 -methyl-3-(5-methylpyrazin-2-vD- lH-pyrazol-5-amine
[00732] Prepared by the method as described for Intermediate PI 07, substituting methyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylate and propionitrile with acetonitrile to afford 3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In Step B, phenylhydrazine was replaced by methylhydrazine to afford the title pyrazole. MS (apci) m/z = 190.2 (Μ+Η).
Intermediate P134
Figure imgf000144_0002
l,4-dimethyl-3-(5-methylpyrazin-2-yl)-lH-pyrazol-5-amine
[00733] Prepared by the method as described for Intermediate PI 07, substituting methyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylate to afford 2-methyl- 3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In Step B, phenylhydrazine was replaced by methylhydrazine to afford the title compound. MS (apci) m/z = 204.1 (M+H).
Intermediate P135
Figure imgf000144_0003
3 -ethoxy-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine
[00734] Step A: Preparation of 5 -amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one: A mixture of ethyl 2-cyanopropanoate (5.0 g, 46 mmol) and phenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 1 10 °C for 17 hours. The crude material was cooled to ambient temperature, concentrated, and triturated with cold EtOH and Et20. The resultant solid was filtered, washed with Et20, and dried under vacuum to give the product as a white solid (3.4 g, 39% yield). MS (apci) m/z = 190.0 (M-H).
[00735] Step B: Preparation of 3 -ethoxy-4-methyl-l -phenyl- lH-pyrazol-5 -amine: To a suspension of 5-amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one (10.0 g, 52.9 mmol) in DMF (100 mL) was added K2C03 (14.6 g, 106 mmol) and bromoethane (4.34 mL, 58.1) at ambient temperature. After stirring for 17 hours, the reaction mixture was treated with EtOAc and washed with water (3x, to obtain the N-alkylation product) and brine, dried with MgS04, filtered, and concentrated to give the product (5.35 g, 47% yield). MS (apci) m/z = 218.1 (Μ+Η).
[00736] The compounds in Table 3 were prepared by the method as described for Intermediate PI 35, substituting bromoethane with the appropriate alkyl halide or alkyl methanesulfonate.
Table 3
Figure imgf000145_0001
Figure imgf000146_0001
Intermediate P136
Figure imgf000146_0002
3-(benzyloxyV 1 -methyl- 1 H-pyrazol-5 -amine
[00737] Step A: Preparation of 5-amino-l-methyl-4-phenyl-lH-pyrazol-3(2H)-one: To a suspension of ethyl 2-cyano-2-phenylacetate (2.56 g, 13.3 mmol) in EtOH (10 mL) was added dropwise methylhydrazine (1.09 mL, 19.9 mmol). The reaction was heated at 85 °C for 15 hours. The reaction mixture was cooled to 0 °C and filtered. The resultant solid was washed with cold EtOH (20 mL) and Et20 (20 mL) to give the desired product (2.10 g, 83.7% yield). MS (apci) m/z = 190.2 (M+H)
[00738] Step B: Preparation of 3-(benzyloxy)-l-methyl-lH-pyrazol-5-amine: A suspension of 5-amino-l-methyl-lH-pyrazol-3(2H)-one (0.35 g, 3.1 mmol), Benzyl chloride (0.43 g, 3.4 mmol), and K2C03 (1.3 g, 9.3 mmol) in DMF (4 mL) was heated at 70 °C for 17 hours. After cooling, the reaction mixture was treated with EtOAc, washed with water and brine, dried with MgS04, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with 2-6% MeOH/DCM to afford the title compound (0.16 g, 25% yield). MS (apci) m/z = 204.0 (M+H).
Intermediate P137
Figure imgf000147_0001
3 -methoxy- 1 -methyl-4-phenyl- 1 H-pyrazol-5-amine
[00739] To a suspension of 5-amino-l-methyl-4-phenyl-lH-pyrazol-3(2H)-one (Step A of the preparation of Intermediate P136; 208 mg, 1.10 mmol) and 2C03 (456 mg, 3.30 mmol) in DMF (5 mL) was added dropwise iodomethane (172 mg, 1.21 mmol). The reaction mixture was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography eluting with 33% EtOAc/Hexanes to give the title pyrazole (66.0 mg, 30.4% yield). MS (apci) m/z = 204.1 (M+H).
Intermediate P138
Figure imgf000147_0002
3-ethoxy-l-methyl-4-phenyl-lH-pyrazol-5-amine
[00740] Prepared as described in Intermediate PI 37, replacing iodomethane with iodoethane in Step B to afford the title compound. MS (apci) m/z = 218.2 (M+H).
Intermediate P139
Figure imgf000147_0003
3 -ethoxy- 1 -phenyl- 1 H-pyrazol-5 -amine
[00741] Prepared according to the procedure described for Intermediate 135, substituting ethyl-2-cyanopropanoate with ethyl-2-cyanoacetate in Step A. MS (apci) m z = 204.0 (Μ+Η).
[00742] The compounds in the following Table were prepared by the method as described for Intermediate PI 35, substituting bromoethane with the appropriate alkyl halide, alkyl methanesulfonate or epoxide.
Figure imgf000148_0001
Intermediate 151
Figure imgf000149_0001
1 '-(2-methoxyethyl)-l -phenyl- 1 H, 1 'H-[3,4'-bipyrazol]-5-amine
[00743] Step A: Preparation of methyl l-methyl-lH-l,2,4-triazole-3-carboxylate: To a stirred suspension of NaH (60% oil dispersion, 0.346 g, 8.66 mmol) in DMF (20 mL) was added dropwise a solution of methyl lH-l ,2,4-triazole-3-carboxylate (1.00 g, 7.87 mmol) in DMF (20 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 1 hour. Mel (0.982 mL, 15.7 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature overnight. The reaction was poured into cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (3: 1 hexanes/EtOAc) to give the title compound (0.380 g, 34% yield) as a white solid. MS (apci) m/z = 142.1 (Μ+Η).
[00744] Step B: Preparation of 1 '-(2-methoxyethylV 1 -phenyl- lH.l'H- [3.4'-bipyrazol]- 5 -amine: Prepared according to the method described for Intermediate P I 09, using methyl 1 - methyl-lH-l ,2,4-triazole-3-carboxylate as a replacement for methyl 2-methoxyacetate, and substituting propionitrile for acetonitrile in Step A. MS (apci) m/z = 255.1 (Μ+Η).
Intermediate 152
Figure imgf000149_0002
-(2-methoxyethyl)-4-methyl-l -phenyl-lH, H-[3,4'-bipyrazol]-5-amine
[00745] Prepared according to the method described for Intermediate PI 09, using ethyl l-(2-methoxyethyl)-lH-pyrazole-4-carboxylate as a replacement for methyl 2- methoxyacetate, and substituting propionitrile for acetonitrile in Step A.
Intermediate 153
Figure imgf000149_0003
5-amino-4-methyl-l-phenyl-lH-pyrazole-3-carbonitrile
[00746] To a stirred solution of aniline (2.02 g, 21.7 mmol) in 6 N HC1 (22 mL) was added dropwise a solution of NaN02 (1.50 g, 21.7 mmol) in water (20 mL) at 0-5 °C. The reaction mixture was stirred at 0 °C for 15 minutes. Acetic acid (10 mL) was added. This solution was added dropwise to a stirred solution of ethyl 2,3-dicyanobutanoate (Prepared according to the procedure described in Bioorganic & Medicinal Chemistry, 2004, 12, 3345 - 3356, 3.60 g, 21.7 mmol) in acetic acid (12 mL) and water (18 mL) at 0 °C. After stirring for 1 hour, concentrated ammonium hydroxide (50 mL) was added dropwise followed by THF (50 mL). The reaction was stirred at ambient temperature overnight. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (3:1 hexanes/EtOAc) to give the title compound (2.95 g, 69% yield). MS (apci) m/z = 198.9 (M+H).
Intermediate 155
Figure imgf000150_0001
4-methyl-3-(2-methyl-2H-l,2,3-triazol-4-yl)-l-phenyl-lH-pyrazol-5-amine
[00747] Step A: Preparation of ethyl 2-methyl-2H-1.2,3-triazole-4-carboxylate: A mixture of ethyl 2H-l,2,3-triazole-4-carboxylate (2.00 g, 14.2 mmol), K2C03 (3.53 g, 25.5 mmol) and methyl iodide (3.54 mL, 56.7 mmol) in acetonitrile (40 mL) was stirred at 50 °C under nitrogen overnight. After cooling to ambient temperature, the mixture was filtered through Celite®. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4:1 hexane/EtOAc) to give the title compound (0.780 g, 35% yield). MS (apci) m/z = 156.0 (M+H).
[00748] Step B: Preparation of 4-methyl-3-(2-methyl-2H-L2.3-triazol-4-vn-l-phenyl- lH-pyrazol-5-amine: Prepared according to the method described for Intermediate PI 09 using ethyl 2-methyl-2H-l,2,3-triazole-4-carboxylate as a replacement for methyl 2- methoxyacetate, and substituting propionitrile for acetonitrile in Step A. MS (apci) m/z = 254.9 (M+H).
Intermediate 156
Figure imgf000150_0002
3-bromo-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine :
[00749] To a stirred solution of 5-amino-4-methyl-l-phenyl-lH-pyrazol-3(2H)-one (Intermediate P135, Step A, 1.00 g, 5.29 mmol) in MeCN (20 mL) was added POBr3 (2.27 g, 7.93 mmol). The reaction mixture was heated at reflux for 3 hours. The reaction was concentrate in vacuo. The residue was taken up in DCM. Saturated aqueous NaHC03 solution was carefully added. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (1 :2 hexane/EtOAc to give the title compound (0.23g, 17% yield). MS (apci) m/z = 251.8 (M+H).
Intermediate 157
Figure imgf000151_0001
3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one
[00750] Step A: Preparation of ethyl 5-amino-4-((methylamino)methyl)-l -phenyl- 1H- pyrazole-3-carboxylate: To a stirred solution of ethyl 5-amino-4-formyl-l -phenyl- 1H- pyrazole-3-carboxylate (Prepared according to the procedure described in J. Heterocyclic Chemistry, 2010, 47, p. 287-291, 142 mg, 0.548 mmol) in DCM (3 mL) was added 2.0 M MeNH2 in THF (0.822 mL, 1.64 mmol). Two drops of acetic acid was added. The reaction mixture was stirred at ambient temperature overnight. MeOH (0.4 mL) was added followed by NaBFL; (31 mg, 0.82 mmol) portionwise. The reaction was quenched by the slow addition of water. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The crude was used in the next step without further purification. MS (apci) m/z = 275.0 (M+H).
[00751] Step B: Preparation of 3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4- c]pyrazol-6(2H)-one: To a stirred solution of ethyl 5-amino-4-((methylamino)methyl)-l - phenyl-lH-pyrazole-3-carboxylate (crude, 65 mg, 0.24 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added 2 N NaOH (0.24 mL, 0.47 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. To the residue was added water. The pH was adjusted to 4-5 using 1 N HC1. Water was evaporated under reduced pressure. The crude acid (58 mg) was dissolved in DMF (3 mL). Et3N (66 μί, 0.47 mmol) was added followed by EDCI (90 mg, 0.47 mmol) and HOBt (32 mg, 0.24 mmol). The reaction mixture was stirred at ambient temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH in DCM) to give the title compound (15 mg, 28%) as a white solid. MS (apci) m/z = 228.9 (M+H).
Intermediate 158
Figure imgf000152_0001
3 -methyl-4-(methylthio)- 1 -phenyl- 1 H-pyrazol-5-amine
[00752] Prepared according to the method described for Intermediate PI 09, replacing methyl 2-methoxyacetate with ethyl acetate and replacing acetonitrile with 2- (methylthio)acetonitrile in Step A to afford the product as a brown oil. MS (apci) m/z = 220.1 (M+H).
Intermediate 159
Figure imgf000152_0002
2-(5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)-2,2-difluoroethanol
[00753] Prepared according to the method described for Intermediate Pi l l, replacing acetonitrile with propionitrile and replacing methyl 3-hydroxy-2,2-dimethylpropanoate with ethyl 2,2-difluoro-3-hydroxypropanoate to afford the product as a pale yellow solid. MS (apci) m/z = 254.1 (M+H).
Intermediate 160
Figure imgf000152_0003
2-(5-amino- 1 -phenyl- 1 H-pyrazol-3-yl -2,2-difluoroethanol
[00754] Prepared according to the method described for Intermediate Pi l l, replacing methyl 3-hydroxy-2,2-dimethylpropanoate with ethyl 2,2-difluoro-3-hydroxypropanoate to afford the product as a pale yellow solid. MS (apci) m/z = 240.0 (M+H). Intermediate 161
Figure imgf000153_0001
2-(5-amino- 1 -phenyl- 1 H-pyrazol-3-yl ethanol
[00755] Prepared according to the method described in Intermediate Pi l l, replacing methyl 3-hydroxy-2,2-dimethylpropanoate with methyl 3-hydroxypropanoate in Step A. MS (apci) m/z = 204.1 (M+H).
Intermediate 162
Figure imgf000153_0002
1 -(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)-2-methylpropan-2-ol
[00756] Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HCl (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
[00757] Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile: To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with H20 (100 mL) and extracted with Et20 (50 mL). The phases were separated and the basic aqueous phase was neutralized with HCl (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgS04), filtered, and concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). 1H NMR (CDC13) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
[00758] Step C: Preparation of l-(5-amino-4-methyl-l -phenyl- lH-pyrazol-3-ylV2- methylpropan-2-ol : To a suspension of phenylhydrazine (0.793 mL, 7.99 mmol) and HC1 (5- 6M in iPrOH, 1.60 mL, 7.99 mmol) in EtOH (25 mL) was added a solution of 5-hydroxy-2,5- dimethyl-3-oxohexanenitrile (1.24 g, 7.99 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 17 hours, then cooled to ambient temperature, diluted with saturated aqueous NaHC03 (10 mL), extracted 10:90 MeOH/DCM (3 x 25 mL), and the combined organic phases were dried (MgS04), filtered and concentrated. Purified by silica column chromatography eluting with 0-75% acetone/hexanes to afford the title compound as an orange oil (1.13 g, 58% yield). MS (apci) mix = 246.1 (M+H).
[00759] The following pyrazole intermediates were prepared according to the method used for the preparation of Intermediate 162, Steps B and C, using the appropriate starting material. For the preparation of Intermediates 168 and 169, the starting material (purchased from Oakwood) was a mixture of cis and trans diastereomers.
Figure imgf000155_0001
Intermediate 170
Figure imgf000156_0001
ethyl 5-amino-4-methyl- 1 -phenyl- 1 H-pyrazole-3-carboxylate
[00760] Prepared according to the method described for Intermediate PI 09, replacing methyl 2-methoxyacetate with diethyl oxalate and replacing acetonitrile with propionitrile in Step A to afford the product as a yellow solid. MS (apci) m/z = 246.1 (M+H).
Intermediate 171
Figure imgf000156_0002
5-amino-4-methyl- 1 -phenyl- 1 H-pyrazole-3-carboxylic acid
[00761] To a solution of ethyl 5-amino-4-methyl-l-phenyl-lH-pyrazole-3-carboxylate (Intermediate 170, 1.52 mg, 6.21 mmol) in THF (12 mL) and MeOH (6 mL) was added LiOH (2M aq, 9.31 mL, 18.6 mmol). The reaction mixture was stirred at ambient temperature for 19 hours, then partially concentrated under reduced pressure, then neutralized with 6M HC1 (3.2 mL), extracted with 10:90 MeOH/DCM (3 x 25 mL), and the combined organic extracts were washed with brine (50 mL), dried (MgS04), filtered and concentrated to give the title compound as a yellow solid (1.3 g, 96% yield) MS (apci) m z = 218.1 (M+H).
Intermediate 172
Figure imgf000156_0003
5-amino-N,4-dimethyl- 1 -phenyl- 1 H-pyrazole-3-carboxamide
[00762] To a solution of 5-amino-4-methyl-l-phenyl-lH-pyrazole-3-carboxylic acid (Intermediate 171, 223 mg, 1.02 mmol) in acetonitrile (10 mL) were added DIEA (0.71 mL, 4.10 mmol), methanamine hydrochloride (138 mg, 2.05 mmol), DMF (2 mL), and then HATU (428 mg, 1.13 mmol). The reaction mixture was stirred at ambient temperature for 19 hours and then partially concentrated under reduced pressure. The mixture was purified by reverse-phase column chromatography, eluting with 5-60% acetonitrile/water to afford the title compound as a pale yellow solid (182 mg, 77% yield). MS (apci) m/z = 231.1 (M+H).
Intermediate 173
Figure imgf000157_0001
5-amino-4-methyl- 1 -phenyl- 1 H-pyrazole-3 -carboxamide
[00763] A solution of 5-amino-4-methyl-l -phenyl- lH-pyrazole-3-carbonitrile (150 mg, 0.757 mmol) in concentrated H2S04 (0.5 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was cooled and neutralized by the addition of aqueous NaOH (2M, 11 mL), then extracted 10% MeOH/DCM (5 x 10 mL), and the combined organic extracts were washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to afford the title compound as a white solid (151 mg, 95% yield). MS (apci) m/z = 239.1 (M+Na).
Intermediate 174
Figure imgf000157_0002
ethyl 5 -amino-3 -ethoxy- 1 -phenyl- 1 H-pyrazole-4-carboxylate
[00764] Step A: Preparation of diethyl 2-cyanomalonate: To a suspension of NaH (60 wt% in mineral oil, 499 mg, 12.49 mmol) in THF (100 mL) under N2 at 0 °C was added diethyl malonate (1.90 mL, 12.49 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 30 minutes, then cooled to 0 °C and cyanic bromide (5M in MeCN, 2.5 mL, 12.49 mmol) was added. The reaction mixture was stirred at ambient temperature for 19 hours, then diluted with H20 (50 mL), extracted with Et20 (50 mL). The aqueous phase was neutralized with HC1 (2M aq, 3 mL) then extracted with DCM (2 x 50 mL). The combined DCM extracts were dried (MgS04), filtered, and concentrated to afford the product as a yellow oil (837 mg, 36% yield). 1H NMR (CDC13) δ 4.46 (s, 1H), 4.35 (q, 4H), 1.35 (t, 6H).
[00765] Step B: Preparation of ethyl 5 -amino-3 -ethoxy- 1 -phenyl- lH-pyrazole-4- carboxylate: Prepared according to the method described for Intermediate PI 35, replacing ethyl 2-cyanopropanoate with diethyl 2-cyanomalonate in Step A to afford the product as a brown syrup (400 mg, 32% yield). MS (apci) m/z = 276.1 (M+H). Intermediate 175
Figure imgf000158_0001
4-methyl-3-(5-methyl-l ,3,4-oxadiazol-2-yl)-l -phenyl-1 H-pyrazol-5-amine
[00766] Step A: Preparation of N'-acetyl-5-amino-4-methyl- 1 -phenyl- 1 H-pyrazole-3- carbohydrazide: To a solution of 5-amino-4-methyl-l -phenyl- lH-pyrazole-3-carboxylic acid (Intermediate 171, 93 mg, 0.428 mmol) in DCM (5 mL) and DIEA (0.149 mL, 0.856 mmol) was added isobutyl carbonochloridate (0.061 mL, 0.471 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then acetohydrazide (48 mg, 0.642 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours, then diluted with H20 (10 mL), extracted DCM (2 x 10 mL), dried (MgS04), filtered and concentrated under reduced pressure to afford the product as a pale yellow solid (1 19 mg, 101% yield). MS (apci) m/z = 274.1 (M+H).
[00767] Step B: Preparation of 4-methyl-3 -( 5-methyl- 1.3.4-oxadiazol-2-vn- 1 -phenyl- 1 H-pyrazol-5 -amine: A mixture of N'-acetyl-5-amino-4-methyl-l-phenyl-lH-pyrazole-3- carbohydrazide (1 17 mg, 0.428 mmol) and POCl3 (0.5 mL) was heated in a pressure tube to 90 °C for 1 hour. The reaction mixture was transferred to a separatory funnel with EtOAc (5 mL), then diluted with saturated aqueous NaHC03 (20 mL), extracted with EtOAc (2 15 mL), dried (MgS04), filtered and concentrated. The residue was purified by silica column chromatography eluting with 0-75% acetone/hexanes to afford the title compound as a yellow solid (19.6 mg, 18% yield). MS (apci) m/z = 256.1 (M+H).
Intermediate 176
Figure imgf000158_0002
4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-viyi -phenyl- lH-pyrazol-5-amine
[00768] To a suspension of NaH (60% in mineral oil, 36 mg, 0.897 mmol) in THF (5 mL) under N2 was added N-hydroxyacetimidamide (66 mg, 0.897 mmol). The reaction mixture was heated to reflux for 1 hour, then cooled to ambient temperature and ethyl 5- amino-4-methyl-l -phenyl- lH-pyrazole-3-carboxylate (Intermediate 170, 200 mg, 0.815 mmol) was added. The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and additional NaH (60% in mineral oil, 18 mg, 0.449 mmol) was added. The reaction mixture was heated to reflux for 4 hours, then diluted with H20 (10 mL), extracted DCM (2 x 15 mL), and the combined organic extracts were dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0-50% acetone/hexanes to afford the title compound as an orange solid (84 mg, 40% yield). MS (apci) m/z = 256.1 (M+H).
Intermediate 177
Figure imgf000159_0001
3-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-l -phenyl- 1 H-pyrazol-5-amine
[00769] Prepared according to the method described in Intermediate 176, replacing ethyl 5-amino-4-methyl-l -phenyl- lH-pyrazole-3-carboxylate with ethyl 5-amino-l-phenyl- lH-pyrazole-3-carboxylate (Nanjing Chemlin Chemical Co.) to afford the product as a tan solid (83 mg, 53% yield). MS (apci) m/z = 242.1 (M+H).
Intermediate 178
Figure imgf000159_0002
4-methyl- 1 -phenyl-3-(3-(trifluoromethyl)- 1 ,2,4-oxadiazol-5-vD- 1 H-pyrazol-5 -amine
[00770] Step A: Preparation of 2,2,2-trifluoro-N'-hydroxyacetimidamide: To a suspension of hydroxylamine hydrochloride (5.45 g, 78.4 mmol) in MeOH (100 mL) was added NaOMe (25 wt % solution in MeOH, 17.9 mL, 78.4 mmol) and the mixture stirred at ambient temperature for 10 minutes, then filtered and the solid was washed with MeOH. The filtrate was cooled to 0 °C and then 2,2,2-trifluoroacetonitrile (7.45 g, 78.4 mmol) gas was bubbled into the solution over 30 minutes. The reaction mixture was then allowed to warm to ambient temperature for 19 hours. The solution was concentrated under reduced pressure to 50 mL and the solids were filtered. The filtrate was concentrated, re-suspended in cold MeOH, and filtered. The filtrate was concentrated, again re-suspended in cold MeOH, and filtered. The filtrate was concentrated to give the product as a waxy white solid (6.7 g, 67% yield). 1H NMR (CD3CN) δ 8.32 (s, 1H), 5.25 (br s, 2H). 19F NMR (CD3CN) δ -71.8 (s). [00771] Step B: Preparation of 4-methyl-l-phenyl-3-(3-(trifluoromethylV1.2.4- oxadiazol-5-νΠ- 1 H-pyrazol-5-amine: To a suspension of NaH (60% in mineral oil, 356 mg, 0.897 mmol) in THF (5 mL, 0.815 mmol) under N2 was added 2,2,2-trifluoro-N'- hydroxyacetimidamide (1 15 mg, 0.897 mmol). The reaction mixture was heated to reflux for 1 hour, then cooled to ambient temperature and powdered 4A molecular sieves (200 mg) and ethyl 5 -amino-4-methyl-l -phenyl- lH-pyrazole-3-carboxy late (Intermediate 170; 200 mg, 0.815 mmol) were added and heated to reflux. The reaction mixture was heated to reflux for 18 hours, then filtered, diluted with H20 (15 mL), extracted DCM (2 x 25 mL), and the combined organic extracts were washed with brine (25 mL), dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0-50% acetone/hexanes to afford the title compound as a white solid (44 mg, 17% yield). MS (apci) m/z = 310.1 (M+H).
Intermediate 179
Figure imgf000160_0001
2-phenyl-2H-indazol-3 -amine
[00772] Step A: Preparation of l-(2-iodophenyl)-2-phenyldiazene: To a solution of 2- iodoaniline (1.00 g, 4.57 mmol) in acetic acid (46 mL) was added nitrosobenzene (0.880 g, 8.22 mmol) and the mixture was heated at 85 °C for 16 hours. The mixture was cooled to ambient temperature, poured into water and slowly treated with saturated NaHC03 until basic. The mixture was extracted with EtOAc (3X) and the combined extracts were washed with water, saturated NaCl and dried over MgS04. The solution was filtered, concentrated and the residue purified by reverse phase chromatography to provide the title compound as a red solid (0.880 g, 63% yield). 1H NMR (CDC13) δ 7.23-7.39 (m, 3H), 7.64 (d, 1H), 7.56-7.51 (m, 3H), 7.45 (t, 1H), 7.1 (t, 1H).
[00773] Step B: 2-(phenyldiazenyl)benzonitrile: To a solution of l-(2-iodophenyl)-2- phenyldiazene (0.44 g, 1.4 mmol) in 1-propanol (14 mL) was added CuCN (0.900 g, 10.0 mmol) and the reaction was heated at reflux for 16 hours. The mixture was cooled to ambient temperature, filtered and the collected solid washed with CH2C12. The combined filtrate and washes were concentrated to provide the title compound as red-orange solid that was dried in vacuum (0.280 g, 95% yield). 1H NMR (CDC13) δ 8.03-8.06 (m, 2H), 7.88 (dd, 2H), 7.71 (t, 1H), 7.54-7.58 (m, 4H). [00774] Step C: 2-phenyl-2H-indazol-3-amine: A mixture of 2- (phenyldiazenyl)benzonitrile (0.28 g, 1.35 mmol) and SnCl2 dihydrate (0.562 mL, 6.76 mmol) in EtOH (14 mL) was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and concentrated. The residue was diluted with EtOAc and water and filtered. The aqueous layer was removed and the EtOAc layer was washed with water. The combined aqueous fractions were basified with saturated NaHC03 and extracted with CH2C12 (2X). The combined organic layers were dried over MgS04, filtered and concentrated to provide the title compound as a light purple solid that was dried in vacuum (0.241 g, 85% yield). 1H NMR (CDC13) δ 7.69 (d, 2H), 7.52-7.58 (m, 3H), 7.47 (d, 2H), 7.26 (t, 1H), 6.90 (t, 1H), 4.28 (br s, 2H).
Intermediate 180
Figure imgf000161_0001
3 -ethoxy-4-methyl- 1 -(pyrazin-2-yl)- 1 H-pyrazol-5-amine
[00775] Step A: 5-amino-4-methyl-l-(pyrazin-2-ylVlH-pyrazol-3(2H)-one: To a mixture of 2-hydrazinylpyrazine (0.551 g, 5.00 mmol) and ethyl 2-cyanopropanoate (0.669 g, 5.00 mmol) in abs. EtOH (10 mL) was added 3M NaOEt in EtOH (0.167 mL, 0.501 mmol) and the mixture was heated at reflux for 64 hours. The mixture was concentrated and the residual yellow-brown solid was treated with EtOAc (30 mL) and sonicated. The resulting tan suspension was stirred vigorously for 8 hours. The solid was collected via vacuum filtration, washed with EtOAc and dried in vacuum to afford the title compound as a light tan powder (682 mg, 71%). 1H NMR (DMSO d6) δ 10.3 (br s, 1H), 8.82 (s, 1H), 8.30 (d, 2H), 6.55 (s, 2H), 1.71 (s, 3H).
[00776] Step B: 3-ethoxy-4-methyl- 1 -(pyrazin-2-yl)- 1 H-pyrazol-5-amine: A mixture of 5-amino-4-methyl-l-(pyrazin-2-yl)-lH-pyrazol-3(2H)-one (382 mg, 2.00 mmol) and powdered 2C03 (552 mg, 4.00 mmol) in dry DMF (3.0 mL) was stirred at ambient temperature for 10 minutes. The mixture was cooled to 0 °C and bromoethane (229 mg, 2.10 mmol) was added. The mixture was allowed to reach ambient temperature and was stirred 24 hours. The reaction mixture poured into cold H20 (12 mL), allowed to reach ambient temperature and was extracted with EtOAc (3X). The combined extracts were washed with saturated NaCl (2X), dried over MgS04 and activated carbon. The dried solution was diluted with and equal volume of hexanes and filtered through a Si02 plug capped with a MgS04 layer eluting with 50% EtOAc-hexanes. The filtrate was concentrated and the residual yellow solid was washed with hexanes (3X) and dried in vacuum to afford the title compound as a light yellow crystalline solid (195 mg, 45%). 1H NMR (CDC13) δ 9.10 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 5.50 (br s, 2H), 4.33 (q, 2H), 1.80 (s, 3H), 1.42 (t, 3H).
Intermediate 181
Figure imgf000162_0001
2-(pyridazin-4-yl -2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
[00777] A suspension of 4-hydrazinylpyridazine hydrobromide (0.368 g, 1.93 mmol) in absolute EtOH (5 mL) was treated with 2-oxocyclopentanecarbonitrile (0.191 g, 1.75 mmol) and the mixture was heated at reflux for 22 hours. The mixture was cooled to ambient temperature and was concentrated to an orange solid. The solid was suspended in 1M NaOH and stirred for 10 minutes. The solid was collected, washed thoroughly with H20 and Et20 and dried in vacuum to furnish title compound as a tan powder (.323 g, 92%). MS (apci) m/z = 202.1 (M+H).
Intermediat 182
Figure imgf000162_0002
(5-amino- 1 -phenyl- 1 H-pyrazol-3 - vDmethanol
[00778] Step A: Ethyl 2-(tert-butyldimethylsilyloxy)acetate: A mixture of ethyl 2- hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-C1 (5.21 g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes to provide the title compound as a colorless oil (4.12 g, 65%). 1H NMR (CDC13) δ 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
[00779] Step B: (5 -amino- 1 -phenyl- 1 H-pyrazol-3 - vDmethanol : A solution of acetonitrile (0.526 mL, 10.1 mmol) in dry THF (20.4 mL, 9.16 mmol) was cooled to -78 °C and 2.5M nBuLi in hexanes (4.21 mL, 10.5 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes and ethyl 2-(tert-butyldimethylsilyloxy)acetate (2.00 g, 9.16 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with ice water and was concentrated. The residual aqueous mixture was acidified to pH=5 and extracted with EtOAc (3X). The combined organics were washed with brine, dried over MgS04, filtered and concentrated. The residual brown oil was dissolved in MeOH (23 mL) and phenyl hydrazine (0.907 mL, 9.14 mmol) was added. The mixture was treated with concentrated HC1 (3.81 mL, 45.7 mmol) and heated at reflux for 18 hours. Upon cooling, the mixture was concentrated and the residue was partitioned into in H20 and CH2C12. The mixture was filtered and the organic layer was removed from the filtrate. The aqueous portion was washed with CH2C12 and was treated with saturated NaHC03 until basic. The aqueous mixture was extracted with CH2C12 (3X) and the combined organic fractions were dried over MgS04, filtered and concentrated. The residue was purified by silica column chromatography using 70-100% EtOAc/hexanes gradient elution followed by 0-5% MeOH/EtOAc. The product pools were combined and concentrated to give the title compound as a yellow foam (0.760 g, 44% yield). MS (apci) m/z = 190.1 (M+H).
Intermediate 183
Figure imgf000163_0001
4-methyl-3 -(( 1 -methyl- 1 H- 1.2.4-triazol-3-yl)methoxy)- 1 -phenyl- 1 H-pyrazol-5-amine
[00780] The title compound was prepared by the method as described for Intermediate PI 35, substituting bromoethane with 3-(chloromethyl)-l -methyl- lH-l,2,4-triazole hydrochloride. The product was isolated as a gold syrup (1 10 mg, 27%). MS (apci) m/z = 285.1 (M+H).
Intermediate 184
Figure imgf000163_0002
5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl dimethylcarbamate
[00781 ] A mixture of 5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3(2H)-one (Intermediate
PI 35 Step A, 0.378 g, 2.00 mmol) and powdered K2C03 (0.553 g, 4.00 mmol) in dry DMF (4 mL) was stirred at ambient temperature for 5 minutes. Dimethylcarbamoyl chloride (0.206 mL, 2.20 mmol) was added and the mixture was stirred for 6 hours. The mixture was poured into chilled H20 (40 mL) and was extracted with EtOAc (3X). The combined extracts were washed with saturated NaCl (2X), dried over MgS04 and filtered through a Si02 plug capped with a MgS04 layer (EtOAc elution). The filtrate was concentrated and the residue dried in vacuum to give the title compound as a light gold syrup (.507 g, 97%). MS (apci) m/z = 261.1 (M+H).
Intermediate 185
Figure imgf000164_0001
5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl morpholine-4-carboxylate
[00782] The title compound was prepared using morpholine-4-carbonyl chloride in the procedure outlined for 5-amino-4-methyl-l -phenyl- lH-pyrazol-3-yl dimethylcarbamate (Intermediate 184). The compound was isolated as a light yellow wax (0.285 g, 47%). 1H NMR (CDC13) δ 7.54 (d, 2H), 7.43 (t, 2H), 7.31 (t, 1H), 3.66-3.78 (m, 8H), 3.57 (br s, 2H), 1.85 (s, 3H).
Intermediate 186
Figure imgf000164_0002
(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-l- phenyl- 1 H-pyrazol-5-amine
[00783] Step A: (SV 1 -(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yloxy)-3- methoxypropan-2-ol : A mixture of 5-amino-4-methyl-l-phenyl-lH-pyrazol-3(2H)-one (P135 Step A, 1.21 g, 6.40 mmol) and powdered K2C03 (1.77 g, 12.8 mmol) in dry DMF (12 mL) was stirred at ambient temperature for 10 minutes. (S)-2-(methoxymethyl)oxirane (0.622 mL, 6.72 mmol) was added and the mixture was stirred at 80 °C for 6 hours. The mixture was cooled to ambient temperature, poured into chilled H20 (25 mL) and extracted with EtOAc (3X). The combined extracts were washed with saturated NaCl (2X), dried over MgS04 and filtered through a Si02 plug capped with a layer of MgS04 eluting with EtOAc. The filtrate was concentrated to give the title compound as a colorless, viscous oil (701 mg, 40%). MS (apci) m/z = 278.1 (M+H).
[00784] Step B: (S)-3-(2-((tert-butyldimethylsilvnoxyV3-methoxypropoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine: To a solution of TBDMS-C1 (725 mg, 4.81 mmol) and imidazole (390 mg, 5.72 mmol) in dry DMF (7.0 mL) was added (S)-l-(5-amino-4-methyl-l- phenyl-lH-pyrazol-3-yloxy)-3-methoxypropan-2-ol (635 mg, 2.29 mmol) in dry DMF (2 mL). The mixture stirred at ambient temperature for 2.5 hours. The mixture added to H20 (70 mL), mixed for 5 minutes and extracted with Et20 (3X). The combined extracts were washed with saturated NaCl (2X) and dried over MgS04. The dried solution was filtered through a Si02 plug capped with a layer of MgS04 (Et20 elution). The filtrate was concentrated to give the title compound as a colorless oil that was dried in vacuum (940 mg, 105%). MS (apci) m/z = 392.2 (M+H). 1H NMR (CDC13) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t, 1H), 4.09-4.30 (m, 3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s, 3H), 1.83 (s, 3H), 0.88 (s, 9H), 0.11 (s, 6H).
Intermediate 187
Figure imgf000165_0001
(R)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-l-phenyl-lH-pyrazol-
5 -amine
[00785] The title compound was prepared using the procedure described for (S)-3-(2- ((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-l-phenyl-lH-pyrazol-5-amine (Intermediate 186) substituting (S)-2-(methoxymethyl)oxirane with (R)-2- (methoxymethyl)oxirane in Step A. The product was obtained as a colorless syrup (921 mg, 38% over 2 steps). MS (apci) m/z = 392.2 (M+H). 1H NMR (CDCI3) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t, 1H), 4.09-4.30 (m, 3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s, 3H), 1.83 (s, 3H), 0.88 (s, 9H), 0.11 (s, 6H).
Intermediate 188
Figure imgf000165_0002
tert-butyl 4-((5-amino- 1 -phenyl- 1 H-pyrazol-3-v0methoxy)piperidine- 1 -carboxylate
[00786] Step A: tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine- 1 -carboxylate: A solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (2.00 g, 9.94 mmol) in dry THF (25 mL) was cooled to 0 °C and KOtBu (1.12 g, 9.94 mmol) was added. The mixture was allowed to reach ambient temperature and was stirred for 10 minutes. The mixture was cooled to 0 °C and ethyl 2-bromoacetate (1.65 mL, 14.9 mmol) was added dropwise. The reaction was allowed to reach ambient temperature and was stirred for 17 hours. The mixture was partitioned into in H20 and EtOAc, mixed and the organic layer was removed. The organic layer was dried over MgS04, filtered and concentrated. The residual thick yellow oil was purified by silica chromatography using a 10-25% EtOAc/hexanes gradient elution to afford the title compound as a colorless oil (0.967 g, 34% yield). 1H NMR (CDC13) δ 4.22 (q, 2H), 4.12 (s, 2H), 3.67-3.84 (m, 2H), 3.52-3.63 (m, 1H), 3.05-3.11 (m, 2H), 1.81-1.90 (m, 2H), 1.53-1.62 (m, 2H), 1.45 (s, 9H), 1.29 (t, 3H).
[00787] Step B: tert-butyl 4-((5-amino- 1 -phenyl- 1 H-pyrazol-3-yl)methoxy)piperidine- 1-carboxylate: A solution of diisopropylamine (1.08 mL, 7.74 mmol) in dry THF (5 mL) was cooled to 0 °C and 2.5M nBuLi in hexanes (2.96 mL, 7.41 mmol) was slowly added. The mixture was stirred at 0 °C for 10 minutes and was cooled to -78 °C. Acetonitrile (0.404 mL, 7.74 mmol) was added and the mixture was stirred for 15 minutes. A solution of tert-butyl 4- (2-ethoxy-2-oxoethoxy)piperidine-l-carboxylate (0.967 g, 3.37 mmol) in THF (2.5 mL) was added and the mixture was stirred at -78 °C for 1 hour. The mixture was allowed to reach ambient temperature, was quenched with ice water and concentrated. The residual aqueous mixture was neutralized with 2M HC1 and was extracted with CH2C12 (3X). The combined organic fractions were dried over MgS04, filtered and concentrated to provide the crude cyano-ketone as a yellow oil that was used immediately in the next step.
[00788] Step C: tert-butyl 4-((5 -amino- 1 -phenyl- 1 H-pyrazol-3-yl)methoxy)piperidine- 1-carboxylate: The crude oil obtained in Step B was dissolved in EtOH (17 mL) and phenylhydrazine (0.396 mL, 3.99 mmol) was added. The mixture was heated at 60°C for 60 hours, was cooled to ambient temperature and was concentrated. The residue was partitioned into EtOAc and water, mixed and the organic layer removed. The aqueous layer was extracted with EtOAc (2X) and the combined EtOAc portions were dried over MgS04, filtered and concentrated. The residual orange oil was purified by silica chromatography using a 10-100% EtOAc/hexanes gradient elution. The pooled product fractions were concentrated and the residual yellow-orange oil was re-purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient to provide the title compound as an orange foam (0.264 g, 21% yield). MS (apci) m/z = 373.2 (M+H). Intermediate 189
Figure imgf000167_0001
1 -phenyl-3-(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazol-5-amine
[00789] Step A: 3-oxo-3-(tetrahvdro-2H-pyran-4-yl)propanenitrile: A 1M solution of
LHMDS in dry THF (26.3 niL, 26.3 mmol) was cooled to -78 °C and acetonitrile (1.43 mL, 27.5 mmol) was added dropwise over 2 minutes. The mixture was stirred at -78 °C for 1 hour and a solution of methyl tetrahydro-2H-pyran-4-carboxylate (3.41 mL, 25.0 mmol) in dry THF (12 mL) was added. The mixture was stirred for 1 hour, the dry ice bath was removed and the mixture allowed to reach ambient temperature. The mixture was poured into chilled H20 (250 mL) and was extracted with Et20 (3X). The aqueous portion was cooled to 0 °C and 6M HCl was added dropwise to pH=3 (starting pH=12). The mixture was extracted with EtOAc (3X) and the combined extracts were dried over MgSC«4. The solution eluted through a Si02 plug eluting with EtOAc. The filtrate was concentrated to give the title compound as a colorless oil (2.52 g, 66%). 1H NMR (CDC13) δ 3.99-4.06 (m, 2H), 3.54 (s, 2H), 3.46 (t, 2H), 2.76-2.86 (m, 1H), 1.70-1.86 (m, 4H).
[00790] Step B: 1 -phenyl-3-(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazol-5 -amine: To a solution of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (2.30 g, 12.8 mmol) in absolute EtOH (35 mL) was added phenylhydrazine hydrochloride (2.21 g, 15.3 mmol) and the mixture was heated at reflux until complete by TLC (5 hours). The mixture was cooled to ambient temperature and was concentrated. The residue was partitioned in H20 (75 mL) and EtOAc (40 mL). 2M NaOH was added to pH=5 with vigorous mixing, the organic layer was removed and the aqueous was extracted with EtOAc (2X). The combined EtOAc fractions were washed with H20 and saturated NaCl. The solution was diluted with an equal volume of hexanes, dried over MgS04/activated carbon and eluted through a Si02 plug eluting with 50% EtOAc-hexanes. The filtrate was concentrated to give a gold syrup. The syrup was treated with Et20 and stirred until a fine, granular suspension formed. The solid was collected, washed with Et20 and dried in vacuum to furnish the title compound as a white solid (2.01 g, 65%). 1H NMR (CDC13) δ 7.55 (d, 2H), 7.46 (t, 2H), 7.32 (t, 1H), 5.49 (s, 1H), 4.00-4.08 (m, 2H), 3.97 (br s, 2H), 3.52 (dt, 2H), 2.86 (m, 1H) 1.73-1.93 (m, 4H).
[00791] The following compounds were prepared according to the method used for the preparation of l-phenyl-3-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-amine (Intermediate 189) using either acetonitrile or propiononitrile in Step A in conjunction with the appropriate ester.
Figure imgf000168_0001
Intermediate 199
Figure imgf000169_0001
Phenyl 1 '.4-dimethyl- 1 -phenyl- 1 H, 1 'H-3,4'-bipyrazol-5-ylcarbamate
[00792] Step A: ethyl 1 -methyl- 1 H-pyrazole-4-carboxylate: To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) to obtain a clear yellowish solution. The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature overnight. The reaction was concentrated on a rotary evaporator to a crude orange oil. The crude was taken up in DCM and re-concentrated, then on high vacuum for 2 days to yield tan orange oil. LC/MS and 1H NMR showed essentially pure ethyl 1-methyl- lH-pyrazole-4-carboxylate (106 g, 99.1%).
[00793] Step B: 2-methyl-3-(l -methyl- lH-pyrazol-4-yl)-3-oxopropanenitrile: To a four-necked 5 -liter round bottomed flask fitted with an overhead stirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.0M in THF). The solution was cooled in an acetone/dry ice bath first (internal temperature of -79 °C) under nitrogen, followed by slow addition of propiononitrile (103 mL, 1444 mmol) via dropping funnel. The mixture was stirred at -80 °C for 90 minutes. A solution of ethyl 1 -methyl- lH-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF (500 mL) was then introduced dropwise via an addition funnel (addition time: about 45 minutes; internal temperature during addition remained below -76 °C) . After the addition was complete, the reaction was allowed to slowly warm to ambient temperature and stirred overnight. An orange glass deposited on the bottom of the flask. The organics were decanted and the glass was dissolved in warm water. The mixture was washed with with ether (3 x 1000 mL). The aqueous phase was then pH-adjusted to 5 (pH paper) using concentrated HC1 and saturated bicarbarbonate solution The aqueous layer was extracted with DCM (3 x 1000 mL). The combined organic extracts were dried over MgS04 filtered and concentrated to yield the 2-methyl-3-(l -methyl- lH-pyrazol-4-yl)-3- oxopropanenitrile as an amber oil (92 g, 82%). MS (apci) m/z = 162.1 (M-H).
[00794] Step C: 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-3.4'-bipyrazol-5 -amine: A 3L, 3 necked round bottomed flask was charged with 2-methyl-3-(l -methyl- lH-pyrazol-4-yl)-3- oxopropanenitrile (60 g, 368 mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazine hydrochloride (58 g, 404 mmol) at ambient temperature to form a yellowish suspension. The reaction vessel was equipped with a water condenser and refluxed (using a heating mantle) overnight.The reaction was concentrated and 1M NaOH (1L) was added and the solid was broken up and collected. The solid was washed with water and hexanes. A second crop crashed out in the filtrate and was collected. The combined solids were crushed and triturated with ether (500 mL). The solid was collected filtration, washed with hexanes and air dried under vacuum to provide l',4-dimethyl-l -phenyl- lH, H-3,4'-bipyrazol-5-amine
(93 g, 100%).
[00795] Step D: phenyl 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-3 ,4'-bipyrazol-5 -ylcarbamate:
In a 3 L, round bottomed flask was charged with l',4-dimethyl- 1 -phenyl- 1Η,1Ή-3, 4'- bipyrazol-5-amine (50 g, 197.4 mmol) and EtOAc (1000 mL) to obtain a clear brownish solution. To this was added NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture (both the aqueous and organic layers were clear but a precipitate was observed in between the two layers). After 3 minutes, phenyl carbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambient temperature exotherm to 33 °C. The reaction stirred at ambient temperature for 2 hours. Additional phenyl carbonochloridate (10 mL) was added. After 30 minutes the organics were separated, washed with brine and concentrated in vacuo. The product was purified by silica gel chromatography (eluting with 75% ethyl acetate in hexanes) to provide phenyl ,4-dimethyl-l-phenyl-lH,rH-3,4'-bipyrazol-5-ylcarbamate (60 g, 81.4%).
Intermediate 200
Figure imgf000170_0001
phenyl 1 *,4- ■<dimethyl- 1 -phenyl- 1 H, 1 Ή-3.4'-bipyrazol-5-ylcarbamate [00796] A 3 L, round bottomed flask was charged with l ',4-dimethyl-l-phenyl- lH,l'H-3,4'-bipyrazol-5-amine (50 g, 197.4 mmol) and EtOAc (1000 mL) to obtain a clear brownish solution. To this was added NaOH (2M aq) (500mL) in one portion to obtain a turbid mixture (the aqueous and organic layers were clear, but a precipitate was observed in between the two layers). After 3 minutes, phenyl carbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambient temperature (the temperature of the reaction mixture increased to 33 °C during the addition). The reaction stirred at ambient temperature for 2 hours. Additional phenyl carbonochloridate (10 mL) was added. After 30 minutes the organics layers were separated, washed with brine and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 75% ethyl acetate in hexanes) to provide phenyl l',4-dimethyl-l -phenyl- lH,l'H-3,4'-bipyrazol-5-ylcarbamate (60 g, 81.4%).
Intermediate 201
Figure imgf000171_0001
phenyl (4-chloro-3-ethoxy-l -phenyl-lH-pyrazol-5-yl)carbamate
[00797] Step A: Preparation of phenyl (3 -ethoxy-1 -phenyl- lH-pyrazol-5-yl)carbamate: To a suspension of 3 -ethoxy-1 -phenyl- lH-pyrazol-5 -amine (Intermediate PI 39, 169 mg, 0.832 mmol) in EtOAc (5 mL) at 0 °C was added 2.0 M aqueous NaOH solution (1.25 mL, 2.50 mmol), followed by dropwise addition of phenyl carbonochloridate (0.178 mL, 1.41 mmol). The reaction was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with EtOAc and phase-separated. The organic layer was washed with water and brine, dried over MgS04, and concentrated. The residue was purified by flash chromatography on silica gel (6:1 hexanes:EtOAc) to give the title compound (219 mg, 81% yield). MS (apci) m/z = 324.1 (M+H).
[00798] Step B: Preparation of phenyl (4-chloro-3-ethoxy-l -phenyl- lH-pyrazol-5- vDcarbamate: To a solution of phenyl 3-ethoxy-l-phenyl-lH-pyrazol-5-ylcarbamate (92 mg, 0.28 mmol) and pyridinium 4-methylbenzenesulfonate (7.2 mg, 0.028 mmol) in DCM (2 mL) was added N-chlorosuccinimide (42 mg, 0.31 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 days and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (9:l,hexanes/EtOAc) to give the title compound (76 mg, 75% yield). MS (apci) m/z = 358.1 (M+H).
Intermediate 203
Figure imgf000172_0001
Phenyl (4-bromo-3-(2-hydroxy-2-methylpropoxy)-l-phenyl-lH-pyrazol-5-yl)carbamate
[00799] Step A: Preparation of 5-amino-l-phenyl-lH-pyrazol-3(2HVone: Prepared according to the method described for Intermediate PI, replacing 4,4-dimethyl-3- oxopentanenitrile with ethyl 2-cyanoacetate, and substituting phenylhydrazine for ethyl 3- hydrazinylbenzoate hydrochloride. MS (apci) m/z = 176.0 (M+H).
[00800] Step B: Preparation of l-((5-amino-l-phenyl-lH-pyrazol-3-yl)oxy)-2- methylpropan-2-ol: A mixture of 5 -amino- 1 -phenyl- lH-pyrazol-3(2H)-one (0.330 g, 1.88 mmol), 2,2-dimethyloxirane (0.143 g, 1.98 mmol) and K2C03 (0.521 g, 3.77 mmol) in DMA (5 mL) was heated at 80 °C for 3 days. After cooling, the reaction mixture was diluted with EtOAc, washed with water and brine and dried over MgS04. The mixture was filtered through a pad of Si02 eluting with EtOAc to yield the title compound. MS (apci) m/z = 248.1 (M+H).
[00801] Step C: Preparation of phenyl (3 -(2-hvdroxy-2-methylpropoxy)-l -phenyl- \H- pyrazol-5-yl carbamate: Prepared according to the method described for Intermediate 201. Step A using l-((5-amino-l -phenyl- lH-pyrazol-3-yl)oxy)-2-methylpropan-2-ol as a replacement for 3-ethoxy-l -phenyl- lH-pyrazol-5-amine. MS (apci) m/z = 368.1 (M+H).
[00802] Step D: Preparation of phenyl (4-bromo-3-(2-hvdroxy-2-methylpropoxy')-l- phenyl- 1 H-pyrazol-5-yl)carbamate: Prepared according to the method described for Intermediate 201, Step B using N-bromosuccinimide as a replacement for N- chlorosuccinimide, and substituting phenyl (3-(2-hydroxy-2-methylpropoxy)-l-phenyl-lH- pyrazol-5-yl)carbamate for phenyl 3-ethoxy-l-phenyl-lH-pyrazol-5-ylcarbamate. MS (apci) m/z = 446.1 (Μ+Η).
[00803] The following compounds prepared according to the method describe for the preparation of Intermediate 200, using the appropriate amino pyrazole intermediate:
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Intermediate 228
Figure imgf000176_0002
tert-butyl 4-((4-chloro-5-((phenoxycarbonyl amino)- 1 -phenyl- 1 H-pyrazol-3- yl)methoxy)piperidine- 1 -carboxylate [00804] To a suspension of tert-butyl 4-((5-(phenoxycarbonylamino)-l -phenyl- 1 H- pyrazol-3-yl)methoxy)piperidine-l-carboxylate (Intermediate 226), 98.5 mg, 0.200 mmol) in DCM (2.0 mL) was added pyridinium 4-methylbenzenesulfonate (PPTS) (5.03 mg, 0.020 mmol) and N-chlorosuccinimide (40.1 mg, 0.300 mmol). The resulting solution was stirred at ambient temperature for 8 days. The mixture was diluted with water and CH2C12, the organic layer was separated and the aqueous was extracted with CH2C12 (2X). The combined organic fractions were dried over MgS04, filtered and concentrated. The residue was purified by silica chromatography using 30-40% EtOAc/hexanes gradient elution to afford the title compound as an orange oil (73.5 mg, 70% yield). MS (apci) m/z = 527.2 (M+H).
Intermediate 229
Figure imgf000177_0001
Phenyl (4-chloro-3 -(hydroxymethyl)- 1 -phenyl- 1 H-pyrazol-5-yl)carbamate
[00805] Prepared from phenyl 3 -(hydroxymethyl)- 1 -phenyl- lH-pyrazol-5-ylcarbamate (Intermediate 227) using the procedure outlined for the preparation of tert-butyl 4-((4-chloro- 5-((phenoxycarbonyl)amino)- 1 -phenyl- 1 H-pyrazol-3 -yl)methoxy)piperidine- 1 -carboxylate (Intermediate 228). In this instance, the compound was isolated a white solid (108 mg, 28%). MS (apci) m/z = 344.0 (M+H).
Intermediate 230
Figure imgf000177_0002
Phenyl (4-bromo-3 -(hydroxymethyl)- 1 -phenyl- 1 H-pyrazol-5-yl carbamate
[00806] To a suspension of phenyl 3-(hydroxymethyl)-l-phenyl-lH-pyrazol-5- ylcarbamate (Intermediate 227, 100 mg, 0.323 mmol) in CH2C12 (1.6 mL) was added pyridinium 4-methylbenzenesulfonate (PPTS) (8.12 mg, 0.0323 mmol) and N- bromosuccinimide (86.3 mg, 0.485 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The resulting suspension was filtered and the collected solid washed briefly with CH2C12 and dried in vacuum to afford the title compound a white solid (48.5 mg, 39%). MS (apci) m/z = 388.0 (M+H).
[00807] The following pyrazole intermediates were made according to the methods described for the preparation of Intermediate 228, 229 or 230.
Figure imgf000178_0001
Figure imgf000179_0001
Intermediate 245
Figure imgf000180_0001
5-methyl-3-pheny -l -(pyrazin-2-vlV 1 H-pyrazol-4-amine
[00808] Step A: 2-(5-methyl-4-nitroso-3 -phenyl- 1 H-pyrazol- 1 -vPpyrazine. To a solution of 2-hydrazinylpyrazine (0.485 g, 4.40 mmol) in HOAc (6 mL) was added (2- (hydroxyimino)-l-phenylbutane-l,3-dione (0.765 g, 4.00 mmol) in small portions over 2 minutes. The mixture was stirred for 5 minutes and the resulting light orange suspension was stirred at 60 °C for 6 hours. EtOH (1 mL) was added and the mixture was heated at 60 °C for an additional 6 hours. The resulting dark green suspension was cooled to ambient temperature and the mixture was diluted with H20 (30 mL). The green suspension was stirred for 1 hour and the solid was collected via vacuum filtration. The collected solid was washed with H20 and dried in vacuum. The solid was suspended in EtOH (25 mL) and concentrated HC1 (500 μί,) was added. The mixture was heated at reflux for 20 hours, cooled to ambient temperature and diluted with chilled H20 (75 mL). The mixture was treated with 1M NaOH to pH=7 and was extracted with Et20 (3X). The combined extracts were washed with saturated NaCl and dried over MgS04. The dried solution was filtered through packed Celite® and concentrated. The residual green-yellow solid was purified on a Si02 column using step gradient elution (25% CH2C12, 50% EtOAc/hexanes) to furnish the title compound as a turquoise solid (325 mg, 31%). MS (apci) m/z = 266.1 (M+H).
[00809] Step B: 5-methyl-3-phenyl- 1 -(pyrazin-2-yD- 1 H-pyrazol-4-amine. To a mixture of 2-(5-methyl-4-nitroso-3-phenyl-l H-pyrazol-l-yl)pyrazine (325 mg, 1.04 mmol) and Zn dust (340 mg, 5.21 mmol) in EtOH (10 mL) was added concentrated HC1 (95.5 iL, 1.15 mmol). The mixture was stirred at ambient temperature for 17 hours, then at 65 °C for 3 hours. The mixture was cooled to ambient temperature and was filtered through packed Celite® eluting with MeOH. The eluent was concentrated, and the residue was treated with H20 and mixed. The resulting orange suspension treated with 2M HC1 to pH=l and the mixture was extracted with Et20 (3X). The aqueous portion was treated with 2M NaOH to pH=8 and extracted with EtOAc (3X). The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO activated carbon. The solution was eluted through a Si02 plug eluting with EtOAc. The eluent was concentrated to give the title compound as a light yellow wax (33 mg, 13%). MS (esi) m/z = 252.2 (M+H). Intermediate 246
Figure imgf000181_0001
1 , 5 -dimethyl-3 -phenyl- 1 H-pyrazol-4-amine
[00810] Step A: 1.5 -dimethy l-4-nitroso-3 -phenyl- 1 H-pyrazole : To a solution of methylhydrazine (0.484 g, 10.5 mmol) in HO Ac (10 mL) was added 2-(hydroxyimino)-l- phenylbutane-l,3-dione (2.01 g, 10.5 mmol) in small portions over 5 minutes. The reaction mixture was heated at 60 °C for 1 hour and was cooled to ambient temperature. Et20 (50 mL) and H20 (10 mL) were added to the mixture followed by slow addition of saturated Na2C03 until pH=8 was obtained. The organic layer was removed and the aqueous layer was extracted with Et20 (2X). The combined organic fractions were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (1 :5 EtOAc/hexanes) to give the title compound as a green solid (1.32 g, 63%). MS (apci) m/z = 202.1 (M+H).
[00811] Step B: 1 ,5-dimethyl-3-phenyl- 1 H-pyrazol-4-amine: To a solution of 1,5- dimethyl-4-nitroso-3 -phenyl- 1 H-pyrazole (1.32 g, 6.60 mmol) in MeOH (50 mL) was added Pd(OH) on carbon (200 mg, 20 wt%, 0.286 mmol) and the reaction mixture was shaken under 50 psi of H2 for 3 hours at ambient temperature. The reaction mixture was evacuated, purged with N2 filtered through a pad of Celite® with MeOH elution. The eluent was concentrated and the residue dried in vacuum to provide the title compound as a tan solid (1.23 g, 100%). MS (apci) m/z = 188.1 (M+H).
Intermediate 247
Figure imgf000181_0002
1 -isopropyl-5-methyl-3-phenyl- 1 H-pyrazol-4-amine
[00812] The title compound was prepared according to the method described for
Intermediate 246, using isopropylhydrazine hydrochloride in place of methylhydrazine in Step A to provide 620 mg (57%) of the title compound over 2 steps. MS (apci) m/z = 216.1 (M+H).
Figure imgf000182_0001
5-methyl-3 -phenyl- 1 -(2,2,2-trifluoroethyl)- 1 H-pyrazol-4-amine
[00813] Step A: 5-methyl-4-nitroso-3-phenyl- 1 -(2,2,2-trifluoroethyl)- 1 H-pyrazole: The title compound was prepared using (2,2,2-trifluoroethyl)hydrazine in place of methylhydrazine in Step A of the procedure described for the preparation of l,5-dimethyl-3- phenyl-lH-pyrazol-4-amine (Intermediate 246). The compound was isolated as a green solid (999 mg, 71%). 1H NMR (CDC13) δ 7.60-7.73 (m, 5H), 4.70 (q, 2H), 2.27 (t, 3H).
[00814] Step B: 5 -methyl-3 -phenyl- 1 -(2.2.2-trifluoroethyl)- 1 H-pyrazol-4-amine: To a mixture of 5-methyl-4-nitroso-3-phenyl-l-(2,2,2-trifluoroethyl)-lH-pyrazole (50 mg, 0.186 mmol) and Zn dust (60.7 mg, 0.929 mmol) in EtOH (0.4 mL) was added concentrated HC1 (17.0 μί, 0.204 mmol) and the mixture was heated at reflux for 3 hours. The mixture was cooled to ambient temperature and was diluted with MeOH and filtered. The filtrate was concentrated and the residue was diluted in water. The aqueous mixture was treated with saturated NaHC03 until pH=10 was achieved. The mixture was extracted with DCM (3X) and the combined extracts were dried over Na2S04, filtered and concentrated afford the title compound as a yellow oil (47.1 mg, 99.4% yield). MS (apci) m/z = 256.1 (M+H).
Intermediate 249
Figure imgf000182_0002
1 -ethyl-5-methyl-3 -phenyl- 1 H-pyrazol-4-amine
[00815] Step A: l-ethyl-5-methyl-4-nitroso-3-phenyl-lH-pyrazole: The title compound was prepared according to the procedure described for the preparation of Intermediate 246, using ethylhydrazine oxalate in place of methylhydrazine in Step A. l-Ethyl-5-methyl-4- nitroso-3 -phenyl- 1 H-pyrazole was isolated as a green oil (288 mg, 26%). 1H NMR (CDC13) δ 8.19 (d, 2H), 7.46-7.50 (m, 3H), 4.15 (q, 2H), 2.43 (s, 3H), 1.50 (t, 3H). The minor regioisomer, l-ethyl-3-methyl-4-nitroso-5-phenyl-l H-pyrazole, was also obtained as a blue- green solid (165 mg, 15%). 1H NMR (CDC13) δ 7.71 (dd, 2H), 7.59 (m, 3H), 4.17 (q, 2H), 2.28 (s, 3H), 1.51 (t, 3H).
[00816] Step B: 1 -ethyl-5-methyl-3-phenyl- 1 H-pyrazol-4-amine: Prepared according to the procedure described for the preparation of Intermediate 248, using l-ethyl-5-methyl-4- nitroso-3 -phenyl- lH-pyrazole in Step B. the title compound was isolated as a light purple solid (281 mg, 104%). MS (apci) m/z = 202.1 (M+H).
Intermediate 250
Figure imgf000183_0001
l-ethyl-3-methyl-5-phenyl-lH-pyrazol-4-amine
[00817] Prepared according to the procedure described for the preparation of Intermediate 249, using l-ethyl-3-methyl-4-nitroso-5-phenyl-lH-pyrazole in Step A. The title compound was prepared according to Step B. The compound was isolated as a colorless oil (82.4 mg, 52.5%) after purification by reverse-phase chromatography. MS (apci) m/z = 202.1 (M+H).
Intermediate 251
Figure imgf000183_0002
1 -methyl-5-phenyl-3-(trifluoromethyl)-l H-pyrazol-4-amine
[00818] Step A: 4,4,4-trifluoro-2-(hvdroxyimino)-l-phenylbutane-l,3-dione: A solution of 4,4,4-trifluoro-l-phenylbutane-l,3-dione (5.00 g, 23.1 mmol) in HO Ac (46.3 mL) was chilled to 10 °C and sodium nitrite (1.84 g, 26.6 mmol) in water (6.0 mL) was added. The mixture was stirred at ambient temperature for 90 minutes and was diluted with H20 (150 mL). The mixture was extracted with Et20 (3X) and the combined organic fractions were carefully washed with saturated NaHC03 until pH=9. The Et20 solution was washed with H20 and saturated NaCl and was dried over MgS04. The dried solution was filtered and concentrated to afford the title compound as a yellow foam (4.21 g, 74.2% yield). MS (apci) m/z = 244.1 (M-H).
[00819] Step B: 4-nitroso-3-phenyl-5-(trifluoromethyl)- 1 H-pyrazole: A solution of hydrazine monohydrate (0.204 g, 4.08 mmol) in EtOH (5 mL) was cooled to 0 °C and 4,4,4- trifiuoro-2-(hydroxyimino)-l-phenylbutane-l,3-dione (1.00 g, 4.08 mmol) in EtOH (15 mL) was added. The reaction mixture was stirred at ambient temperature for 3 hours, excess powdered MgS04 was added and the mixture was heated at 60 °C for 16 hours. The mixture was cooled to ambient temperature, filtered and concentrated to afford the crude title compound as a green solid (78.7 mg, 8.0%) that was taken directly to the next step. MS (apci) m/z = 240.0 (M-H).
[00820] Step C: 1 -methyl-5-phenyl-3-rtrifluoromethylV 1 H-pyrazol-4-amine: To a solution of 4-nitroso-3-phenyl-5-(trifluoromethyl)-lH-pyrazole (78.7 mg, 0.326 mmol) in DMF (1.6 mL) was added NaH (14.4 mg, 0.359 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The mixture was treated with methyl iodide (40.6 μί, 0.653 mmol) and stirred for 17 hours. The reaction mixture was directly purified by reverse phase HPLC using 20-100%) acetonitrile/water gradient elution to provide a light blue solid (40.2 mg). The solid was dissolved in EtOH (0.35 mL) and was subjected to the reduction procedure described in Step B of the preparation of 5-methyl-3-phenyl-l -(2,2,2- trifluoroethyl)-lH-pyrazol-4-amine (Intermediate 248). The title compound was obtained as white solid (25.1 mg, 66.1%).
Intermediate 252
Figure imgf000184_0001
1 -methyl-3-phenyl-5-(trifluoromethyl)- 1 H-pyrazol-4-amine
[00821] Step A: 1 -methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)- 1 H-pyrazole. To a solution of methylhydrazine (0.214 mL, 4.08 mmol) in EtOH (20 mL) was added 4,4,4- trifluoro-2-(hydroxyimino)-l-phenylbutane-l,3-dione (Intermediate 251, Step A; 1.00 g, 4.079 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and excess MgS04 was added. The mixture was stirred at 60 °C for 48 hours and was cooled to ambient temperature. The mixture was filtered and the filtrate concentrated to a green residue. The residue was purified by silica gel chromatography using a 10-30% EtOAc/hexanes gradient for elution to provide the title compound as a green solid (482 mg, 46%). 1H NMR (CDC13) δ 7.89 (d, 2H), 7.45-7.52 (m, 3H), 4.15 (s, 3H).
[00822] Step B: 1 -methyl-3-phenyl-5-(trifluoromethylVl H-pyrazol-4-amine. Prepared from l-methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-lH-pyrazole according to the method described for the preparation of Intermediate 248, Step B. The title compound was obtained as white solid (309 mg, 68%). 1H NMR (CDC13) δ 7.65 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 3.93 (s, 3H), 3.52 (br s, 2H). Example 1
Figure imgf000185_0001
1 -(2-cyclopropyl-5-(methoxymethyl)benzylV3-(4-mem^ 1 - phenyl- 1 H-pyrazol-5-yl)urea
[00823] To a reaction tube containing 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl- lH-pyrazol-5-amine (50 mg, 0.19 mmol), dry dichloromethane (2 mL), was added triphosgene (28 mg, 0.094 mmol). A yellow precipitate formed, but immediately went into solution upon the addition of di-isopropylethylamine (98 μί, 0.56 mmol). The reaction mixture was allowed to stir at ambient temperature for 30 minutes, then a dichloromethane solution (1 mL) of (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine (36 mg, 0.19 mmol) was added and the mixture was stirred at ambient temperature for 16 hours, then concentrated under reduced pressure. The resulting crude material was triturated with acetonitrile and the solids collected to give l-(2-cyclopropyl-5-(methoxymethyl)benzyl)-3-(4- methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl-lH-pyrazol-5-yl)urea (42 mg, 46%). MS (APCI) lz = 483.3 (M+H).
Example 2
Figure imgf000185_0002
l-(2-cyclopropyl-5-(methoxymethyl)benzyl)-3-(3-ethoxy-4-methyl-l-phenyl-lH-pyrazol-5- yPurea
[00824] To a reaction tube containing phenyl (3 -ethoxy-4-methyl-l -phenyl- 1H- pyrazol-5-yl)carbamate (50 mg, 0.15 mmol) was added dry 1,2-DCE (2 mL) and (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine (28 mg, 0.15 mmol). DIEA (77 μί, 0.44 mmol) was then added, tube sealed and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure and purified by reverse phase HPLC. The fractions containing the product were combined, neutralized with 10% aqueous potassium carbonate, extracted with EtOAc, the extracts dried over sodium sulfate and concentrated under reduced pressure to give l-(2-cyclopropyl-5- (methoxymethyl)benzyl)-3 -(3 -ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)urea (21 mg, 33% yield) as a white solid. MS (APCI) m/z = 435.2 (M+H).
Example 3
Figure imgf000186_0001
1 -(2-cvclopropyl-5-(methoxymethyl)benzvn-3-(4-methyl-3-(6-methylpyridin-3-yl)- 1 -phenyl-
1 H-pyrazol-5-y0urea
[00825] Prepared by the method as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)-l-phenyl-lH-pyrazol-5-amine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (35 mg, 38% yield) as a white solid. MS (APCI) m/z = 482.2 (M+H).
Example 4
Figure imgf000186_0002
l-(2-cvclopropyl-5-(methoxymethyl)benzyl')-3-(4-methyl-3-(l-methyl-6-oxo-1.6- dihydropyridin-3 -yl)- 1 -phenyl- 1 H-pyrazol-5-vDurea
[00826] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (4-methyl-3-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)-l-phenyl-lH-pyrazol-5-yl)carbamate to give the title compound (27 mg, 43% yield). MS (APCI) m/z = 498.2 (M+H). Example 5
Figure imgf000187_0001
1 -(2-cyclopropyl-5-(methoxymethyObenzyl)-3-(3 ,4-dimethyl- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[00827] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (3 ,4-dimethyl- 1-phenyl- lH-pyrazol-5-yl)carbamate to give the title compound (35 mg, 53% yield). MS (APCI) m/z = 405.2 (M+H).
Example 6
Figure imgf000187_0002
1 -(2-cyclopropyl-5-(methoxymethyl benzyl)-3 -( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-[3 ,4'- bipyrazol]-5-yl)urea
[00828] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (1 ',4-dimethyl-l -phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate to give the title compound (9 mg, 5% yield). MS (APCI) m/z = 471.3 (M+H).
Example 7
Figure imgf000187_0003
1 -(2-cvclopropyl-5-(methoxymethyl benzyl)-3 -(4-methyl-3 -( 1 -methyl-2-oxo- 1 ,2- dihydropyridin-4-ylV 1 -phenyl- 1 H-pyrazol-5 -vPurea
[00829] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (4-methyl-3-(l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-l -phenyl- 1 H-pyrazol-5 -yl)carbamate to give the title compound (30 mg, 48% yield). MS (APCI) m/z = 496.1 (M-H).
Example 8
Figure imgf000188_0001
l-(2-cyclobutyl-5-(methoxymethyl)benzyl -3-(4-methyl-3-(6-methylpyridin-3-yl)-l-phenyl-
1 H-pyrazol-5-yl)urea
[00830] Prepared by the metod as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)- 1 -phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-cyclobutyl-5-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potssium carbonate to give the title compound (20 mg, 21% yield) as a tan solid. MS (APCI) m/z - 496.3 (M+H).
Example 9
Figure imgf000188_0002
1 -(2-cyclobutyl-5-(methoxymethyl)benzyl)-3-(4-methyl-3-(l -methyl-6-oxo- 1 ,6- dihydropyridin-3-yl)-l-phenyl-lH-pyrazol-5-yl)urea [00831] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (4-methyl-3-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)-l -phenyl- lH-pyrazol-5-yl)carbamate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (2-cyclobutyl-5-
(methoxymethyl)phenyl)methanamine. The crude was purified by trituration with acetonitrile to give the title compound (18 mg, 16% yield). MS (APCI) m/z = 510.2 (M-H).
Example 10
Figure imgf000189_0001
l-(2-cvclobutyl-5-(methoxymethyl)benzyl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-l- phenyl- 1 H-pyrazol-5-yl)urea
[00832] Prepared by the method described in Example 1, Step A, replacing (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (2-cyclobutyl-5-
(methoxymethyl)phenyl)methanamine to give the title compound (37 mg, 44% yield) as a white solid. MS (APCI) m/z = 495.2 (M-H).
Example
Figure imgf000189_0002
1 -(2-cvclobutyl-5-(methoxymethvnbenzvn-3-( 1 '.4-dimethyl-l -phenyl-lH.l Ή-Γ3.4'- bipyrazol1-5-yl)urea
[00833] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,rH-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-cyclobutyl-5- (methoxymethyl)phenyl)methanamine to give the title compound (45 mg, 50% yield). MS (APCI) m/z = 485.2 (M+H).
Example 12
Figure imgf000190_0001
l-(2-cyclopentyl-5-(methoxymethyl)benzyl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl')-l- phenyl- 1 H-pyrazol-5-yl urea
[00834] Prepared by the method as described in Example 1, Step A, replacing (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (2-cyclopentyl-5-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (17 mg, 25% yield) as a white solid. MS (APCI) m/z = 51 1.3 (M+H).
Example 13
Figure imgf000190_0002
l-(2-cyclopentyl-5-(methoxymethyl)benzyl)-3-(4-methyl-3-(6-methylpyridin-3-yn-l-phenyl-
1 H-pyrazol-5-yl)urea
[00835] Prepared by the method as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5 -amine with 4-methyl-3-(6- methylpyridin-3-yl)- 1 -phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-cyclopentyl-5-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (28 mg, 41% yield). MS (APCI) m/z = 510.3 (M+H). Example 14
Figure imgf000191_0001
1 -(2-(cyclopropylmethoxy)-5 -(methoxymethyl)benzyl)-3-( 1 ',4-dimethyl- 1 -phenyl- 1 H J Ή-
[3.4'-bipyrazol1-5-yl)urea
[00836] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (1',4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(cyclopropylmethoxy)-5-
(methoxymethyl)phenyl)methanamine (material from HPLC purification was triturated with methanol) to give the title compound (1 1 mg, 16% yield). MS (APCI) m/z = 501.2 (M+H).
Example 15
Figure imgf000191_0002
1 -(2-cyclopropyl-5-ethoxybenzyl)-3 -( 1 '.4-dimethyl- 1 -phenyl- 1 H, 1 Ή- [3 ,4'-bipyrazol] -5- yOurea
[00837] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l -phenyl - lH,rH-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-cyclopropyl-5-ethoxyphenyl)methanamine) to give the title compound (55 mg, 58% yield). MS (APCI) m/z = 471.2 (M+H). Example 16
Figure imgf000192_0001
l-(2-cvclobutyl-5-(l-methoxyethyl)ber^
phenyl- 1 H-pyrazol-5-vDurea
[00838] Prepared by the method as described in Example 1, Step A, replacing (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (2-cyclobutyl-5-( 1 - methoxyethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (12 mg, 17% yield) as a white solid. MS (APCI) m/z = 509.3 (M-H).
Example 17
Figure imgf000192_0002
1 -(1 '.4-dimethyl-l -phenyl- 1 H.1 'H-r3.4'-bipyrazol1-5-vn-3-(2-ethoxy-5- (methoxymethyl)benzyPurea
[00839] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-ethoxy-5-
(methoxymethyl)phenyl)methanamine to give the title compound (3 mg, 9% yield). MS (APCI) m/z = 475.2 (M+H). Example 18
Figure imgf000193_0001
1 -(2-cvclobutoxy-5 -( methoxymethvnbenzylV 3 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή-Γ3.4'- bipyrazoll-5-ynurea
[00840] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,rH-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-cyclobutoxy-5-
(methoxymethyl)phenyl)methanamine to give the title compound (12 mg, 45% yield). MS (APCI) m/z = 501.2 (M+H).
Example 19
Figure imgf000193_0002
1 -(2-cvclobutoxy-5-(methoxymethyl)benzyl)-3 -(4-methyl-3 -(6-methylpyridin-3 -ylV 1 - phenyl- lH-pyrazol-5-vDurea
[00841] Prepared by the method as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)- 1 -phenyl- 1 H-pyrazol-5 -amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-cyclobutoxy-5-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (34 mg, 50% yield). MS (APCI) m/z = 512.3 (M+H).
Figure imgf000194_0001
1 -(2-( difluoromethoxyV 5 -( methoxymethyl benzyl -3 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή-[3.4'- bipyrazol]-5-yl)urea
[00842] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (1',4-dimethyl-l -phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (15 mg, 23% yield). MS (APCI) m/z = 497.2 (M+H).
Example 21
Figure imgf000194_0002
1 -(f2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3-(4-methyl-3-(6-methylpyridin-3-vn- 1 - phenyl- 1 H-pyrazol-5-yDurea
[00843] Prepared by the method as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)-l-phenyl-l H-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (23 mg, 24% yield). MS (APCI) m/z = 508.2 (M+H). Example 22
Figure imgf000195_0001
1 -fl '.4-dimethyl-l -phenyl- 1 H.1 Ή-Γ3.4'-ΜρνΓ8ζο11-5-ν1)-3-( 5-fmethoxymethvn-2-
(trifluoromethoxy benzvOurea
[00844] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (r,4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (20 mg, 29% yield). MS (APCI) m/z = 515.2 (M+H).
Example 23
Figure imgf000195_0002
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl -3-(4-methyl-3-(6-methylpyridin-3-yn-l- phenyl- 1 H-pyrazol-5-yPurea
[00845] Prepared by the method as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)- 1 -phenyl- 1 H-pyrazol-5 -amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (26 mg, 26% yield). MS (APCI) m/z = 524.2 (M-H). Example 24
Figure imgf000196_0001
1 -(2-( 1 -methoxycvclobutyl)-5 -(methoxymethv0benzyl)-3 -(4-methyl-3 -(6-methylpyridin-3 - yl)- 1 -phenyl- 1 H-pyrazol-5-yl urea
[00846] Prepared by the method as described in Example 1 , Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl-l H-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)-l-phenyl-l H-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-( 1 -methoxycyclobutyl)-5-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (26 mg, 52% yield). MS (APCI) m/z = 526.3 (M+H).
Example 25
Figure imgf000196_0002
1 -(2-(2,2-difluorocyclopropyl)-5-(methoxymethyl)benzylV3-( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-
[3.4'-bipyrazol1-5-yl)urea 2,2,2-trifluoroacetate
[00847] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- l H-pyrazol-5-yl)carbamate with phenyl (l ',4-dimethyl-l-phenyl- lH,rH-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethy l)phenyl)methanamine with (2-(2,2-difluorocyclopropy l)-5 -
(methoxymethyl)phenyl)methanamine 2,2,2-trifluoroacetate (no neutralization performed) to give the title compound (20 mg, 29% yield) as a TFA salt. MS (APCI) m/z = 507.2 (M+H). Example 26
Figure imgf000197_0001
1 -(cyclopropyl(3-(methoxymethyl)phenyl)methylV3-(4-methyl-3-('l -methyl-6-oxo-l ,6- dihydropyridin-3 -ylV 1 -phenyl- 1 H-pyrazol-5-yl)urea
[00848] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (4-methyl-3-(l-methyl-6- oxo- 1 ,6-dihydropyridin-3-yl)- 1 -phenyl- 1 H-pyrazol-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with cyclopropyl(3-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (12 mg, 39% yield). MS (APCI) m/z = 496.2 (M-H).
Example 27
Figure imgf000197_0002
1 -(cvclopropyl(3-(methoxymethyl)phenyl methyl)-3-(4-methyl-3-d -methyl-2-oxo-l .2- dihvdropyridin-4-νΠ- 1 -phenyl- 1 H-pyrazol-5-ynurea
[00849] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (4-methyl-3-(l-methyl-2- oxo- 1 ,2-dihydropyridin-4-yl)- 1 -phenyl- 1 H-pyrazol-5-yl)carbamate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with cyclopropyl(3-
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (7 mg, 43% yield). MS (APCI) m/z = 496.3 (M-H).
Example 28
Figure imgf000198_0001
l-(cyclopropyl(3-(methoxymethyl)phenyl)methyl)-3-( ,4-dimethyl-l -phenyl-lH,rH-[3,4'- bipyrazol] -5 -vPurea
[00850] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (cyclopropyl(3-
(methoxymethyl)phenyl)methanamine to give the title compound (26 mg, 41% yield). MS (APCI) m/z = 471.2 (M+H).
Example 29
Figure imgf000198_0002
1 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή-Γ3 ,4'-bipyrazol1-5-vP-3-( 1 -(3- (methoxymethyPphenyPethyPurea 2,2,2 -trifluoroacetate
[00851] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with l-(3-(methoxymethyl)phenyl)ethanamine (no neutralization performed) to give the title compound (1.5 mg, 2.5% yield) as a TFA salt. MS (APCI) m/z = 445.2 (M+H). Example 30
Figure imgf000199_0001
1 -( 1 -(2-cvclopropyl-5-(methoxymethyl)phenvDethvI)-3 -( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-
[3 ,4'-bipyrazol] -5-yHurea
[00852] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,rH-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with l-(2-cyclopropyl-5-
(methoxymethyl)phenyl)ethanamine to give the title compound (3 mg, 2% yield). MS (APCI) m/z = 485.3 (M+H).
Example 31
Figure imgf000199_0002
l-(l',4-dimethyl-l-phenyl-lH.l,H-r3.4'-bipyrazoll-5-vn-3-(2-(3-fluorooxetan-3-ylV5-
(methoxymethyl)benzyDurea
[00853] Prepared by the method described in Example 2, Step A, replacing phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (l',4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(3-fluorooxetan-3-yl)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (7 mg, 21% yield). MS (APCI) m/z = 505.2 (M+H).
Figure imgf000200_0001
l-(2-(3-fluorooxetan-3-yl)-5-(methoxymethyl benzvn-3-(4-methyl-3-(6-methylpyridin-3-yl)-
1 -phenyl- 1 H-pyrazol-5-yl urea
[00854] Prepared by the method as described in Example 1, Step A, replacing 4- methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- 1 H-pyrazol-5-amine with 4-methyl-3-(6- methylpyridin-3-yl)- 1 -phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with ((2-(3-fluorooxetan-3 -yl)-5 -
(methoxymethyl)phenyl)methanamine. The crude material was purified by reverse phase prep HPLC and neutralization with 10% aqueous potassium carbonate to give the title compound (21 mg, 26% yield). MS (APCI) m/z = 516.3 (M+H).
Example 33
Figure imgf000200_0002
1 -( 1 '.4-dimethyl- 1 -phenyl- 1H.1 'H-r3,4'-bipyrazol1-5-vn-3-(5-(methoxymethyl)-2-
(trifluoromethyl)benzyQurea
[00855] Step A: Preparation of (3-fluoro-4-(trifluoromethyl)phenvDmethanol: Charged a round bottomed flask plus stir bar with 3-fluoro-4-(trifluoromethyl)benzaldehyde (2.0 g, 10 mmol) and anhydrous MeOH (20 mL). The flask was chilled in an ice bath and sodium borohydnde (0.47 g, 12 mmol) was added in portions. Removed ice bath and allowed reaction to warm to ambient temperature. Added saturated NH4CI (2 mL) and concentrated mixture in vacuo. The residue was diluted with additional saturated NH4CI (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried (MgS04), filtered, and concentrated. Yield: 1.8 g (80%). Product carried forward without purification. [00856] Step B: Preparation of 2-fluoro-4-(methoxymethyr)-l- (trifluoromethyl)benzene : Charged a dry round bottomed flask plus stir bar with (3-fluoro-4- (trifluoromethyl)phenyl)methanol (1.6 g, 8.24 mmol) and anhydrous DMF (25 mL). Cooled in an ice bath under N2, and added sodium hydride (0.659 g, 16.5 mmol; 60% wt. in mineral oil) in portions over a 20 min period. Removed ice bath and stirred at ambient temperature for 20 minutes. The reaction mixture was again cooled in an ice bath and iodomethane was added (1.55 mL, 24.7 mmol) dropwise. Removed from ice bath and stirred for 30 min. Quenched reaction by careful addition of saturated aqueous NH4CI (50 mL). Then extracted product with EtOAc (50 mL, then 30 mL). Washed combined organics with water (50 mL), brine (30 mL), dried (MgS04), filtered, and concentrated. Yield: 1.8 g (84%). The product carried forward without purification.
[00857] Step C: Preparation of 5-(methoxymethyl)-2-(trifluoromethyl)benzonitrile:
Charged a thick walled glass pressure vessel with 2-fluoro-4-(methoxymethyl)-l- (trifluoromethyl)benzene (1.9 g, 9.1 mmol), anhydrous DMSO (25 mL) and KCN (0.71 g, 1 1.0 mmol). Heated to 120 °C overnight with stirring. Charged the reaction mixture with more KCN (0.71 g, 1 1.0 mmol) and continued heating at 120 °C for another day. After cooling to ambient temperature, the mixture was partitioned between EtOAc (75 mL) and water (75 mL). The phases were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were washed with water (2 x 50 mL), brine (50 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by Biotage Flash 40 silica gel column, eluting with a gradient of 5%-20% EtOAc/hexanes. Yield: 537 mg (26%).
[00858] Step D: Preparation of (5-(methoxymethviy2-
(trifluoromethvDphenvDmethanamine: Charged a dry round bottomed flask bar with 5- (methoxymethyl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.23 mmol), anhydrous THF (1 mL), and lastly lithium aluminum hydride (232 μί, 0.232 mmol; 1M in diethyl ether). Heated to reflux under N2 for 2 hours. After cooling to ambient temperature, quenched excess hydride reagent by addition of water (30 μί), then stirring for 2-3 minutes. Added 2N NaOH (30 μΕ), again stirring 2-3 minutes, and then more water (100 μί), followed by stirring for 15 min at ambient temperature. Diluted with MTBE, and filtered suspension through Celite®, rinsing with MTBE. Concentrated filtrate, azeotroping with toluene to remove residual water (3 x 5 mL), to obtain 32 mg (50% yield) of desired product. Product carried forward without purification. [00859] Step E: Preparation of 1 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 'H-[3,4'-bipyrazol1-5- yl)-3-(5-(methoxymethyl)-2-('trifluoromethyl)benzyl)urea: Charged a vial plus stir bar with phenyl ( ,4-dimethyl-l-phenyl-lH,rH-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5, 45 mg, 0.12 mmol), anhydrous 1 ,2-dichloroethane (0.5 mL), (5-(methoxymethyl)-2- (trifluoromethyl)phenyl)methanamine (32 mg, 0.14 mmol), and DIEA (63 ί, 0.36 mmol). Stirred overnight at ambient temperature. Diluted reaction with DCM (20 mL) and washed with 0.5 M aqueous HC1 (2 x 10 mL). Organic phase was dried (MgS04), filtered, and concentrated. Purified crude product by preparative TLC (1 mm thickness, Rf = 0.31) eluting with 7.5% MeOH/DCM. Yield: 13 mg (19%). MS m/z (APCI-pos) M+l = 499.
Example 34
Figure imgf000202_0001
1 -(1 '.4-dimethyl- 1 -phenyl- 1 F 1 'H-r3.4'-bipyrazoll-5-yl)-3-(2-isopropyl-5- (methoxymethvDbenzvDurea
[00860] Step A: Preparation of 5-formyl-2-(prop-l-en-2-yl)benzonitrile: Charged a thick walled glass pressure vessel with 2-bromo-5-formylbenzonitrile (Preparation A, Step A, 1.0 g, 4.8 mmol) and anhydrous toluene (20 mL). To this was added potassium isopropenyl- trifluoroborate (2.82 g, 19.0 mmol), Pd(OAc)2 (0.053 g, 0.29 mmol), and dicyclohexyl(2',6'- diisopropoxy-[l,l'-biphenyl]-2-yl)phosphine (0.22 g, 0.48 mmol), followed by 3P04 (3.0 g, 14 mmol), and water (5 mL). Sparged with Ar gas for 5-10 minutes. Heated to 110 °C overnight. After cooling to ambient temperature, the mixture was transferred to a separatory funnel with EtOAc (30 mL) and water (30 mL). Separated phases. Washed organic phase with brine (30 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by Biotage Flash 40 silica gel chromatography, eluting with a gradient of 10%-20% EtOAc/hexanes. Yield: 756 mg (91%).
[00861] Step B: Preparation of 5-(hydroxymethyl)-2-isopropylbenzonitrile: Charged a round bottomed flask plus stir bar with 5-formyl-2-(prop-l-en-2-yl)benzonitrile (750 mg, 4.38 mmol), EtOAc (20 mL), and lastly Pd(OH)2 (308 mg, 0.438 mmol; 20% wt/wt. Degussa type). Purged with N2, and then stirred overnight under a balloon of H2. Filtered reaction mixture through Celite®, rinsing with DCM. Concentrated filtrate to obtain an oil. Yield: 735 mg (91%). Product carried forward without purification.
[00862] Step C: Preparation of 2-isopropyl-5-(methoxymethyl)benzonitrile: The title compound was prepared from 5-(hydroxymethyl)-2-isopropylbenzonitrile (730 mg, 4.17 mmol) according to the procedure provided for Example 33, Step B. Yield: 860 mg (93%).
[00863] Step D: Preparation of (2-isopropyl-5-(methoxymethy0phenyl)methanamine: The title compound was prepared from 2-isopropyl-5-(methoxymethyl)benzonitrile (200 mg, 1.06 mmol) according to the procedure provided for Example 33, Step D. Yield: 195 mg (81%).
[00864] Step E: Preparation of 1 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 'H-r3.4'-bipyrazoll-5- vD-3 -(2-isopropyl-5 -(methoxymethyl benzvDurea: The title compound was prepared from (2- isopropyl-5-(methoxymethyl)phenyl)methanamine (23 mg, 0.12 mmol) and phenyl (l',4- dimethyl-l-phenyl-lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5, 30 mg, 0.080 mmol) according to the procedure provided for Example 33, Step E. Purified crude product by preparative TLC (1 mm thickness, Rf = 0.42) eluting with 10% MeOH/DCM. Yield: 29 mg (69%). MS m/z (APCI-pos) M+l = 473.
Example 35
Figure imgf000203_0001
1 -( 2-( fe -butylV 5-( methoxymethvnbenzvn-3 -f 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή-Γ3.4'- bipyrazoll-5-vPurea
[00865] Step A: Preparation of 2-bromo-l-(fert-butylV4-nitrobenzene: Charged a round bottomed flask plus stir bar with l-(tert-butyl)-4-nitrobenzene (9.0 g, 50 mmol), 90% sulfuric acid (50 mL), and Ag2S04 (10 g, 32 mmol). To this stirred mixture was added bromine (2.6 mL, 50 mmol) dropwise. Stirred at ambient temperature overnight. The reaction mixture was then slowly poured into an ice cold 10% aqueous solution of sodium bisulfite (200 mL) with mixing by spatula, and the product then extracted into EtOAc (3 x 75 mL). The combined organic phases were dried (MgS04), filtered, and concentrated to a beige solid. Yield: 12.8 g (84%). Product carried forward without purification. [00866] Step B: Preparation of 2-(fert-butyl)-5-nitrobenzonitrile: Charged a stainless steel bomb with 2-bromo-l-(tert-butyl)-4-nitrobenzene (9.7 g, 38 mmol), anhydrous dimethylacetamide (60 mL), and lastly copper(I) cyanide (3.7 g, 41 mmol). Heated to 150 °C for 3 days. After cooling to ambient temperature, the mixture was transferred to a separatory funnel with diethyl ether (100 mL) and water (100 mL). Added diethyl amine (10 mL) to the mixture, which resulted in formation of a precipitate. Separated phases, and re-extracted aqueous phase with diethyl ether (3 x 50 mL). The combined organic phases were washed with 10% aqueous KCN (50 mL), then with water (100 mL). The combined organic phases were dried (MgS04), filtered, and concentrated. The crude material was purified by Biotage Flash 65 silica gel chromatography, eluting with a gradient of 5%-15% EtOAc/hexanes. Yield: 4.6 g (59%).
[00867] Step C: Preparation of 5-amino-2-(fert-butyl)benzonitrile: Charged a round bottomed flask with 2-(tert-butyl)-5-nitrobenzonitrile (4.8 g, 24 mmol) and EtOH (100 mL). Heated mixture to reflux under N2. Added ammonium formate (4.4 g, 71 mmol), followed by palladium on carbon (2.5 g, 2.4 mmol; 10% wt/wt). Continued heating for 2 hours at reflux. Cooled to ambient temperature. Filtered through Celite®, rinsing with DCM. Concentrated in vacuo. Took residue back up in DCM (30 mL) and washed with water (30 mL). Re-extracted aqueous with DCM (30 mL). The combined organic phases were dried (MgS04), filtered, and concentrated to an oil. Yield: 4.1 g (80%). Product carried forward without purification.
[00868] Step D: Preparation of 5-bromo-2-(fert-butyl)benzonitrile: Charged a round bottomed flask plus stir bar with 5-amino-2-(tert-butyl)benzonitrile (2.0 g, 12 mmol), acetonitrile (20 mL) and hydrogen bromide (1.43 mL, 12.6 mmol; 48% wt/wt in water). Cooled in an ice bath and added sodium nitrite (0.950 g, 13.8 mmol) dissolved in water (2 mL) drop wise with stirring, maintaining internal temperature below 5 °C. Stirred for 15 min. Copper(II) bromide (5.13 g, 23.0 mmol) and copper(I) bromide (0.329 g, 2.30 mmol) were added. Continued stirring overnight at ambient temperature, allowing reaction to warm slowly. Partioned mixture between EtOAc (50 mL) and aqueous saturated NaHC03 (50 mL). Stirred mixture for 15 min until gas evolution ceased. Filtered through Celite®. Separated phases. Re-extracted aqueous phase with EtOAc (30 mL). The combined organic phases were washed with brine (50 mL), dried (MgS04), filtered, and concentrated. Partially purified crude by Biotage Flash 40 silica gel column, eluting with a gradient of 5%-10% EtOAc/hexanes. Purified isolated material by a second Biotage Flash 40 silica gel column, eluting with a gradient of neat hexanes to 2.5%-10% EtOAc/hexanes. Yield: 415 mg (12%). [00869] Step E: Preparation of 2-(tert-butyl)-5-(methoxymethyl)benzonitrile: Charged a thick walled glass pressure vessel with 5-bromo-2-(tert-butyl)benzonitrile (520 mg, 2.18 mmol), dicyclohexyl(2',6'-dimethoxy-[l, -biphenyl]-2-yl)phosphine ("S-Phos") (179 mg, 0.437 mmol), Pd(OAc)2 (49.0 mg, 0.218 mmol), potassium (methoxymethyl)trifluoroborate (664 mg, 4.37 mmol), CS2CO3 (2.8 g, 8.7 mmol), and 1 :1 dioxane/water (10 mL). Sparged with N2 for several minutes, then heated to 100 °C overnight with stirring. After cooling to ambient temperature, partioned mixture between EtOAc (20 mL) and water (20 mL). Separated phases, re-extracting aqueous with EtOAc (10 mL). Combined organics were washed with brine (20 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by Biotage Flash 40 silica gel column, eluting with a gradient of 5%-10% EtOAc/hexanes. Yield: 187 mg (36%).
[00870] Step F: Preparation of (2-(/grt-butyl)-5-(methoxymethyl)phenyl)methanamine: The title compound was prepared from 2-(tert-butyl)-5-(methoxymethyl)benzonitrile (187 mg, 0.920 mmol) according to the procedure provided for Example 33, Step D. Yield: 169 mg (53%).
[00871] Step G: Preparation of l-(2-(fert-butyl)-5-(methoxymethvnbenzvn-3-(l '.4- dimethyl-l-phenyl-lHJ'H-[3,4'-bipyrazol]-5-yl)urea: The title compound was prepared from (2-(fert-butyl)-5-(methoxymethyl)phenyl)methanamine (50 mg, 0.24 mmol) and phenyl ( ,4- dimethyl-l-phenyl-lH,rH-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5, 90 mg, 0.24 mmol) according to the procedure provided for Example 33, Step E. Purified crude product by preparative TLC (2 mm thickness, Rf = 0.39) eluting with 7.5% MeOH/DCM. Yield: 52 mg (36%). MS m/z (APCI-pos) M+l = 487.
Example 36
Figure imgf000205_0001
1 -((5-cyclobutyl-2-(methoxymethyl)pyridin-4- vf)methyl)-3 -( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-
[3 ,4'-bipyrazol] -5 -vDurea
[00872] Step A: Preparation of 3-bromoisonicotinaldehyde oxime: Charged a round bottomed flask (equipped with a water condenser) with 3-bromoisonicotinaldehyde (25.0 g, 134 mmol), sodium acetate (13.8 g, 168 mmol), and water (1 L). Heated to reflux with stirring. Hydroxylamine hydrochloride (14.0 g, 202 mmol) was added, resulting in immediate precipitate formation. Cooled the suspension to ambient temperature, then in an ice bath. Filtered solids, washing with ice cold water, then dried solids by toluene azeotrope on a rotary evaporator (3 x 100 mL). Yield: 24.4 g (89%). Carried product forward without purification.
[00873] Step B: Preparation of 3-bromoisonicotinonitrile: Charged a round bottomed flask plus stir bar with 3-bromoisonicotinaldehyde oxime (24.4 g, 121 mmol), anhydrous THF (200 mL), and Et3N (68 mL, 486 mmol). Cooled in an ice bath under N2, and then added POCI3 (11.7 mL, 127 mmol) dropwise. Continued stirring in the ice bath for 3 hours. The mixture was partitioned between EtOAc (400 mL) and saturated aqueous NaHC03 (400 mL). Separated phases. Re-extracted aqueous with EtOAc (2 x 150 mL). The combined organic phases were dried (Na2S04), filtered, and concentrated. Triturated crude with pentane (100- 150 mL), and filtered pink solids. Concentrated the mother liquor. Triturated the resulting solids with more pentane (50-75 mL) to obtain a second crop. Pooled the first and second crops (which contained some triethyl amine hydrochloride by NMR) and partitioned the combined crops between 10% EtOAc in Et20 (150 mL) and water (50 mL). Neutralized the aqueous layer with saturated aqueous NaHC03 (50-100 mL). Separated phases, and re- extracted aqueous phase with more 10% EtOAc in Et20 (2 x 50 mL). The combined organic phases were dried (MgS04), filtered, and concentrated to provide desired product as a solid. Yield: 19.7 g (87%).
[00874] Step C: Preparation of 3-cyclobutylisonicotinonitrile: Charged a dry round bottomed flask plus stir bar with 3-bromoisonicotinonitrile (6.1 g, 33 mmol), anhydrous THF (150 mL), dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine "S-Phos" (1.0 g, 2.5 mmol), and Pd(OAc)2 (0.37 g, 1.7 mmol). Purged the reaction mixture with N2. Added cyclobutylzinc(II) bromide (100 mL, 50 mmol; 0.5 M in THF) over 15 minutes via cannula. Stirred the reaction mixture for 2 hours at ambient temperature. Partioned mixture between EtOAc (200 mL) and water (200 mL), and filtered through Celite® to remove insoluble solids, rinsing with EtOAc. Separated phases, and re-extracted aqueous phase with EtOAc (100 mL). The combined organic phases were washed with brine (150 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by Biotage Flash 65 silica gel column, eluting with a gradient of 10% EtOAc/hexanes to 1 :1 EtOAc/hexanes. Yield: 2.3 g (43%). [00875] Step D: Preparation of 5-cyclobutyl-2-(methoxymethyl)isonicotinonitrile: Charged a thick walled glass vessel plus stir bar with 3-cyclobutylisonicotinonitrile (1.0 g, 6.3 mmol), 1 :1 acetic acid/water (20 mL), trifluoroacetic acid (0.48 mL, 6.3 mmol), and potassium (methoxymethyl)trifluoroborate (1.92 g, 12.6 mmol). Stirred to dissolve, then added triacetoxymanganese dihydrate (4.24 g, 15.8 mmol). Heated to 60 °C with stirring. After 1 hour, added more triacetoxymanganese dihydrate (4.24 g, 15.8 mmol), and continued heating for 2 hours. After cooling to ambient temperature, the reaction mixture was filtered through Celite®, rinsing with EtOAc. Concentrated filtrate in vacuo. Performed a toluene azeotrope (2 x 20 mL) to remove excess acid and water. Partially purified crude mixture on a Redi-Sep 220 g silica gel column eluting with a gradient of neat DCM to 3% MeOH in DCM. Product containing fractions were re-purified by preparative TLC eluting with 5% MeOH in DCM. A second preparative TLC purification was performed to further enrich the concentration of the title compound in the mixture, eluting with 5% acetone in DCM. The title compound (260 mg) also contained 3-cyclobutylisonicotinonitrile (unreacted starting material) and 3-cyclobutyl-2,6-bis(methoxymethyl)isonicotinonitrile by-product, and it was carried forward to the next step as a mixture.
[00876] Step E: Preparation of (5-cyclobutyl-2-(methoxymethy0pyridin-4- yDmethanamine: The title compound was prepared from 5-cyclobutyl-2- (methoxymethyl)isonicotinonitrile (130 mg, 0.64 mmol) according to the procedure provided for Example 33, Step D. Crude product was obtained as mixture with (3-cyclobutylpyridin-4- yl)methanamine and (3-cyclobutyl-2,6-bis(methoxymethyl)pyridin-4-yl)methanamine that were formed from reduction of 3-cyclobutylisonicotinonitrile and 3-cyclobutyl-2,6- bis(methoxymethyl)isonicotinonitrile, respectively, that were present in the starting material. The crude mixture (1 15 mg) was carried forward to the next step without separation of products.
[00877] Step F: Preparation of l-((5-cyclobutyl-2-(methoxymethyl)pyridin-4- yl)methyl)-3-(l ',4-dimethyl-l -phenyl-lH,rH-[3,4'-bipyrazol]-5-yl)urea: The title compound was prepared from (5-cyclobutyl-2-(methoxymethyl)pyridin-4-yl)methanamine (115 mg, 0.56 mmol) and phenyl (r,4-dimethyl-l-phenyl-lH, H-[3,4'-bipyrazol]-5-yl)carbamate from (Intermediate 5, 208 mg, 0.56 mmol) according to the procedure provided for Example 33, Step E. Partially purified crude product mixture by preparative TLC (2 mm thickness, Rf = 0.13-0.23) eluting with 5% MeOH (containing 7N NH3) in DCM. The product containing bands were pooled and an aliquot from these were re-purified by reverse phase HPLC (YMC ODS-AQ, 250 x 20 mm column) to obtain analytically pure title compound. MS m/z (APCI- pos) M+l = 486.
Example 37
Figure imgf000208_0001
l-((3-cvclobutylDyridin-4-vnmethylV3-(l'.4-dimethyl-l-phenyl-lH.l'H-[3.4'-bipyrazol]-5- vDureaea
[00878] The title compound was obtained from the purification of the crude reaction mixture described for Example 36, Step F, by reverse phase HPLC (YMC ODS-AQ, 250 x 20 mm column). MS m/z (APCI-pos) M+l = 442.
Example 38
Figure imgf000208_0002
1 -(2-(3.3-difluorocvclobutvn-5-(methoxymethyl)benzylV3-( 1 ',4-dimethyl- 1 -phenyl- 1H, 1 Ή-
[3,4'-bipyrazol]-5-yl)urea
[00879] Step A: Preparation of 2-bromo-4-(methoxycarbonyl)benzenediazonium tetrafluoroborate : To a stirred solution of BF3-etherate (2.9 mL, 23 mmol) in DCM (10 mL) cooled in an ice/NaCl bath under N2 was added methyl 4-amino-3-bromobenzoate (3.5 g, 15 mmol) dissolved in DCM (20 mL) dropwise. Next added a solution of tert-butyl nitrite (2.2 mL, 18 mmol) dissolved in DCM (5 mL) dropwise over a 10 min period. Following complete addition, left stirring in the ice/NaCl bath for 10 minutes. The reaction vessel was removed and placed in a regular ice water bath, stirring for 20 min more. Diluted the suspension with pentane, and filtered solids. Washed solids with pentanes then diethyl ether multiple times. Dried under high vacuum and stored in a -10 °C freezer. Yield: 4.9 g (97%). [00880] Step B: Preparation of methyl 3-bromo-4-vinylbenzoate: Charged a round bottomed flask plus stir bar with dioxane (50 mL), potassium vinyltrifluoroborate (2.40 g, 17.9 mmol), and Pd(OAc)2 (0.167 g, 0.745 mmol). Sparged mixture with N2 for several minutes. Added 2-bromo-4-(methoxycarbonyl)benzenediazonium tetrafluoroborate (4.9 g, 15 mmol) over a 5-10 minute period in portions as a solid while stirring at ambient temperature. Reaction was somewhat exothermic, so placed in an ice bath for a few minutes when the flask became warm to the touch. Wrapped flask in Al foil to minimize light exposure and continued stirring under N2 for 1 hour. Partioned mixture between EtOAc (50 mL) and aqueous saturated NaHC03 (50 mL). Separated phases, and re-extracted aqueous with EtOAc (30 mL). The combined organic phases were shaken with brine (50 mL), and the biphase was filtered through GF/F paper to remove insoluble solids, then the phases were separated. Organic phase was dried (MgS04), filtered, and concentrated. The crude material was purified by Red-Sep 120 silica gel column, eluting with 5% EtOAc/hexanes. Yield: 1.53 g (41%). Stored product in -10 °C freezer.
[00881] Step C: Preparation of (3-bromo-4-vinylphenyl)methanol: Charged a round bottomed flask plus stir bar with methyl 3-bromo-4-vinylbenzoate (1.8 g, 7.47 mmol) and anhydrous DCM (15 mL). Cooled to -78 °C under N2, and added DIBAL-H (14.9 mL, 22.4 mmol; 1.5 M in toluene) dropwise. Stirred for 30 min at -78 °C. Carefully quenched with dropwise MeOH addition (1-2 mL) at -78 °C (gas evolution), and then warmed to 0 °C before adding reaction mixture to 30% Rochelle's salt (75 mL). Much gas evolution—vent adequately. Diluted mixture with more DCM (75 mL) and stirred for 2-3 hours with Rochelle's salt. Filtered through GF/F paper and separated the phases, re-extracting aqueous with DCM (30 mL). The combined organic phases were washed with brine (30 mL), dried (MgS04), filtered, and concentrated. Yield: 1.68 g (95%).
[00882] Step C: Preparation of 2-bromo-4-(methoxymethyl)-l-vinylbenzene: Charged a round bottomed flask plus stir bar with (3-bromo-4-vinylphenyl)methanol (1.68 g, 7.88 mmol) and anhydrous THF (20 mL). Cooled in an ice bath under N2, and added sodium hydride (0.473 g, 1 1.8 mmol; 60% in mineral oil). Left stirring in the ice bath for 1 hour. Then added iodomethane (0.98 mL, 16 mmol) dropwise. Removed bath and warmed to ambient temperature, stirring for 1 hour. Carefully quenched with aqueous saturated NHtCl solution (5 mL) venting adequately until gas evolution ceased. Partioned mixture between water (20 mL) and EtOAc (20 mL). Separated phases, then re-extracted aqueous with EtOAc (20 mL). The combined organic phases were washed with 10% sodium thiosulfate (20 mL), brine (20 mL), dried (MgS0 ), filtered, and concentrated. This crude product was then purified by Redi-Sep 120 silica gel column, eluting with a gradient of neat hexanes to 10% EtOAc/hexanes. Yield: 1.15 g (61%).
[00883] Step D: Preparation of 3-(2-bromo-4-(methoxymethyl phenylV2.2- dichlorocyclobutanone: Charged a dry round bottomed flask plus stir bar with 2-bromo-4- (methoxymethyl)-l-vinylbenzene (1.1 g, 4.8 mmol), diethyl ether (20 mL), and activated zinc (0.950 g, 14.5 mmol; prepared as described in J Org. Chem. 1978, 43, 2879-2882). Heated to reflux, then added a solution of POCl3 (0.486 mL, 5.33 mmol) and 2,2,2-trichloroacetyl chloride (1.09 mL, 9.69 mmol) dissolved in diethyl ether (5 mL) over a 30 min period. Continued heating at reflux for 1 hour. Stirred at ambient temperature, overnight. As mostly unreacted starting material remained, added more activated zinc reagent (0.950 g, 14.5 mmol) as well as additional 2,2,2-trichloroacetyl chloride (0.55 mL, 4.8 mmol) and POCl3 (0.24 mL, 2.7 mmol) dissolved in diethyl ether (3 mL) to the reaction mixture. Heated reaction to reflux, and continued heating at reflux overnight. Cooled reaction to ambient temperature, then filtered mixture through GF/F paper, rinsing multiple times with diethyl ether. Diluted the filtrate with EtOAc (15 mL) and ether (15 mL) and washed organic phase with water (20 mL), aqueous saturated NaHC03 (20 mL), then brine (20 mL). The organic phase was dried (MgS04), filtered, and concentrated. Yield: 1.39 g (68%). Carried crude product forward to the next step without purification.
[00884] Step E: Preparation of 3-(2-bromo-4-(methoxymethyl)phenyl)cyclobutanone: Added 3-(2-bromo-4-(methoxymethyl)phenyl)-2,2-dichlorocyclobutanone (1.39 g, 4.1 1 mmol) dissolved in acetic acid (5 mL) to a stirred suspension of zinc dust (1.08 g, 16.4 mmol) in acetic acid (10 mL) that was cooled in an ice bath. Heated the mixture to 70 °C for 2 hours. After cooling to ambient temperature, concentrated the mixture in vacuo. Partitioned residue between Et20 (30 mL) and washed organic phase with water (20 mL), aqueous saturated NaHC03 (20 mL), and brine (20 mL). The organic phase was dried (MgSC^), filtered, and concentrated. Yield: 1.09 g (84%). Carried product forward to the next step without purification.
[00885] Step F: Preparation of 2-bromo- 1 -(3 ,3 -difluorocyclobutyO-4-
(methoxymethyl)benzene : Charged a round bottomed flask plus stir bar with 3-(2-bromo-4- (methoxymethyl)phenyl)cyclobutanone (1.09 g, 4.05 mmol), anhydrous DCM (10 mL), and cooled in an ice bath under N2. Next added diefhylaminosulfur trifluoride (DAST) (1.07 mL, 8.10 mmol) drop wise. Removed ice bath after addition was complete and stirred overnight at ambient temperature. Poured reaction mixture into aqueous saturated NaHC03 (150 mL) stirred with ice chunks, then diluted mixture with more DCM (50 mL). Stirred for 2 hours, then separated phases. Re-extracted the aqueous layer with more DCM (50 mL). The combined organic phases were dried (MgS04), filtered, and concentrated. Purifed crude by RediSep 80 silica gel column, eluting with a gradient of neat hexanes to 10% EtOAc/hexanes. Yield: 720 mg (52%).
[00886] Step G: Preparation of 2-(3.3-difluorocvclobutvn-5- (methoxymethyl)benzonitrile: Charged a stainless steel bomb containing a teflon insert plus stir bar with 2-bromo-l-(3,3-difluorocyclobutyl)-4-(methoxymethyl)benzene (670 mg, 2.30 mmol), DMA (5 mL), Pd(PPh3)4 (266 mg, 0.230 mmol), and Zn(CN)2 (270 mg, 2.30 mmol). Sparged with N2 for several minutes, then sealed up bomb and heated to 130 °C for 2 days. After cooling to ambient temperature, the reaction mixture was partitioned between EtOAc (20 mL) and aqueous saturated NaHC03 (20 mL). Separated phases, then re-extracted aqueous with EtOAc (10 mL). Washed organic phase with water (3 x 20 mL), brine (20 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by Redi-Sep 40 silica gel column, eluting with a gradient of 10%-20% EtOAc/hexanes. Yield: 337 mg (59%).
[00887] Step H: Preparation of (2-(3.3-difluorocvclobutylV5- (methoxymethyDphenyl)methanamine: The title compound was prepared from 2 -(3, 3- difluorocyclobutyl)-5-(methoxymethyl)benzonitrile (200 mg, 0.84 mmol) according to the procedure provided for Example 33, Step D. Yield: 195 mg (91%).
[00888] Step I: Preparation of l-(2-(3.3-difluorocvclobutyl)-5- (methoxymethyl)benzyl)-3-(l ',4-dimethyl- 1 -phenyl- 1 H.1 'H- 3,4'-bipyrazoll-5-yl)urea: The title compound was prepared from (2-(3,3-difluorocyclobutyl)-5- (methoxymethyl)phenyl)methanamine (25 mg, 0.10 mmol) and phenyl (l',4-dimethyl-l- phenyl-lH,rH-[3,4'-bipyrazol]-5-yl)carbamate from (Intermediate 5, 39 mg, 0.10 mmol) according to the procedure provided for Example 33, Step E. Purified crude product by preparative TLC (0.5 mm thickness, Rf = 0.44) eluting with 10% MeOH/DCM. Yield: 34 mg (60%). MS m/z (APCI-pos) M+l = 521.
Example 39
Figure imgf000211_0001
l-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(l-phenyl-2-o- tolylethyPurea
[00889] Step A: Preparation of l-phenyl-2-o-tolylethanamine. Phenylmagnesium chloride (3M in ether, 766 μί, 2.29 mmol) was added dropwise to a solution of 2-o- tolylacetonitrile (100 mg, 0.762 mmol) in ether (1 mL) at ambient temperature. The reaction was stirred for 2 hours and MeOH (2 mL) added slowly (very exothermic!). NaBH4 (115 mg, 3.05 mmol) was added in small portions and the reaction was stirred overnight and poured into a mixture of IN NaOH (13 mL) and Brine (15 mL). The mixture was extracted with EtOAc (suspension that separated after a few minutes) and the organic extract was washed with brine, dried (MgS04) and concentrated to provide the title compound (155 mg, 0.734 mmol, 96.2 % yield). MS (apci) m/z = 212.1 (M+H).
[00890] Step B: Preparation of 1 -(2-phenyl-2 A5,6-tetrahydrocvclopenta[c}pyrazol-3- yl)-3 -( 1 -phenyl-2-o-tol ylethvDurea. l-phenyl-2-o-tolylethanamine (8 mg, 0.038 mmol), phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (10 mg, 0.032 mmol) and DIEA (4.1 mg, 0.032 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was loaded onto a samplet and purified by reverse- phase column chromatography, eluting with 0-80% acetonitrile/water, to afford the title compound (4.4 mg, 0.010 mmol, 32 % yield). MS (apci) m/z = 437.2 (M+H).
[00891] Table 1 provides a list of commercially available amines that were used in the synthesis of the compounds described in Table 2.
Table 1
Figure imgf000212_0001
Structure Vendor/Catalog# CAS#
NH2
o6 Ryan Scientific/ EN300-30476 91245-72-6
[00892] The compounds in Table 2 were prepared by reacting the appropriate amine from Table 1 with the appropriate intermediate phenylcarbamate using the method as described for Example 39, Step 2.
Table 2
Figure imgf000213_0001
Figure imgf000214_0001
[00893] Table 3 provides a list of commercially available nitriles that were used in the synthesis of the compounds described in Table 4.
Table 3
Figure imgf000214_0002
[00894] The compounds in Table 4 were prepared by reacting the appropriate nitrile from Table 3 with either phenylmagnesium chloride or benzylmagnesium chloride and then elaborating using the method as described for Example 39.
Table 4
Example # Structure Name MS (apci) m/z
1 -(2-(2-chlorophenyl)- 1 - phenyl ethyl)-3 -(2 -phenyl -
°γΝΗ
45 2,4,5,6- 457.2 (M+H)
HN tetrahydrocyclopenta[c]pyr
azol-3-yl)urea Example # Structure Name MS (apci) m/z
1 -( 1 -(2-chlorophenyl)-3 - phenylpropan-2-yl)-3-(2-
471.2 (M+H)
46 phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyr
HN
azol-3-yl)urea
1 -( 1 -(3 ,4-difluorophenyl)-
3-phenylpropan-2-yl)-3-(2-
47
phenyl-2,4,5,6- 473.2 (M+H).
HN tetrahydrocyclopenta[c]pyr
azol-3-yl)urea
1 -( 1 -(2-methoxyphenyl)-3- phenylpropan-2-yl)-3-(2-
48
°γΝΗ phenyl-2,4,5,6- 467.2 (M+H).
tetrahydrocyclopenta[c]pyr
HN
azol-3-yl)urea
l-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyr
49 ΟγΝΗ azol-3-yl)-3-(5,5,5- 443.2 (M+H).
HN trifluoro- 1 -phenylpentan-2- yl)urea
Example 50
Figure imgf000215_0001
-<T 1.1 '-biphenyll-2-ylmethyl)-3-(l '.4-dimethyl- 1 -phenyl- 1 H.1 'H-r3.4'-bipyrazon-5-yl)urea [00895] To a solution of [l,r-biphenyl]-2-ylmethanamine (12 mg, 0.065 mmol) in DCM (1 mL) were added phenyl (l *,4-dimethyl-l-phenyl-lH,l 'H-[3,4'-bipyrazol]-5- yl)carbamate (Intermediate 5, 24.5 mg, 0.065 mmol) then DIEA (0.023 mL, 0.131 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then purified by reverse- phase column chromatography, eluting with 0-85% acetonitrile/water, to afford the title compound as a white solid (10 mg, 0.022 mmol, 34% yield). MS (apci) m/z = 463.2 (M+H).
Example 51
Figure imgf000216_0001
5-(3-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)ureido)-N,4-dimethyl-l-phenyl-lH- pyrazole-3-carboxamide
[00896] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl-lH-pyrazol-5-amine with 3-(6-methoxypyridin-3-yl)-4- methyl-1 -phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (21%). MS (APCI) m/z = 524.2 (M+H).
Example 52
Figure imgf000216_0002
l-(2-(difluoromethoxy)-5-(methoxymethyl)benzylV3-(3-(5-methoxypyridin-3-yl)-4-methyl-
1 -phenyl- 1 H-pyrazol-5-vPurea
[00897] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5 -yl)- 1 -phenyl- 1 H-pyrazol-5 -amine with 3 -(5 -methoxypyridin-3 -yl)-4- methyl-1 -phenyl- lH-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (27%). MS (APCI) m/z = 524.2 (M+H).
Example 53
Figure imgf000217_0001
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzvn-3-(3-(6-methoxypyridin-3-vn-4-methyl-
1 -phenyl- 1 H-pyrazol-5 -vPurea
[00898] Prepared according to the procedure of Example 1 , substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 3-(6-methoxypyridin-3-yl)-4- methyl-1 -phenyl- lH-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyI)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (43%). MS (APCI) m/z = 542.2 (M+H).
Example 54
Figure imgf000217_0002
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(3-(5-methoxypyridin-3-yl)-4-methyl-
1 -phenyl- 1 H-pyrazol-5 -vDurea
[00899] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5 -amine with 3-(5-methoxypyridin-3 -yl)-4- methyl-1 -phenyl- lH-pyrazol-5 -amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (49%). MS (APCI) m/z = 542.2 (M+H).
Example 55
Figure imgf000218_0001
5-(3-(5-(methoxymethyl -2-(trifluoromethoxy benzyl)ureido)-N,4-dimethyl-l-phenyl-lH- pyrazole-3 -carboxamide
[00900] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 5-amino-N,4-dimethyl- 1 -phenyl- 1 H-pyrazole-3 -carboxamide and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (49%). MS (APCI) m/z = 492.2 (M+H).
Example 56
Figure imgf000218_0002
5-(3-(2- difluoromethoxy)-5-(methoxymethyl)benzyl)ureido)-N,4-dimethyl-l-phenyl-lH- pyrazole-3 -carboxamide
[00901] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 5-amino-N,4-dimethyl- 1 -phenyl- 1 H-pyrazole-3 -carboxamide and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-(methoxymethyl)phenyl)methanamine to give the title compound (39%). MS (APCI) m/z = 474.2 (M+H).
Example 57
Figure imgf000219_0001
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(2-phenyl-4,6-dihvdro-2H-thieno 3,4- c]pyrazol-3-yl)urea
[00902] Prepared according to the procedure of Example 2, substituting phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (2-phenyl-4,6-dihydro- 2H-thieno[3,4-c]pyrazol-3-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (40%). MS (APCI) m/z = 477.1 (M-H).
Example 58
Figure imgf000219_0002
l-(5,5-dioxido-2-phenyl-4,6-dihvdro-2H-thienof3,4-c]pyrazol-3-yl)-3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)urea
[00903] Prepared according to the procedure of Example 2, substituting phenyl (3- ethoxy-4-methyl-l -phenyl- lH-pyrazol-5-yl)carbamate with phenyl (5,5-dioxido-2-phenyl- 4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (41%). MS (APCI) m z = 511.1 (M-H). Example 59
Figure imgf000220_0001
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl -3-(3-(2-methoxypyrimidin-5-yl)-4- methyl- 1 -phenyl- 1 H-pyrazol-5-vDurea
[00904] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5 -amine with 3-(2-methoxypyrimidin-5-yl)-4- methyl-1 -phenyl- lH-pyrazol-5 -amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (21%). MS (APCI) m/z = 543.2 (M+H).
Example 60
1 -(3-(2-fluoroethoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzvDurea
[00905] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 3 -(2-fluoroethoxy)-4-methyl- 1 - phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (20%). MS (APCI) m/z = 497.2 (M+H). Example 61
Figure imgf000221_0001
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzvn-3-(4-methyl-3-((5-methyl-1.3,4- oxadiazol-2-yl)methoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[00906] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- 1 H-pyrazol-5-amine with 4-methyl-3 -((5 -methyl- 1,3,4- oxadiazol-2-yl)methoxy)- 1 -phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl-5 -
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifiuoromethoxy)phenyl)methanamine to give the title compound (38%). MS (APCI) m/z = 545.2 (M-H).
Example 62
Figure imgf000221_0002
l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3-(3-(2-methoxypyrimidin-5-yl)-4- methyl- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[00907] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 3-(2-methoxypyrimidin-5-yl)-4- methyl-1 -phenyl- lH-pyrazol-5-amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (15%). MS (APCI) m/z = 523.2 (M-H).
Figure imgf000222_0001
1 -(3 -(2-hvdroxyethoxy)-4-methyl-l -phenyl- 1 H-pyrazol-5-y0-3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)urea
[00908] Step A: Preparation of l-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4- methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with 3-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine and (2-cyclopropyl- 5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (44%).
[00909] Step B: Preparation of 1 -(3 -(2-hydroxyethoxy)-4-methyl-l -phenyl- 1H- pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: To a round bottom flask containing 1 -(3 -(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl- 1 -phenyl- 1 H- pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea (0.027 g, 0.044 mmol) was added 0.3 mL of AcOH, 0.1 mL of THF, and 0.1 mL of water. This mixture was warmed to 65 °C for 2 hours and then allowed to cool to ambient temperature. The mixture was diluted with EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC. The fractions containing the product were combined in 10% aqueous potassium carbonate and extracted with EtOAc. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to provide 15 mgs (68%) of the title compound. MS (APCI) m/z = 493.2 (M-H).
Figure imgf000223_0001
5-(3 -(5 -bromo-2-(trifluoromethoxy benzyl)ureidoVN,4-dimethyl- 1 -phenyl- 1 H-pyrazole-3 - carboxamide
[00910] Step A: Preparation of 5-bromo-2-(trifluoromethoxy)benzaldehyde oxime: A flask equipped with a nitrogen inlet was charged with 5-bromo-2- (trifluoromethoxy)benzaldehyde (1.00 g, 3.72 mmol), 30 mL of ethanol, and 10 mL of water. To this was added hydroxylamine hydrochloride (0.387 g, 5.58 mmol). This mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide 900 mgs of 5-bromo-2-(trifluoromethoxy)benzaldehyde oxime as a white solid.
[00911] Step B: (5-bromo-2-(trifluoromethoxy)phenyl)methanamine: A flask equipped with a nitrogen inlet was charged with 5-bromo-2-(trifluoromethoxy)benzaldehyde oxime (0.500 g, 1.76 mmol) and 20 mL of AcOH. To this was added zinc dust (0.460 g, 7.04 mmol) and the mixture was warmed to 70 °C for 16 hours, then allowed to cool to ambient temperature. The mixture was filtered through GF/F filter paper and the filtrate was concentrated under reduced pressure. The resulting crude material was taken up in EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 386 mgs of (5-bromo-2- (trifluoromethoxy)phenyl)methanamine as an oil.
[00912] Step C: Preparation of 5-(3-(5-bromo-2-(trifluoromethoxy)benzyl)ureido)- N,4-dimethyl-l -phenyl- lH-pyrazole-3 -carboxamide: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl-lH-pyrazol-5-amine with 5-amino-N,4-dimethyl-l-phenyl-lH-pyrazole-3-carboxamide and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-bromo-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (1 1%). MS (APCI) m/z— 524.1 (M+H). Example 65
Figure imgf000224_0001
(R)-l-(,3-(2 -dihydroxypropoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5- (memoxymethy0-2-(trifluoromethoxy)benzyl urea
[00913] Step A: Preparation of (S)-l-(3-((2,2-dimethyl-l ,3-dioxolan-4-yl)methoxy)-4- methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 1 , substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (S)-3-((2,2-dimethyl-l,3-dioxolan- 4-yl)methoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5 -amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine (54%).
[00914] Step B: Preparation of R)-l -(3 -(2,3 -dihydroxypropoxy)-4-methyl-l -phenyl - lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: A round bottom flask was charged with (S)-l-(3-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-4-methyl-l- phenyl-1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea (0.025 g, 0.044 mmol), 1 mL of THF and 1 mL of IN aqueous HC1. This mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with 10% aqueous potassium carbonate (20 mL), extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC. The fractions containing the product were combined in 10% aqueous potassium carbonate and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give 1 1 mgs (47%) of the title compound as a white solid. MS (APCI) m/z = 523.2 (M-H). Example 66
Figure imgf000225_0001
l-(5-(methoxymethyl -2-(trifluoromethoxy benzyl)-3-(4-methyl-l-phenyl-3-(pip
1 H-pyrazol-5-yl)urea
[00915] Step A: Preparation of tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)piperidine- 1 - carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- 1 H-pyrazol-5-amine with 4 tert-butyl 4-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)piperidine- 1 -carboxylate and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (58%).
[00916] Step B: Preparation of l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3- (4-methyl-l-phenyl-3-(piperidin-4-yl)-lH-pyrazol-5-yl)urea: A round bottom flask was charged with tert-butyl 4-(5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4- methyl-1 -phenyl- lH-pyrazol-3-yl)piperidine-l -carboxylate (0.050 g, 0.081 mmol) and 1 mL of TFA. The mixture was stirred at ambient temperature for 2 hours, then concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC. The fractions containing the product were combined in 10% aqueous potassium carbonate and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (55%). MS (APCI) m/z = 518.3 (M+H).
Example 67
Figure imgf000225_0002
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzvn-3-(4-methyl-l-phenyl-3-(piperidin-4- ylmethoxy )- 1 H-pyrazol-5-yl urea
[00917] Step A: Preparation of tert-butyl 4-(((5-amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)methyl)piperidine-l -carboxylate: A pressure tube containing a stir bar was charged with 5-amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one (0.500 g, 2.64 mmol) and 26 mL of DMA. To this was added tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate (0.775 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.29 mmol). The tube was sealed and heated to 110 °C for 16 hours. The mixture was poured into 200 mL of water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was passed through an 80 g Redi Sep column, eluting with 1 :1 ethyl acetate/hexane, to give 423 mgs of t the title compound (41%).
[00918] Step B: Preparation of tert-butyl 4-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)piperidine-l -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with tert- butyl 4-(5-amino-4-methyl-l -phenyl- 1 H-pyrazol-3 -yl)piperidine-l -carboxylate and (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (36%).
[00919] Step C: Preparation of l-(5-(methoxymethyl)-2-(trifiuoromethoxy)benzyl)-3- (4-methyl-l-phenyl-3-(piperidin-4-ylmethoxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 67, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)piperidine- 1 - carboxylate with tert-butyl 4-(((5-amino-4-methyl-l -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)piperidine-l -carboxylate to give the title compound (59%). MS (APCI) m/z = 548.3 (M+H).
Example 68
Figure imgf000226_0001
5-(3-(5-(methoxymethyl)-2-(2,2,2-trifluoroethoxy)benzynureido)-N,4-dimethyl-l-pheny|- 1 H-pyrazole-3 -carboxamide
[00920] Step A: Preparation of 5-bromo-2-(2,2,2-trifluoroethoxy)benzonitrile: A round bottom flask was charged with 5-bromo-2-hydroxybenzonitrile (5.00 g, 25.3 mmol), dry DMF (100 mL), cesium carbonate (16.5 g, 50.5 mmol) and 2,2,2-trifluoroethyl 4- methylbenzenesulfonate (7.70 g, 30.3 mmol). This mixture was warmed to 60 °C for 2 hours. Approximately 250 mgs of TBAI were added and the mixture was warmed to 100 °C for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water, extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was passed through a 120 g Redi Sep column, eluting with 10% ethyl acetate/hexane, and then by preparative TLC (6 x 1 mm plates, 5% ethyl acetate/hexane, eluted multiple times) to give 5- bromo-2-(2,2,2-trifluoroethoxy)benzonitrile (contaminated with a small amount of the tosylate).
[00921] Step B: Preparation of 5-(methoxymethyl)-2-(2,2,2- trifluoroethoxy)benzonitrile: A round bottom flask was charged with 5-bromo-2-(2,2,2- trifluoroethoxy)benzonitrile (940 mgs, 3.36 mmol) and 33 mL of dioxane. To this was added cesium carbonate (5.03 mL, 10.1 mmol, 2M aqueous solution), potassium methoxymethyl trifluoroborate (867 mgs, 5.71 mmol), and l,l'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (274 mgs, 0.336 mmol). This mixture was heated to 100 °C for 24 hours, then allowed to cool to ambient temperature. The mixture was diluted with water/EtOAc, and filtered through GF/F filter paper. The combined organic layers were isolated, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was passed through a 120 g Redi Sep column, eluting with 15% ethyl acetate/hexane to give the title compound (44%).
[00922] Step C: Preparation of (5-(methoxymethyl)-2-(2,2,2- trifluoroethoxy)phenyl)methanamine: A round bottom flask equipped with a reflux condenser was charged with 5-(methoxymethyl)-2-(2,2,2-trifluoroethoxy)benzonitrile (0.355 g, 1.45 mmol) and dry THF (14 mL). LAH (2.90 mL, 2.90 mmol, 1M in THF) was added and the mixture was heated to reflux for 2 hours, then allowed to cool to ambient temperature. The reaction mixture was carefully quenched with 0.11 mL of water, 0.11 mL of 15% aqueous NaOH, and then 0.33 mL of water. The mixture was stirred vigorously for 15 minutes and then diluted with MTBE. The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound (92%) as an oil.
[00923] Step D: Preparation of 5-(3-(5-(methoxymethyl)-2-(2,2,2- trifluoroethoxy)benzyl)ureido)-N,4-dimethyl- 1 -phenyl- 1 H-pyrazole-3-carboxamide:
Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5 -amine with 5-amino-N,4-dimethyl- 1 -phenyl- 1 H-pyrazole-3-carboxamide and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-(2,2,2-trifluoroethoxy)phenyl)methanamine to give the title compound (11%). MS (APCI) m/z = 504.1 (M-H).
Example 69
Figure imgf000228_0001
l-(5-(methoxymethyl)-2-('2,2,2-trifluoroethoxy)benzyl)-3-(3-(2-methoxypyrimidin-5-vn-4- methyl- 1 -phenyl- 1 H-pyrazol-5 -yPurea
[00924] Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl-1 H-pyrazol-5 -amine with 3-(2-methoxypyrimidin-5-yl)-4- methyl-1 -phenyl- 1 H-pyrazol-5 -amine and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-(2,2,2- trifluoroethoxy)phenyl)methanamine to give the title compound (10%). MS (APCI) m/z = 557.3 (M+H).
Example 70
Figure imgf000228_0002
1 -(3-((4-fluoropiperidin-4-yl)methoxy)-4-methyl- 1 -phenyl-1 H-pyrazol-5-yl)-3-( 5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[00925] Step A: Preparation of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate: To a 0 °C solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-l,4-dicarboxylate (5.0 g, 18.16 mmol) in 90 mL THF was added 1M lithium aluminum hydride in THF (36.32 mL, 36.32 mmol) slowly by syringe. The reaction mixture was stirred at 0 °C for 1 hour and then quenched by the slow addition of 1 :1 Na2SO4/10 H20:Celite. The mixture was then diluted with additional THF, warmed to ambient temperature, and stirred vigorously for 2 hours. The slurry was vacuum filtered through GF/F paper on a Buchner funnel and rinsed with THF. The filtrate was concentrated in vacuo to give the title compound (4.0 g, 94.42 % yield) as a thick oil. The crude material was used in the next step without further purification.
[00926] Step B: Preparation of tert-Butyl 4-fluoro-4-
(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate: To a 0 °C solution of tert-butyl 4- fluoro-4-(hydroxymethyl)piperidine-l-carboxylate (3.50 g, 15.0 mmol) and TEA (5.23 mL, 37.5 mmol) in 90 mL DCM was added neat MsCl (2.09 mL, 27.0 mmol) dropwise by syringe. The mixture was allowed to gradually warm to ambient temperature and stirred for 17 hours. The reaction was cooled to 0 °C, and an additional 1.5 equivalents of TEA and 1.1 equivalents of MsCl were added. The reaction mixture was allowed to warm to ambient temperature and then saturated NaHC03 was added. The mixture was extracted with DCM, and combined extracts were dried (Na2S04), filtered, and concentrated under reduced pressure. The crude material was purified on an SP1 (Snap 340g) column. The fractions containing product were concentrated, then concentrated twice from ether to give solids which were dried under vacuum to give the title compound (4.20 g, 89.9 % yield) as a white powder.
[00927] Step C: Preparation of tert-butyl 4-(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol- 3-yl)oxy)methyl)-4-fluoropiperidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with tert-butyl 4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-l-carboxylate to give the title compound (58%).
[00928] Step D: Preparation of tert-butyl 4-fluoro-4-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)piperidine-l-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with tert- butyl 4-(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)-4-fluoropiperidine- 1 - carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (33%).
[00929] Step E: Preparation of l-(3-((4-fluoropiperidin-4-yl)methoxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l-carboxylate with tert-butyl 4-fluoro-4-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)piperidine-l-carboxylate to give the title compound (48%). MS (APCI) m/z = 566.3 (M+H).
Example 71
Figure imgf000230_0001
1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl- 1 -phenyl-3-(pyrrolidin-3- ylmethoxyV 1 H-pyrazol-5-yl)urea
[00930] Step A: Preparation of tert-butyl 3-(((5-amino-4-methyl-l-phenyl-lH- pyrazol-3-yl)oxy)methyl)pyrrolidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-l-carboxylate to give the title compound (48%).
[00931] Step B: Preparation of tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)pyrrolidine-l-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert- butyl 3-(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)pyrrolidine- 1 - carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (56%).
[00932] Step C: Preparation of l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-
(4-methyl-l-phenyl-3-(pyrrolidin-3-ylmethoxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)pyrrolidine-l -carboxylate to give the title compound (58%). MS (APCI) m/z = 534.3 (M+H).
Example 72
Figure imgf000231_0001
l-(3-(azetidin-3-ylmethoxy -4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl -2-
(trifluoromethoxy)benzvQurea
[00933] Step A: Preparation of tert-butyl 3-(hydroxymethyl)azetidine-l-carboxylate:
A round bottom flask equipped with a condenser was charged with dry THF (52 mL) and sodium borohydride (0.587 mgs, 22.99 mmol), followed by addition of 1 -(tert- butoxycarbonyl)azetidine-3-carboxylic acid (1.04 g, 5.17 mmol). The mixture was cooled to 0 °C, and iodine (1.31 mgs, 5.17 mmol) in 10 mL of THF was added over a 10 minute period to the reaction mixture. The reaction mixture was stirred at 0 °C for 15 minutes, then heated to reflux for 16 hours, during which time the iodine color was discharged. The mixture was then carefully quenched with methanol (20 mL). The reaction mixture was concentrated under reduced pressure and taken up in 200 mL of 20% aqueous KOH, and stirred at ambient temperature for 4 hours. The mixture was extracted with DCM, and the combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide 608 mgs (63%) of the title compound as an oil.
[00934] Step B: Preparation of tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l- carboxylate: A round bottom flask containing tert-butyl 3-(hydroxymethyl)azetidine-l- carboxylate (0.605 g, 3.23 mmol) and a stir bar was charged with dry DCM (30 mL) and DIEA (0.844 mL, 4.85 mmol). To this was added MsCl (0.275 mL, 3.55 mmol) and the mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with DCM, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated to provide a quantitative yield of the title compound as an oil.
[00935] Step C: Preparation of tert-butyl 3-(((5-amino-4-methyl-l -phenyl- lH-pyrazol- 3-yl)oxy)methyl)azetidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l-carboxylate to give the title compound (44%).
[00936] Step D: Preparation of tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)azetidine- 1-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3- (2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 3-(((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1 -carboxylate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (51%).
[00937] Step E: Preparation of l-(3-(azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH- pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)piperidine- 1 - carboxylate with tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1 -carboxylate to give the title compound (45%). MS (APCI) m/z = 520.2 (M+H).
Example 73
Figure imgf000232_0001
1 -(3 -((3 -fluoropyrrolidin-3 -yl)methoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3 -(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[00938] Step A: Preparation of methyl l-benzyl-3-fluoropyrrolidine-3-carboxylate: A flask equipped with a nitrogen inlet was charged with methyl 2-fluoroacrylate (2.00 g, 19.2 mmol) and dry DCM (77 mL). To this was added N-benzyl-l-methoxy-N- ((trimethylsilyl)methyl)methanamine (5.47 g, 23.1 mmol) and the mixture was cooled to 0 °C. To this was added TFA (0.740 mL, 9.61 mmol) and the mixture was allowed to warm to ambient temperature overnight. The mixture was concentrated under reduced pressure and the crude material was passed through a 120 g Redi Sep column, eluting with 3:1 Hexane/ethyl acetate, to give the title compound (48%).
[00939] Step B: Preparation of 1 -tert-butyl 3-methyl 3-fluoropyrrolidine-l,3- dicarboxylate: A round bottom flask was charged with methyl l-benzyl-3-fluoropyrrolidine- 3-carboxylate (2.20 g, 9.27 mmol) and 45 mL of EtOAc. To this was added BOC anhydride (2.23 g, 10.2 mmol) and Pearlman's catalyst (2 g, 20 % Pd(OH)2, Degussa type) and the mixture was hydrogenated under a balloon of hydrogen for 2 hours and then purged with nitrogen. The reaction mixture was filtered under a nitrogen atmosphere through GF/F filter paper, and the filtrate was concentrated under reduced pressure to give the title compound (91%) as an oil.
[00940] Step C: Preparation of tert-butyl 3-fluoro-3-(hydroxymethyl)pyrrolidine-l- carboxylate: A flask equipped with a nitrogen inlet was charged with 1 -tert-butyl 3 -methyl 3-fluoropyrrolidine- 1,3 -dicarboxylate (2.08 g, 8.41 mmol) and dry THF (42 mL). This mixture was cooled to 0 °C and LAH (10.1 mL, 10.1 mmol, 1M in THF) was then added and the mixture was stirred at 0 °C for 2 hours. The mixture was carefully quenched with 0.383 mL of water, 0.383 mL of 15% aqueous NaOH, and 1.15 mL of water. This mixture was vigorously stirred for 30 minutes, diluted with MTBE, and filtered through GF/F paper. The filtrate was concentrated under reduced pressure to provide the title compound (71%) as an oil.
[00941] Step D: Preparation of tert-butyl 3-fluoro-3-
(((methylsulfonyl)oxy)methyl)pyrrolidine-l-carboxylate: A flask equipped with a nitrogen inlet was charged with tert-butyl 3-fluoro-3-(hydroxymethyl)pyrrolidine-l -carboxylate (1.30 g, 5.93 mmol) and dry DCM (60 mL). To this was added DIEA (2.07 mL, 11.9 mmol) and the mixture was cooled to 0 °C. MsCl (0.815 g, 7.12 mmol) was added and the mixture was stirred at 0 °C for 2 hours. This mixture was diluted with 100 mL of DCM, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was passed through an 80 g Redi Sep column, eluting with 3:1 ethyl acetate/hexane, to provide the title compound as an oil (53%).
[00942] Step E: Preparation of tert-butyl 3-(((5-amino-4-methyl-l -phenyl- 1 H-pyrazol- 3-yl)oxy)methyl)-3-fluoropyrrolidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with tert-butyl 3-fluoro-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-l- carboxylate to give the title compound (32%).
[00943] Step F: Preparation of tert-butyl 3-fluoro-3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)pyrrolidine-l-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with tert- butyl 3 -(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)-3 -fluoropyrrolidine- 1 - carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (48%).
[00944] Step G: Preparation of l-(3-((3-fluoropyrrolidin-3-yl)methoxy)-4-methyl-l- phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)piperidine- 1 -carboxylate with tert-butyl 3-fluoro-3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)pyrrolidine-l -carboxylate to give the title compound (59%). MS (APCI) m/z = 552.2 (M+H).
Example 74
Figure imgf000234_0001
l-(3-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3- (5-(,methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[00945] Prepared according to the procedure of Example 1 , substituting 4-methyl-3-(2- methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)- 1 ,3 -dimethylpyridin-2( 1 H)-one and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (29%). MS (APCI) m/z = 554.2 (M-H). Example 75
Figure imgf000235_0001
l-(5-(methoxymethyl -2-(trifluoromethoxy benzyl)-3-(4-methyl-3-((l-methylazeti
vDmethoxyV 1 -phenyl- 1 H-pyrazol-5-yl)urea
[00946] A round bottom flask containing l-(3-(azetidin-3-ylmethoxy)-4-methyl-l- phenyl-1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea (0.020 g, 0.0385 mmol) was charged with THF (0.5 mL), followed by 37% aqueous formaldehyde (2.87 μΐ,, 0.0385 mmol) and sodium triacetoxyborohydride (0.01 12 g, 0.05 mmol). The mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The crude material was taken up in 1M aqueous NaOH (5 mL) and stirred at ambient temperature for 1 hour, then extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated. The crude material was purified by reverse phase chromatography to give the title compound (20%). MS (APCI) m/z = 534.2 (M-H).
Example 76
Figure imgf000235_0002
1 -(3-((3 -fluoro- 1 -methylpyrrolidin-3 -yl)methoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3 -(5 - (methoxymethyl)-2-(trifluoromethoxy)benzyl urea
[00947] Prepared according to the procedure of Example 75, Step A, substituting l-(3-
(azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(3-((3-fluoropyrrolidin-3-yl)methoxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea, to give the title compound (16%). MS (APCI) m/z = 566.2 (M+H). Example 77
Figure imgf000236_0001
l-(5-(methoxymethylV2-(trifluoro
pyrazol-5-yl)urea
[00948] Step A: Preparation of 4-methyl-3-phenoxy-l-phenyl-lH-pyrazol-5-amine: A round bottom flask containing 5-amino-4-methyl-l -phenyl- lH-pyrazol-3(2H)-one (0.050 g, 0.264 mmol) was charged with 1,2-DCE (2.5 mL), phenyl boronic acid (0.084 g, 0.687 mmol), copper acetate (0.072 g, 0.396 mmol), pyridine (0.064 g, 0.806 mmol), and powdered 4 A molecular sieves (100 mgs). The mixture was stirred at ambient temperature for 16 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The crude material was purified through a 24 g edi Sep column, eluting with 100% ethyl acetate, to give the title compound (57%).
[00949] Step B: Preparation of l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3- (4-methyl-3-phenoxy-l-phenyl-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5- amine with 4-methyl-3-phenoxy-l-phenyl-lH-pyrazol-5-amine and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (16%). MS (APCI) lz = 525.2 (M-H).
Figure imgf000237_0001
1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl- 1 -phenyl-3-(piperidin-4- yloxyV 1 H-pyrazol-5-yl urea
[00950] Step A: Preparation of tert-butyl 4-((5-amino-4-methyl-l -phenyl- 1 H-pyrazol-
3- yl)oxy)piperidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with tert- butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate to give the title compound (34%).
[00951] Step B: Preparation of tert-butyl 4-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)piperidine- 1 - carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 4-((5-amino-4-methyl-l- phenyl- 1 H-pyrazol-3 -yl)oxy)piperidine- 1 -carboxylate and (2-cyclopropyl-5 - (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (45%).
[00952] Step C: Preparation of 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3- (4-methyl-l-phenyl-3-(piperidin-4-yloxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with tert-butyl 4-((5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-
4- methyl-l -phenyl- 1 H-pyrazol-3 -yl)oxy)piperidine-l -carboxylate to give the title compound (48%). MS (APCI) m/z = 534.2 (M+H).
Figure imgf000238_0001
1 -(3-(2-azaspiro[3.3]heptan-6-yloxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-(5- (methoxymethyl)-2-('trifluoromethoxy)benzyl)urea
[00953] Step A: Preparation of tert-butyl 6-((methylsulfonyl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l-carboxylate with tert- butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate to give the title compound (75%).
[00954] Step B: Preparation of tert-butyl 6-((5-amino-4-methyl-l -phenyl- lH-pyrazol- 3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate to give the title compound (48%).
[00955] Step C: Preparation of tert-butyl 6-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate: Prepared according to the procedure of Example 1 , substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with tert- butyl 6-((5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (55%).
[00956] Step D: Preparation of l-(3-(2-azaspiro[3.3]heptan-6-yloxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l-carboxylate with tert-butyl 6-((5-amino-4-methyl-l-phenyl-lH-pyrazol-3- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate to give the title compound (59%). MS (APCI) m/z = 546.2 (M+H).
Example 80
Figure imgf000239_0001
l-(3-(( 3S^R)-4-fluoropyrrolidin-3-yl)oxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5- (ηΐ6ί1ιοχνηΐ6ΐ1ΐν1 -2-(ίπιΐηοΓοη 6ΐ1ιοχν^εηζνΠ^63
[00957] Step A: Preparation of (3R,4R)-tert-butyl 3-fluoro-4-
((methylsulfonyl)oxy)pyrrolidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (3R,4R)-tert-butyl 3 -fluoro-4-hydroxypyrrolidine-l -carboxylate to give the title compound (90%).
[00958] Step B: Preparation of (3 S,4R)-tert-butyl 3-((5-amino-4-methyl-l-phenyl-lH- pyrazol-3-yl)oxy)-4-fluoropyrrolidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (3R,4R)-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate to give (3S,4R)-tert-butyl 3-((5-amino-4-methyl-l -phenyl- lH-pyrazol-3-yl)oxy)- 4-fluoropyrrolidine- 1 -carboxylate ( 18%).
[00959] Step C: Preparation of (3R,4S)-tert-butyl 3-fluoro-4-((5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)pyrrolidine-l -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3 -(2-methylpyrimidin-5 -yl)- 1 -phenyl- 1 H-pyrazol-5-amine with (3S,4R)-tert-butyl 3-((5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)-4-fluoropyrrolidine- 1 -carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (45%).
[00960] Step D: Preparation of l-(3-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea:
Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)piperidine-l-carboxylate with (3R,4S)-tert-butyl 3-fiuoro-4-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)pyrrolidine- 1 - carboxylate to give the title compound. (47%). MS (APCI) m/z = 538.2 (M+H).
Example 81
Figure imgf000240_0001
l-(3-(((3S,4R)-4-fluoro-l-methylpyrrolidin-3-yl)oxy -4-methyl-l-phenyl-lH-pyrazol-5-yl -
3-(5-(methoxymethyl -2-(trifluoromethoxy)benzyl urea
[00961] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with l-(3-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea to give the title compound (14%). MS (APCI) m/z = 552.2 (M+H).
Example 82
Figure imgf000240_0002
(R)-l-(5-(methQxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl-3-((l-methylpyrrolidin-
3-yl)oxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[00962] Prepared according to the procedure of Example 75, Step A, substituting l-(3-
(azetidin-3-ylmethoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with (R)-l -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)- 3-(4-methyl-l-phenyl-3-(pyrrolidin-3-yloxy)-lH-pyrazol-5-yl)urea, to give the title compound (6%). MS (APCI) m/z = 534.2 (M+H). Example 83
Figure imgf000241_0001
(S -(5-(methoxymethyiy2-(trifluorom
3-yloxy)-lH-pyrazol-5-yl urea
[00963] Step A: Preparation of (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert- butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate with (R)-tert-butyl 3- hydroxypyrrolidine-l-carboxylate to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine- l-carboxylate (100%).
[00964] Step B: Preparation of (S)-tert-butyl 3-((5-amino-4-methyl-l-phenyl-lH- pyrazol-3-yl)oxy)pyrrolidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate to give the title compound (40%).
[00965] Step C: Preparation of (S)-tert-butyl 3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)pyrrolidine- 1 - carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (S)-tert-butyl 3-((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)pyrrolidine- 1 -carboxylate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (33%).
[00966] Step D: Preparation of (S)-l-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)-3 -(4-methyl- 1 -phenyl-3 -(pyrrolidin-3 -yloxy)- 1 H-pyrazol-5- yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl-l-phenyl-lH- pyrazol-3-yl)piperidine-l -carboxylate with (S)-tert-butyl 3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)pyrrolidine- 1 - carboxylate to give the title compound (19%). MS (APCI) m/z = 520.2 (M+H). Example 84
Figure imgf000242_0001
(R)-l-(5-(methoxymethylV2-(trifl
3-yloxy)-lH-pyrazol-5-yl urea
[00967] Step A: Preparation of (S)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert- butyl 4-fluoro-4-(hydroxymethyl)piperidine-l-carboxylate with (S)-tert-butyl 3- hydroxypyrrolidine-l-carboxylate to give the title compound (100%).
[00968] Step B: Preparation of (R)-tert-butyl 3-((5-amino-4-methyl-l-phenyl-lH- pyrazol-3-yl)oxy)pyrrolidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with (S)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate to give the title compound (48%).
[00969] Step C: Preparation of (R)-tert-butyl 3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy pyrrolidine- 1 - carboxylate: Prepared according to the procedure of Example 1 , substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- 1 H-pyrazol-5-amine with (R)-tert-butyl 3-((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy pyrrolidine- 1 -carboxylate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (57%).
[00970] Step D: Preparation of (R)-l-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)-3-(4-methyl-l-phenyl-3-(pyrrolidin-3-yloxy)-lH-pyrazol-5- yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl-l-phenyl-lH- pyrazol-3-yl)piperidine-l -carboxylate with (R)-tert-butyl 3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy pyrrolidine- 1 - carboxylate to give the title compound (35%). MS (APCI) m/z = 520.2 (M+H). Example 85
Figure imgf000243_0001
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyn-3-(4-methyl-3-((2-methyl-2- azaspiro[3.3]heptan-6-yl)oxy)-l-phenyl-lH-pyrazol-5-yl)urea
[00971] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(3-(2-azaspiro[3.3]heptan-6-yloxy)-4-methyl-l -phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea, to give the title compound (6%). MS (APCI) m/z = 560.2 (M+H).
Example 86
Figure imgf000243_0002
l-(3-((3-fluoroazetidin-3-yl methoxy)-4-methyl-l-phenyl-lH-pyrazol-5-vn-3-(5- (methoxymethvn-2-(trifluoromethoxy)benzyl)urea
[00972] Step A: Preparation of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-l- carboxylate: Prepared as outlined in Van Hende, et al., J. Org. Chem. 2009, 74, 2250-2253.
[00973] Step B: Preparation of tert-butyl 3-fluoro-3-
(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with tert-butyl 3 -fluoro-3-(hydroxymethyl)azetidine-l -carboxylate to give the title compound (86%).
[00974] Step C: Preparation of tert-butyl 3-(((5-amino-4-methyl-l -phenyl- lH-pyrazol-
3-yl)oxy)methyl)-3-fluoroazetidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with tert-butyl 3-fluoro-3-(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate to give the title compound (40%).
[00975] Step D: Preparation of tert-butyl 3-fluoro-3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)azetidine- 1 -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3- (2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 3-(((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)-3 -fluoroazetidine- 1 -carboxylate and (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (61%).
[00976) Step E: Preparation of l-(3-((3-fluoroazetidin-3-yl)methoxy)-4-methyl-l- phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l -carboxylate with tert-butyl 3-fluoro-3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1 -carboxylate to give the title compound (64%). MS (APCI) m/z = 538.2 (M+H).
Example 87
Figure imgf000244_0001
1 -(3 -(((3 S.4SV 3 -fluoropiperidin-4-yl)methoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3 -C5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[00977] Step A: Preparation of tert-butyl 3-fluoro-4-oxopiperidine-l -carboxylate: Prepared according to the procedure described in International patent publication WO 2008/124323 Al .
[00978] Step B: Preparation of (3S,4S)-tert-butyl 3-fiuoro-4-
(hydroxymethyl)piperidine- 1 -carboxylate
[00979] and (3S,4R)-tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-l-carboxylate: Prepared according to the procedure described in Koudih, R. et al., European Journal of Medicinal Chemistry, 2012, 53, p.408 - 415.
[00980] Step C: Preparation of (3S,4S)-tert-butyl 3-fluoro-4- (((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (3S,4S)-tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate to give the title compound (100%).
[00981] Step D: Preparation of (3S,4S)-tert-butyl 4-(((5-amino-4-methyl-l-phenyl- lH-pyrazol-3-yl)oxy)methyl)-3-fluoropiperidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4- (((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate with (3S,4S)-tert-butyl 3-fluoro-4- (((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate to give the title compound (38%).
[00982] Step E: Preparation of (3S,4S)-tert-butyl 3-fluoro-4-(((5-(3-(5-
(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)piperidine-l -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with (3S,4S)-tert-butyl 4-(((5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)methyl)-3- fluoropiperidine- 1 -carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (54%).
[00983] Step F: Preparation of l-(3-(((3S,4S)-3-fluoropiperidin-4-yl)methoxy)-4- methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)piperidine-l -carboxylate with (3S,4S)-tert-butyl 3-fluoro-4-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)piperidine-l -carboxylate to give the title compound (55%). MS (APCI) m/z = 566.2 (M+H).
Example 88
Figure imgf000245_0001
1 -(3-((Y3 S,4R)-3-fluoropiperidin-4-yl)methoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-( 5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)urea 2,2,2-trifluoroacetate [00984] Step A: Preparation of (3S,4R)-tert-butyl 3-fluoro-4-
(((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (3S,4R)-tert-butyl 3 -fluoro-4-(hydroxymethyl)piperidine-l -carboxylate (Example 87, Step B) to give the title compound (89%).
[00985] Step B: Preparation of (3S,4R)-tert-butyl 4-(((5-amino-4-methyl-l-phenyl- lH-pyrazol-3-yl)oxy)methyl)-3-fluoropiperidine-l -carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4- (((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate with (3S,4R)-tert-butyl 3-fluoro-4- (((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate to give the title compound (13%).
[00986] Step C: Preparation of (3S,4R)-tert-butyl 3-fluoro-4-(((5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)piperidine-l -carboxylate: Prepared according to the procedure of Example 1 , substituting 4-methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with (3S,4R)-tert-butyl 4-(((5-amino-4-methyl-l -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)-3- fluoropiperidine- 1 -carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (46%).
[00987] Step D: Preparation of l -(3-(((3S,4R)-3-fluoropiperidin-4-yl)methoxy)-4- methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea 2,2,2-trifluoroacetate: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4- methyl-1 -phenyl- lH-pyrazol-3-yl)piperidine-l -carboxylate with (3S,4R)-tert-butyl 3-fiuoro- 4-(((5 -(3 -(5 -(methoxymethy l)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H- pyrazol-3-yl)oxy)methyl)piperidine-l -carboxylate. The fractions from the reverse phase HPLC purification were concentrated under reduced pressure to give the title compound (67%) as a TFA salt. MS (APCI) m/z = 566.3 (M+H). Example 89
Figure imgf000247_0001
l-(3-(azetidin-3-yloxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)urea
[00988] Step A: Preparation of tert-butyl 3-((methylsulfonyl)oxy)azetidine-l- carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert- butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate with tert-butyl 3- hydroxyazetidine-1 -carboxylate to give the title compound (100%).
[00989] Step B: Preparation of tert-butyl 3-((5-amino-4-methyl-l-phenyl-lH-pyrazol-
3- yl)oxy)azetidine-l -carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate with tert- butyl 3-((methylsulfonyl)oxy)azetidine-l -carboxylate to give the title compound (45%).
[00990] Step C: Preparation of tert-butyl 3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)azetidine- 1 - carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 3-((5-amino-4-methyl-l- phenyl- 1 H-pyrazol-3-yl)oxy)azetidine- 1 -carboxylate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (48%).
[00991] Step D: Preparation of l-(3-(azetidin-3-yloxy)-4-methyl-l-phenyl-lH- pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with tert-butyl 3-((5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-
4- methyl-l -phenyl- 1 H-pyrazol-3 -yl)oxy)azetidine-l -carboxylate to give the title compound (12%). MS (APCI) m/z = 506.2 (M+H). Example 90
Figure imgf000248_0001
1 -(3-Π -azaspiro[3.3]heptan-6-yloxy)-4-methyl-l -phenyl- 1 H-pyrazol-5-yl)-3-(5- (methoxymethylV2-(trifluoromethoxy)benzyl)urea
[00992] Step A: Preparation of tert-butyl 6-((methylsulfonyl)oxy)-l- azaspiro[3.3]heptane-l-carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l-carboxylate with tert- butyl 6-hydroxy-l-azaspiro[3.3]heptane-l-carboxylate to give the title compound (97%).
[00993] Step B: Preparation of tert-butyl 6-((5-amino-4-methyl-l -phenyl- lH-pyrazol- 3-yl)oxy)-l-azaspiro[3.3]heptane-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with tert-butyl 6-((methylsulfonyl)oxy)-l-azaspiro[3.3]heptane-l-carboxylate to give the title compound (1 1%).
[00994] Step C: Preparation of tert-butyl 6-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)- 1 - azaspiro[3.3]heptane-l-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with tert- butyl 6-((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)- 1 -azaspiro[3.3]heptane- 1 - carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound.
[00995] Step D: Preparation of l-(3-(l-azaspiro[3.3]heptan-6-yloxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l -carboxylate with tert-butyl 6-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)- 1 - azaspiro[3.3]heptane-l -carboxylate to give the title compound (22%). MS (APCI) m/z 546.2 (M+H).
Example 91
Figure imgf000249_0001
(R)-l-(3-(azetidin-2-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yn-3-(5-(methoxymethyl)-
2-(trifluoromethoxy benzyl)urea
[00996] Step A: Preparation of (R)-tert-butyl 2-
(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (R)-tert-butyl 2-(hydroxymethyl)azetidine-l -carboxylate to give the title compound (100%).
[00997] Step B: Preparation of (R)-tert-butyl 2-(((5-amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)methyl)azetidine-l -carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (R)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate to give the title compound (44%).
[00998] Step C: Preparation of (R)-tert-butyl 2-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1 -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3- (2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (R)-tert-butyl 2-(((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1 -carboxylate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (62%).
[00999] Step D: Preparation of (R)-l-(3-(azetidin-2-ylmethoxy)-4-methyl-l -phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l -carboxylate with (R)-tert-butyl 2-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine 1 -carboxylate to give the title compound (26%). MS (APCI) m/z = 520.2 (M+H).
Example 92
Figure imgf000250_0001
(SV 1 -(3-(azetidin-2-ylmethoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethylV
2-(trifluoromethoxy)benzyl)urea
[001000] Step A: Preparation of (S)-tert-butyl 2-
(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (S)-tert-butyl 2-(hydroxymethyl)azetidine-l -carboxylate to give the title compound (95%).
[001001] Step B: Preparation of (S)-tert-butyl 2-(((5-amino-4-methyl- 1 -phenyl- 1 H- pyrazol-3-yl)oxy)methyl)azetidine-l -carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate to give the title compound (46%).
[001002] Step C: Preparation of (S)-tert-butyl 2-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)azetidine- 1 -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3- (2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (S)-tert-butyl 2-(((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1 -carboxylate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (64%).
[001003] Step D: Preparation of (S)-l-(3-(azetidin-2-ylmethoxy)-4-methyl-l-phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l -carboxylate with (S)-tert-butyl 2-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)azetidine- 1-carboxylate to give the title compound (29%). MS (APCI) m/z = 520.2 (M+H).
Example 93
Figure imgf000251_0001
l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl-3-(n-methylpiperidin-4- vDmethoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001004] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4- methyl-l-phenyl-3-(piperidin-4-ylmethoxy)-lH-pyrazol-5-yl)urea (Example 67), to give the title compound (55%). MS (APCI) m/z = 562.3 (M+H).
Example 94
Figure imgf000251_0002
1 -(5-(methoxymethyl)-2-(trifluoromethoxy')benzyl)-3-( 4-methyl-3-( ( 1 -methyl- 1 - azaspiro[3.3 jheptan-6-yl)oxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea 2,2,2-trifluoroacetate
[001005] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3 -ylmethoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3 -(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(3 -( 1 -azaspiro[3.3 ]heptan-6-yloxy)-4-methyl- 1 -phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea (Example 89), to give the title compound (39%) as the TFA salt. MS (APCI) m/z = 560.2 (M+H). Example 95
Figure imgf000252_0001
1 -(3-r(,(3R,4RV3-fluoropiperidin-4-vnoxyV4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3-( 5-
(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[001006] Step A: Preparation of (3S,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-l- carboxylate and (3R,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate: A round bottom flask was charged with tert-butyl 3-fluoro-4-oxopiperidine-l-carboxylate (3.00 g, 13.8 mmol, Example 86, Step A) and 140 mL of dry methanol. This mixture was cooled to 0 °C and sodium borohydride (1.57 g, 41.4 mmol) was then added in one portion. After 15 minutes at 0 °C, the mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was concentrated under reduced pressure and the resulting crude material was taken up in 50 mL of 1M aqueous NaOH and stirred for 30 minutes. The mixture was extracted with EtOAc, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product as a mixture of diastereomers. The mixture of diastereomers was passed through an 80 g Redi Sep column, eluting with 5% Ethyl acetate/DC M, to give 0.245 g (9%) of a less polar isomer and 1.14 g (44%) of a more polar isomer. Based on 1H NMR, the more polar isomer was consistent with the cis diastereomer.
[001007] Step B: Preparation of (3S,4R)-tert-butyl 3-fluoro-4-
((methylsulfonyl)oxy)piperidine-l-carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (3S,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate to give the title compound (97%).
[001008] Step C: Preparation of (3S,4S)-tert-butyl 4-((5-amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)-3-fluoropiperidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (3S,4R)-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-l -carboxylate to give the title compound (25%).
[001009] Step D: Preparation of (3S,4S)-tert-butyl 3-fluoro-4-((5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)piperidine-l -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with (3 S,4S)-tert-butyl 4-((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)-3-fluoropiperidine- 1 -carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to the title compound.
[001010] Step E: Preparation of l-(3-(((3S,4S)-3-fluoropiperidin-4-yl)oxy)-4-methyl-l- phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl-l-phenyl-lH-pyrazol-3- yl)piperidine-l -carboxylate with (3S,4S)-tert-butyl 3-fluoro-4-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)piperidine- 1 - carboxylate to give the title compound (47%). MS (APCI) m/z = 552.2 (M+H).
Example 96
Figure imgf000253_0001
(SV 1 -(3 -(2-aminopropoxy')-4-methyl-l -phenyl- 1 H-pyrazol-5-viy3-(5-(methoxymethvO-2-
(trifluoromethoxy)benzyDurea
[001011] Step A: Preparation of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate with (S)-tert-butyl (1- hydroxypropan-2-yl)carbamate to give the title compound (97%).
[001012] Step B: Preparation of (S)-tert-butyl (1 -((5 -amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)propan-2-yl)carbamate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate with ((S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate to give the title compound (28%).
[001013] Step C: Preparation of (S)-tert-butyl (l-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)propan-2- yl)carbamate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (S)-tert-butyl (l-((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)propan-2-yl)carbamate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (42%).
[001014] Step D: Preparation of (S)-l -(3 -(2-aminopropoxy)-4-methyl-l -phenyl- 1H- pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with (S)-tert-butyl (l-((5-(3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)propan-2- yl)carbamate to give the title compound (24%). MS (APCI) m/z = 508.2 (M+H).
Example 97
Figure imgf000254_0001
( )-l-(3-(2-aminopropoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethvn-2-
(trifluorornethoxy)benzyl urea
[001015] Step A: Preparation of (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate with (R)-tert-butyl (1- hydroxypropan-2-yl)carbamate to give the title compound (97%).
[001016] Step B: Preparation of (R)-tert-butyl ( l -((5-amino-4-methyl-l -phenyl- 1 H- pyrazol-3-yl)oxy)propan-2-yl)carbamate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate with ((R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate to give the title compound (28%).
[001017] Step C: Preparation of (R)-tert-butyl (l-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)propan-2- yl)carbamate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (R)-tert-butyl (l-((5-amino-4- methyl-l-phenyl-lH-pyrazol-3-yl)oxy)propan-2-yl)carbamate and (2-cyclopropyl-5- (methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (42%).
[001018] Step D: Preparation of (R)-l-(3-(2-aminopropoxy)-4-methyl-l -phenyl- 1H- pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with (R)-tert-butyl (l-((5-(3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)ureido)-4-methyl-l -phenyl- 1 H-pyrazol-3 -yl)oxy)propan-2- yl)carbamate to give the title compound (26%). MS (APCI) m/z = 508.2 (M+H).
Example 98
Figure imgf000255_0001
l-(3-((('3R,4R)-3-fluoro-l-methylpiperidin-4-vnoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-
(5-(methoxymethv0-2-(trifluoromethoxy)benzyl)urea
[001019] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(3 -(((3 R,4R)-3 -fluoropiperidin-4-yl)oxy)-4-methyl- 1 - phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea to give the title compound (39%). MS (APCI) m/z = 566.2 (M+H). Example 99
Figure imgf000256_0001
l-(3-(((3S,4RV3-fluoropiperidin-4-yl)oxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[001020] Step A: Preparation of (3S,4S)-tert-butyl 3-fluoro-4-
((methylsulfonyl)oxy)piperidine-l -carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (3S,4S)-tert-butyl 3 -fluoro-4-hydroxypiperidine-l -carboxylate (Example 95) to give the title compound (95%).
[001021] Step B: Preparation of (3S,4R)-tert-butyl 4-((5-amino-4-methyl-l-phenyl- lH-pyrazol-3-yl)oxy)-3-fluoropiperidine-l -carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with ((R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate to give the title compound (26%).
[001022] Step C: Preparation of (3S,4R)-tert-butyl 3-fluoro-4-((5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)piperidine-l -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with (3 S,4R)-tert-butyl 4-((5 -amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)-3 -fluoropiperidine- 1 -carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (49%).
[001023] Step D: Preparation of l-(3-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)-4-methyl- l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea:
Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)piperidine-l-carboxylate with (3S,4R)-tert-butyl 3-fluoro-4-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)piperidine- 1 - carboxylate to give the title compound (24%). MS (APCI) m/z = 552.2 (M+H).
Example 100
Figure imgf000257_0001
l-(3-((lr,3r)-3-aminocvclobutoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl')-3-(5- (methoxymethyl)-2-(trifluoromethoxy benzyl)urea
[001024] Step A: Preparation of (ls,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate with tert-butyl ((ls,3s)-3- hydroxycyclobutyl)carbamate to give the title compound (92%).
[001025] Step B: Preparation of tert-butyl ((1 r,3r)-3-((5-amino-4-methyl- 1 -phenyl- 1 H- pyrazol-3-yl)oxy)cyclobutyl)carbamate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l -carboxylate (ls,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate to give the title compound (38%).
[001026] Step C: Preparation of tert-butyl ((lr,3r)-3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)cyclobutyl)carbamate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine with ((lr,3r)-3-((5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)cyclobutyl)carbamate and (2- cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (56%).
[001027] Step D: Preparation of l-(3-((lr,3r)-3-aminocyclobutoxy)-4-methyl-l-phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)piperidine-l -carboxylate with tert-butyl ((lr,3r)-3-((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)cyclobutyl)carbamate to give the title compound (28%). MS (APCI) m/z
(M+H).
Example 101
Figure imgf000258_0001
1 -(3-(((3S. iR -3-fluoro- 1 -methylpiperidin-4-yl)oxyV4-methyl- 1 -phenyl-1 H-pyrazol-5-yl)-3-
(5-(methoxymethylV2-(trifluoromethoxy)benzyl)urea
[001028] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with l-(3-(((3S,4R)-3 -fluoropiperidin-4-yl)oxy)-4-methy 1- 1 - phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea (Example 99), to give the title compound (46%). MS (APCI) m/z = 566.3 (M+H).
Example 102
Figure imgf000258_0002
(R)-l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl-3-(morpholin-3- ylmethoxy - 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001029] Step A: Preparation of (R)-tert-butyl 3-
(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4- (hydroxymethyl)piperidine-l-carboxylate with (S)-tert-butyl 3-(hydroxymethyl)morpholine- 4-carboxylate to give the title compound (94%).
[001030] Step B: Preparation of (R)-tert-butyl 3-(((5-amino-4-methyl-l-phenyl-lH- pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate to give the title compound (16%).
[001031] Step C: Preparation of (R)-tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with (R)- tert-butyl 3-(((5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)methyl)mo holine-4- carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (20%).
[001032] Step D: Preparation of (R)-l-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)-3-(4-methyl-3-(morpholin-3-ylmethoxy)-l-phenyl-lH-pyrazol-5- yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl-l-phenyl-lH- pyrazol-3-yl)piperidine-l-carboxylate with (R)-tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)mo holine-4-carboxylate to give the title compound (10%). MS (APCI) m/z = 550.3 (M+H).
Example 103
Figure imgf000259_0001
(S)- 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl-3-( ηιοφ1ιο1ϊη-3- ylmethoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001033] Step A: Preparation of (S)-tert-butyl 3- (((methylsulfonyl)oxy)methyl)mo holine-4-carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4- (hydroxymethyl)piperidine-l-carboxylate with (R)-tert-butyl 3-(hydroxymethyl)morpholine- 4-carboxylate to give the title compound (94%).
[001034] Step B: Preparation of (S)-tert-butyl 3-(((5-amino-4-methyl-l-phenyl-lH- pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (S)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate to give the title compound (19%).
[001035] Step C: Preparation of (S)-tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifiuoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with (S)- tert-butyl 3-(((5-amino-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)methyl)mo holine-4- carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (51%).
[001036] Step D: Preparation of (S)-l-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)-3-(4-methyl-3-(morpholin-3-ylmethoxy)-l-phenyl-lH-pyrazol-5- yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H- pyrazol-3-yl)piperidine-l-carboxylate with (S)-tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)mo holine-4-carboxylate to give the title compound (39%). MS (APCI) m/z = 550.3 (M+H).
Example 104
Figure imgf000260_0001
l-(3-((lr,3r -3-(dimethylamino)cyclobutoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl -3-(5- (methoxymethyn-2-(trifluoromethoxy)benzyl)urea
[001037] Prepared according to the procedure of Example 75, Step A, substituting l-(3-
(azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(3-((l r,3r)-3-aminocyclobutoxy)-4-methyl- 1 -phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea (Example 100) to give the title compound (20%). MS (APCI) m/z = 548.3 (M+H).
Example 105
Figure imgf000261_0001
l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3-(4-methyl-l-phenyl-3-(piperidin-4- ylmethoxy)- 1 H-pyrazol-5-yl)urea
[001038] Step A: Preparation of 2-(5-bromo-2-(difluoromethoxy)phenyl)-l,3- dioxolane: A round bottom flask equipped with a Dean-Stark trap and condenser was charged with 5-bromo-2-(difluoromethoxy)benzaldehyde (2.91 g, 1 1.6 mmol) and 58 mL of toluene. To this was added ethane- 1,2-diol (0.72 g, 1 1.6 mmol) and p-TsOH.H20 (22 mgs, 0.116 mmol). The mixture was heated to reflux and stirred for 6 hours. The mixture was allowed to cool to ambient temperature concentrated under reduced pressure. The resulting crude material was taken up in DCM, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as an oil (92%).
[001039] Step B: Preparation of 2-(2-(difluoromethoxy)-5-vinylphenyl)-l,3-dioxolane: A round bottom flask equipped with a condenser was charged with 2-(5-bromo-2- (difluoromethoxy)phenyl)-l,3-dioxolane (2.1 g, 7.12 mmol) and 70 mL of THF. To this was added potassium vinyltrifluoroborate (1.91 g, 14.2 mmol), triphenylphospine (112 mgs, 0.427 mmol), PdCl2 (25 mgs, 0.142 mmol) and aqueous cesium carbonate (10.7 mL, 21.4 mmol, 2M in water). The mixture was heated to reflux for 16 hours then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude material was purified by passing it through an 80 g Redi Sep column, eluting with 10% ethyl acetate/hexane, to give the title compound (43%). [001040] Step C: Preparation of 4-(difluoromethoxy)-3-(l,3-dioxolan-2- yl)benzaldehyde: A round bottom flask equipped with a plastic cap was charged with 2-(2- (difluoromethoxy)-5-vinylphenyl)-l,3-dioxolane (0.970 g, 4.00 mmol) and 40 raL of dry DCM. The mixture was cooled to -78 °C and ozone was bubbled through the solution for about 30 minutes until a persistent blue color was observed. The ozone was then purged from the mixture by bubbling nitrogen through the solution for about 5 minutes. PS- triphenylphosine (5.27 g, 12 mmol, 2.28 mmol/g) was then added followed by 25 mL of DCM, and the mixture was allowed to warm to ambient temperature. After stirring for 20 minutes at ambient temperature, the mixture was filtered. The resin was rinsed multiple times with DCM and the filtrate was concentrated under reduced pressure. This material was purified by passing it through a 40 g Redi Sep column, eluting with 35% ethyl acetate/hexane to give the title compound (60%).
[001041] Step D: Preparation of (4-(difluoromethoxy)-3-(l ,3-dioxolan-2- yl)phenyl)methanol: A round bottom flask equipped with a stir and nitrogen inlet was charged with 4-(difluoromethoxy)-3-(l ,3-dioxolan-2-yl)benzaldehyde (0.590 g, 2.42 mmol) and 24 mL of methanol. This mixture was cooled to 0 °C and sodium borohydride (0.183 g, 4.83 mmol) was added. The mixture was stirred at 0 °C for 2 hours. The mixture was quenched with saturated ammonium chloride solution (50 mL). Water (50 mL) was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (86%).
[001042] Step E: Preparation of 2-(2-(difluoromethoxy)-5-(methoxymethyl)phenyl)- 1,3-dioxolane: A round bottom containing (4-(difluoromethoxy)-3-(l,3-dioxolan-2- yl)phenyl)methanol (0.510 g, 2.07 mmol) was charged with dry THF (21 mL) under a nitrogen atmosphere. This mixture was cooled to 0 °C and sodium hydride (0.166 g, 4.14 mmol, 60% dispersion is mineral oil) was added in one portion and the mixture was stirred at 0 °C for 20 minutes. Methyl iodide (0.882 g, 6.21 mmol) was added and the mixture was allowed to warm to ambient temperature. After 1.5 hours the mixture was carefully quenched with saturated ammonium chloride solution (50 mL). Water (50 mL) was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to the title compound (100%).
[001043] Step F: Preparation of 2-(difluoromethoxy)-5-(methoxymethyl)benzaIdehyde: A round bottom flask was charged with 2-(2-(difluoromethoxy)-5-(methoxymethyl)phenyl)- 1,3-dioxolane (0.59 g, 2.27 mmol) and acetone (23 mL). To this was added concentrated HC1 (0.189 mL, 2.27 mmol) and the mixture was allowed to stir at ambient temperature for 16 hours. The mixture was diluted with 50 mL of EtOAc, washed with 10% aqueous potassium carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was passed through an 80 g Redi Sep column, eluting with 20% ethyl acetate/hexane, to give the title compound (40%).
[001044] Step G: Preparation of (E)-2-(difluoromethoxy)-5-
(methoxymethyl)benzaldehyde oxime: Prepared according to Preparation G, Step B, substituting 5-(methoxymethyl)-2-(trifluoromethoxy)benzaldehyde with 2- (difluoromethoxy)-5-(methoxymethyl)benzaldehyde, to give the title compound (84%).
[001045] Step H: Preparation of (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine: Prepared according to Preparation G, Step C, substituting 5-(methoxymethyl)-2-(trifluoromethoxy)benzaldehyde oxime with (E)-2- (difluoromethoxy)-5-(methoxymethyl)benzaldehyde oxime to give the title compound (84%).
[001046] Step I: Preparation of tert-butyl 4-(((5-(3-(2-(difluoromethoxy)-5- (methoxymethyl)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)piperidine- 1-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3- (2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 4-(((5-amino-4- methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)piperidine- 1 -carboxylate and (2-cyclopropyl- 5-(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (53%).
[001047] Step J: Preparation of l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3- (4-methyl-l-phenyl-3-(piperidin-4-ylmethoxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)piperidine- 1 - carboxylate with tert-butyl 4-(((5-(3-(2-(difluoromethoxy)-5-
(methoxymethyl)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)piperidine- 1 -carboxylate to give the title compound (6%). MS (APCI) m/z = 530.3 (M+H).
Example 106
Figure imgf000264_0001
H-CI
l-(5-fmethoxymethyl)-2-(trifluorom
yl methoxy)-l-phenyl-lH-pyrazol-5-yl)urea hydrochloride
[001048] Prepared according to the procedure of Example 75, Step A, substituting l-(3-
(azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4- methyl-l-phenyl-3-(pyrrolidin-3-ylmethoxy)-lH-pyrazol-5-yl)urea (Example 71). The crude material was then stirred with 5 mL of 6M HC1/IPA for 3 hours and concentrated under reduced pressure to give the title compound (33%). MS (APCI) m/z = 548.3 (M+H).
Example 107
Figure imgf000264_0002
l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3-(4-methyl-3-((l-methylpyrrolidin-3- vDmethoxy - 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001049] Step A: Preparation of tert-butyl 3-(((5-(3-(2-(difluoromethoxy)-5- (methoxymethyl)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)pyrrolidine- 1-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3- (2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 3-(((5-amino-4- methyl-1 -phenyl- lH-pyrazol-3-yl)oxy)methyl)pyrrolidine-l -carboxylate (Example 71) and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (2-(difluoromethoxy)-5- (methoxymethyl)phenyl)methanamine to give the title compound (46%).
[001050] Step B: Preparation of l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3- (4-methyl-l-phenyl-3-(pyrrolidin-3-ylmethoxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with tert-butyl 3-(((5-(3-(2-(difluoromethoxy)-5-
(methoxymethyl)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)pyrrolidine- 1 -carboxylate to give the title compound (9%).
[001051] Step C: Preparation of l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3- (4-methyl-3-((l-methylpyrrolidin-3-yl)methoxy)-l-phenyl-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 75, Step A, substituting l-(3-(azetidin-3-ylmethoxy)- 4-methyl- 1 -phenyl- 1 H-pyrazol-5 -yl)-3 -(5 -(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea with 1 -(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3-(4-methyl- 1 -phenyl-3-(pyrrolidin- 3-ylmethoxy)-lH-pyrazol-5-yl)urea to give the title compound (39%). MS (APCI) m/z = 530.3 (M+H).
Example 108
Figure imgf000265_0001
1 -(2-(difluoromethoxy)-5 -(memoxymethv0benzylV3 -(4-methyl-3 -((2-methyl-2- azaspiro[3.3]heptan-6-yl)oxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001052] Step A: Preparation of tert-butyl 6-((5-(3-(2-(difluoromethoxy)-5- (methoxymethyl)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3 -(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5 -amine
[001053] tert-butyl 6-((5-amino-4-methyl-l -phenyl- 1 H-pyrazol-3 -yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate (Example 79) and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (2-(difiuoromethoxy)-5-
(methoxymethyl)phenyl)methanamine to give the title compound (20%).
[001054] Step B: Preparation of l-(3-(2-azaspiro[3.3]heptan-6-yloxy)-4-methyl-l- phenyl- 1 H-pyrazol-5-yl)-3-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)piperidine-l -carboxylate with tert-butyl 6-((5-(3-(2-(difluoromethoxy)-5- (methoxymethyl)benzyl)ureido)-4-methyl-l-phenyl-lH-pyrazol-3-yl)oxy)-2
azaspiro[3.3]heptane-2-carboxylate to give the title compound (89%).
[001055] Step C: Preparation of l-(2-(difluoromethoxy)-5-(methoxymethyl)benzyl)-3- (4-methyl-3-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)-l-phenyl-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 75, Step A, substituting l-(3-(azetidin-3- ylmethoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)-3 -(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with tert-butyl 6-((5-(3-(2-(difluoromethoxy)-5- (methoxymethyl)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)-2
azaspiro[3.3]heptane-2-carboxylate to give the title compound (33%). MS (APCI) m/z = 542.3 (M+H).
Example 109
Figure imgf000266_0001
(R)-l-(3-(2-amino-3-hydroxypropoxy)-4-methyl-l-phenyl-lH-pyrazol-5-vn-3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
[001056] Step A: Preparation of (R)-3-(benzyloxy)-2-((tert- butoxycarbonyl)amino)propyl methanesulfonate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l- carboxylate with (S)-tert-butyl (l-(benzyloxy)-3-hydroxypropan-2-yl)carbamate to give the title compound (100%).
[001057] Step B: Preparation of (R)-tert-butyl (1 -((5 -amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)-3-(benzyloxy)propan-2-yl)carbamate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (R)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate to give the title compound (33%).
[001058] Step C: Preparation of (R)-tert-butyl (l-(benzyloxy)-3-((5-(3-(5- (methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)propan-2-yl)carbamate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with (R)- tert-butyl ( 1 -((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)-3 -(benzyloxy)propan-2- yl)carbamate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (61%).
[001059] Step D: Preparation of (R)-l-(3-(2-amino-3-(benzyloxy)propoxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
hydrochloride: A round bottom flask was charged with (R)-tert-butyl (l-(benzyloxy)-3-((5- (3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol- 3-yl)oxy)propan-2-yl)carbamate (0.100 g, 0.140 mmol) and 10 mL of 6M HC1/IPA. This mixture was stirred at ambient temperature for 2 hours, and then concentrated under reduced pressure to give the title compound (100%).
[001060] Step E: Preparation of (R)-l-(3-(2-amino-3-hydroxypropoxy)-4-methyl-l- phenyl- 1 H-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea: A round bottom flask was charged with (R)-l-(3-(2-amino-3-(benzyloxy)propoxy)-4-methyl-l- phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea
hydrochloride (0.091 g, 0.140 mmol) and 1.5 mL of MeOH. To this was added 10% Pd/C (90 mgs, 1 weight eq.). This mixture was stirred at ambient temperature under an atmosphere of hydrogen for 16 hours, then filtered through GF/F filter paper. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by reverse phase HPLC. The fractions containing the product were combined in 2M aqueous NaOH and extracted with 25% IPA/DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (25%). MS (APCI) m/z = 524.3 (M+H). Example 110
Figure imgf000268_0001
(S)-l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl -3-f4-methyl-3-((4-methylmo
3-yl)methoxy -l-phenyl-lH-pyrazol-5-yl)urea
[001061] Prepared according to the procedure of Example 75, Step A, substituting l-(3-
(azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with (S)- 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)- 3-(4-methyl-3-(morpholin-3-ylmethoxy)-l-phenyl-lH-pyrazol-5-yl)urea to give the title compound (25%). MS (APCI) m/z = 564.3 (M+H).
Example 111
Figure imgf000268_0002
1 -(5-(methoxymethyl)-2-(trifluoromethoxy benzyn-3-(4-methyl-3-(( 1 -methylpiperidin-3- yPmethoxy)-! -phenyl- 1 H-pyrazol-5-yl)urea
[001062] Step A: Preparation tert-butyl 3-(((5-amino-4-methyl-l-phenyl-lH-pyrazol-3- yl)oxy)methyl)piperidine-l-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with tert-butyl 3-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate to give the title compound (55%).
[001063] Step B: Preparation of tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)piperidine-l-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert- butyl 3-(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)piperidine- 1 -carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (57%).
[001064] Step C: Preparation of l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3- (4-methyl-l-phenyl-3-(piperidin-3-ylmethoxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with tert-butyl 3-(((5-(3-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 - yl)oxy)methyl)piperidine-l -carboxylate to give the title compound (49%).
[001065] Step D: Preparation of l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3- (4-methyl-3 -(( 1 -methylpiperidin-3 -yl)methoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea: Prepared according to the procedure of Example 75, Step A, substituting l-(3-(azetidin-3-ylmethoxy)- 4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)urea with 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl- 1 -phenyl-3-(piperidin- 3-ylmethoxy)-lH-pyrazol-5-yl)urea to give the title compound (22%). MS (APCI) m/z = 562.3 (M+H).
Example 112
Figure imgf000269_0001
S)-l-(5- methoxymethyl)-2-(trifluoromethoxy)benzvΠ-3- 4-methyl-3-(moφholin-2- ylmethoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001066] Step A: Preparation of (S)-tert-butyl 2-
(((methylsulfonyl)oxy)methyl)mo holine-4-carboxylate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4- (hydroxymethyl)piperidine-l -carboxylate with (S)-tert-butyl 2-(hydroxymethyl)morpholine- 4-carboxylate to give the title compound (100%).
[001067] Step B: Preparation of (S)-tert-butyl 2-(((5-amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l- carboxylate with (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate to give the title compound (30%).
[001068] Step C: Preparation of (S)-tert-butyl 2-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)morpholine-4-carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with (S)- tert-butyl 2-(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)oxy)methyl)morpholine-4- carboxylate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5- (methoxymethyl)-2-(trifluoromethoxy)phenyl)methanamine to give the title compound (47%).
[001069] Step D: Preparation of (S)-l-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)-3-(4-methyl-3-(morpholin-2-ylmethoxy)-l-phenyl-lH-pyrazol-5- yl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H- pyrazol-3-yl)piperidine-l-carboxylate with (S)-tert-butyl 2-(((5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3- yl)oxy)methyl)morpholine-4-carboxylate to give the title compound (18%). MS (APCI) m/z = 550.2 (M+H).
Example 113
HN HN
(R)-l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3-(4-methyl-3-((4-methylmorpholin-
3-yl)methoxy)-l-phenyl-lH-pyrazol-5-yl)urea
[001070] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l-phenyl-lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with (R)- 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)- 3-(4-methyl-3-(morpholin-3-ylmethoxy)-l-phenyl-lH-pyrazol-5-yl)urea to give the title compound (15%). MS (APCI) m/z = 564.3 (M+H).
Example 114
Figure imgf000271_0001
(SH-(5-(methoxymethyiy2-(trifluorometh^
2-yl)methoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001071] Prepared according to the procedure of Example 75, Step A, substituting l-(3- (azetidin-3-ylmethoxy)-4-methyl-l -phenyl- lH-pyrazol-5-yl)-3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)urea with (S)- 1 -(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)- 3-(4-methyl-3-(mo holin-2-ylmethoxy)-l phenyl- lH-pyrazol-5-yl)urea to give the title compound (60%). MS (APCI) m/z = 564.3 (M+H).
Example 115
Figure imgf000271_0002
l-(4-methyl-3-((l-methylpiperidin-4-yl)methoxy -l-phenyl-lH-pyrazol-5-yl)-3-(2-
(trifluoromethoxy)benzvDurea
[001072] Step A: Preparation of tert-butyl 4-(((4-methyl-l-phenyl-5-(3-(2- (trifluoromethoxy)benzyl)ureido)- 1 H-pyrazol-3-yl)oxy)methyl)piperidine- 1 -carboxylate: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-amine with tert-butyl 4-(((5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)oxy)methyl)piperidine- 1 -carboxylate and (2-cyclopropyl-5 - (methoxymethyl)phenyl)methanamine with (2-(trifluoromethoxy)phenyl)methanamine to give the title compound (52%). [001073] Step B: Preparation of l-(4-methyl-l-phenyl-3-(piperidin-4-ylmethoxy)-lH- pyrazol-5-yl)-3-(2-(trifluoromethoxy)benzyl)urea: Prepared according to the procedure of Example 66, Step B, substituting tert-butyl 4-(5-(3-(5-(methoxymethyl)-2- (trifluoromethoxy)benzyl)ureido)-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -yl)piperidine- 1 - carboxylate with tert-butyl 4-(((4-methyl-l-phenyl-5-(3-(2-(trifluoromethoxy)benzyl)ureido)- 1 H-pyrazol-3 -yl)oxy)methyl)piperidine-l-carboxylate to give the title compound (45%).
[001074] Step C: Preparation of l-(4-methyl-3-((l-methylpiperidin-4-yl)methoxy)-l- phenyl-lH-pyrazol-5-yl)-3-(2-(trifluoromethoxy)benzyl)urea: A microwave reaction vial was charged with the l-(4-methyl-l-phenyl-3-(piperidin-4-ylmethoxy)-lH-pyrazol-5-yl)-3- (2-(trifluoromethoxy)benzyl)urea (0.059 g, 0.117 mmol) and 1 mL of methanol. To this was added a 37% aqueous solution of formaldehyde (0.0262 mL, 0.352 mmol) and formic acid (0.0221 mL, 0.586 mmol). The tube was sealed and warmed to 70 °C for 3 hours and then concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC. The fractions containing the product were combined in 2M aqueous NaOH and extracted with 25% IPA/DCM. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (51%). MS (APCI) m/z = 518.3 (M+H).
Example 116
Figure imgf000272_0001
1 -( 1 ',4-dimethyl- 1 -phenyl- 1 H.1 Ή-Γ3.4,-bipyrazol]-5-ylV3-((4-(methoxymethylVr 1.1 '- biphenyl]-2-yl)methyl urea
[001075] Step A: Preparation of 4-(methoxymethyn- l,r-biphenyl]-2-carbonitrile: A vial was charged with phenylboronic acid (108 mg, 0.885 mmol), cesium carbonate (576 mg, 1.77 mmol), dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine (18 mg, 0.044 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), and 2-bromo-5-(methoxymethyl)benzonitrile (Preparation L, Step B; 100 mg, 0.442 mmol). 1 : 1 dioxane/water (2 mL) was added. The mixture was sparged with Ar, and then heated to 90 °C overnight. The mixture was partitioned between EtOAc and saturated aqueous NaHC03. The organic phase was separated and washed with aqueous with EtOAc. The combined organic phases were washed with brine, dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (2 mm thickness, Rf = 0.48) eluting with 25% EtOAc/hexanes to provide the title compound (86 mg; 85%).
[001076] Step B: Preparation of (4-(methoxymethyl)-|T , 1 '-biphenyl1-2-yl)methanamine: A flask was charged with 4-(methoxymethyl)-[l,r-biphenyl]-2-carbonitrile (86 mg, 0.39 mmol), MeOH (3 mL) and cobalt chloride hexahydrate (183 mg, 0.77 mmol). The mixture was degassed by vacuum purging with N2 three times. The mixture was cooled in an ice bath under N2 and NaBH4 (146 mg, 3.9 mmol) was added. The mixture was stirred for 5 minutes in ice bath and then at ambient temperature for 2 hours. The mixture was quenched with saturated aqueous NH4C1 (2-3 mL), then concentrated under vacuum. The crude material was diluted residue with 2N aqueous NaOH (10 mL) and DCM (10 mL). The biphasic solution was filtered through GF/F paper, rinsing with multiple portions of DCM. The phases were separated, and the aqueous phase was extracted with DCM (2 x 10 mL). Combined organic phases were dried (MgS04), filtered, and concentrated to provide the title compound (63 mg; 65%).
[001077] Step C: Preparation of 1 -Π '.4-dimethyl- 1 -phenyl- 1 H.1 'H-r3.4'-bipyrazol1-5- yl)-3-((4-(methoxymethyl)- l,r-biphenyl]-2-yl)methyl)urea: A vial was charged with phenyl (l',4-dimethyl-l-phenyl-lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 49 mg, 0.13 mmol), 1 ,2-dichloroethane (0.5 mL), (4-(methoxymethyl)-[l,l'-biphenyl]-2-yl)methanamine (30 mg, 0.13 mmol), and N-ethyl-N-isopropylpropan-2-amine (69 μί, 0.40 mmol). The mixture was stirred over the weekend for convenience at ambient temperature. The crude material was purified by preparative TLC (1 mm thickness, Rf = 0.29) eluting with 7.5% MeOH/DCM to provide the title compound (50 mg; 71%). MS m/z (APCI-pos) M+l = 507.2.
Example 117
Figure imgf000273_0001
1 -(2-cvclobutyl-4-fluoro-5-( methoxymethvnbenzylV3 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή-Γ3.4'- bipyrazol]-5-yl)urea [001078] Step A: Preparation of 2-amino-5-bromo-4-fluorobenzonitrile: A flask was charged with 2-amino-4-fluorobenzonitrile (10.0 g, 73.5 mmol), DMF (100 mL), and 1- bromopyrrolidine-2,5-dione (13.7 g, 77.1 mmol). The mixture was heated to 100 °C for 2 hours. After cooling to ambient temperature, the mixture was partitioned between EtOAc (200 mL) and water (200 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic phases were washed with water (100 mL), 10% aqueous sodium thiosulfate (100 mL), and brine (100 mL), dried (MgS04), filtered and concentrated to provide the title compound (16.1 g; 92%). The material was used in the next step without further purification.
[001079] Step B: Preparation of 2,5-dibromo-4-fluorobenzonitrile: To an open round bottomed flask containing a stirred suspension of 2-amino-5-bromo-4-fluorobenzonitrile (10.0 g, 46.5 mmol) in dioxane (20 mL) was added 48% aqueous hydrogen bromide (106 mL, 930 mmol). The mixture was cooled in an ice bath and sodium nitrite (3.53 g, 51.2 mmol) dissolved in water (15 mL) was carefully added dropwise over a 30 minute period, maintaining internal temperature below 3 °C, resulting in much gas evolution. The mixture was stirred in an ice bath for 30 minutes, then carefully poured into a stirred mixture of copper(I) bromide (8.67 g, 60.5 mmol) and 48% aqueous HBr (50 mL) that was cooled in an ice bath, with some gas evolution. The mixture was stirred for 15 minutes in the ice bath, then at ambient temperature for 1 hour, and then heated to 50 °C for 1 hour. After cooling to ambient temperature, the mixture was diluted with water and extracted with 10% EtOAc/diethyl ether. The combined organic extracts were washed with 10% aqueous sodium thiosulfate solution (250 mL) and saturated aqueous NH4C1 (250 mL), dried (MgS04), filtered, and concentrated. The crude product was passed through a Redi-Sep 330 silica gel column eluting with a gradient of hexanes to 10% EtOAc/hexanes. The isolated 10.7 g of an off-white solid was recrystallized twice by dissolving in hot hexanes (50 mL) and allowing solution to cool to ambient temperature, to provide the title compound (6.1 g; 45%).
[001080] Step C: Preparation of 2-bromo-4-fluoro-5-formylbenzonitrile: A flask was charged with isopropylmagnesium lithium chloride (18 mL, 24 mmol; 1.3 M in THF). The mixture was cooled to -30 to -40 °C (dry ice/acetonitrile slurry) under N2. 2,5-Dibromo-4- fluorobenzonitrile (6.0 g, 22 mmol) dissolved in THF (30 mL) was added dropwise. The mixture was stirred for 1 hour at -30 to -40 °C. N,N-dimethylformamide (5.0 mL, 65 mmol) was added dropwise. The reaction flask was removed from the cold bath and warmed to ambient temperature, and the mixture was stirred for 1 hour, then quenched with saturated aqueous NH4C1 (30 mL) and diluted with EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with water and brine, dried (MgS04), filtered, and concentrated. The crude material was passed through a Redi-Sep 330 silica gel column eluting with a gradient of 5%-20% EtOAc/hexanes to provide the title compound (1.3 g; 24%).
[001081] Step D: Preparation of 2-bromo-4-fluoro-5-(hydroxymethyl)benzonitrile: A flask was charged with 2-bromo-4-fluoro-5-formylbenzonitrile (1.4 g, 6.1 mmol) and anhydrous MeOH (20 mL). Sodium borohydride (0.47 g, 12 mmol) was added in portions. The mixture was stirred for an hour at ambient temperature and then concentrated under vacuum. Aqueous IN HC1 (20 mL) was added, and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried (MgS04), filtered, and concentrated to a solid. The crude material was taken up in aqueous IN HC1 (20 mL) and extracted into 10% EtOAc/diethyl ether (30 mL). The aqueous phase was extracted with 10% EtOAc/diethyl ether (20 mL). The combined organic phases were washed with aqueous IN NaOH (20 mL), dried (MgS04), filtered, and concentrated to provide the title compound (1.26 g; 82%).
[001082] Step E: Preparation of 2-bromo-4-fluoro-5-(methoxymethyl)benzonitrile: A flask was charged with 2-bromo-4-fluoro-5-(hydroxymethyl)benzonitrile (0.96 g, 4.2 mmol), anhydrous acetonitrile (10 mL), iodomethane (0.78 mL, 13 mmol), and Ag20 (1.45 g, 6.26 mmol). The flask was wrapped with Al foil and heated at 60 °C for 5 hours. Due to incomplete reaction, additional Ag20 (500 mg) and iodomethane (250 μί) were added the mixture was heated at 60 °C for 2 hours, then cooled to ambient temperature. The reaction mixture was filtered through GF/F paper rinsing with DCM. The filtrate was concentrated under vacuum, and the crude material was dried under high vacuum to provide the title compound (1.02 g; 80%). The material was used in the next step without further purification.
[001083] Step F: Preparation of 2-cvclobutyl-4-fluoro-5-(methoxymethyl)benzonitrile: A dry flask was charged with 2-bromo-4-fluoro-5-(methoxymethyl)benzonitrile (200 mg, 0.82 mmol), anhydrous THF (2 mL), dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2- yl)phosphine (34 mg, 0.082 mmol), and Pd(OAc)2 (9 mg, 0.04 mmol). The mixture was sparged with N2 for 3 minutes, then cooled in an ice bath under N2. Cyclobutylzinc(II) bromide (2.5 mL, 1.2 mmol; 0.5 M in THF) was added over 5 minutes via syringe. The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous NEUCl and extracted with EtOAc. The organic phase was washed with brine, dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (2 mm thickness, Rf = 0.68) eluting with 25% EtOAc/hexanes to provide the title compound (82 mg; 45%).
[001084] Step G: Preparation of (2-cvclobutyl-4-fluoro-5-
(methoxymethyPphenyl)methanamine: A dry flask equipped with a reflux condensor was charged with 2-cyclobutyl-4-fluoro-5-(methoxymethyl)benzonitrile (82 mg, 0.37 mmol), anhydrous THF (2 mL), and L1AIH4 (374 μί, 0.37 mmol; 1M in THF). The reaction mixture was to reflux with stirring under N2 for 1 hour. After cooling to ambient temperature, the reaction was quenched reaction by addition of water (120 μί), then stirred for 2-3 minutes. NaOH (2N, 120 μί) was added, and the mixture was stirred for 2-3 minutes. Water (400 μΐ) was added, and the mixture was stirred for 15 minutes at ambient temperature. The mixture was diluted with 2-methoxy-2-methylpropane and filtered, rinsing with 2-methoxy-2- methylpropane. The filtrate was concentrated, using toluene (3 x 3 mL) to azeotrope water to provide the title compound (80 mg; 48%). he material was used in the next step without further purification.
[001085] Step H: Preparation of 1 -(2-cvclobutyl-4-fluoro-5-(methoxymethyl)benzyl -3- ( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-[3 ,4'-bipyrazol]-5-yl)urea: A vial was charged with phenyl (l',4-dimethyl-l -phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 67 mg, 0.18 mmol), 1 ,2-dichloroethane (0.5 mL), (2-cyclobutyl-4-fluoro-5-
(methoxymethyl)phenyl)methanamine (40 mg, 0.18 mmol), and N-ethyl-N-isopropylpropan- 2-amine (94 μί, 0.54 mmol). The mixture was stirred overnight at ambient temperature. The crude material was purified by preparative TLC (1 mm thickness, Rf = 0.39) eluting with 7.5% MeOH/DCM. The resulting product was triturated with diethyl ether, and the resulting white solids were isolated by filtration to provide the title compound (14 mg; 15%). MS m/z (APCI-pos) M+l = 503.2.
Example 118
Figure imgf000276_0001
1 -(2-( aminomethylV5-i methoxymethyl)benzylV3 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή- [3.4'- bipyrazol1-5-yl)urea
[001086] Step A: Preparation of. fert-butyl 2-cvano-4- (methoxymethyl)benzy lcarbamate : A vial was charged with potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (210 mg, 0.885 mmol; Prepared according to the procedure in Org. Lett., 2012, 14 (12), pp 3138-3141), cesium carbonate (576 mg, 1.77 mmol), dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine (18 mg, 0.044 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), and 2-bromo-5-(methoxymethyl)benzonitrile (Preparation L, Step B; 100 mg, 0.442 mmol). A 1 : 1 mixture of dioxane/water (2 mL) was added. The flask was sparged with Ar, and then heated to 90 °C overnight. After cooling to ambient temperature, the mixture was partitioned between EtOAc (2 mL) and saturated aqueous NaHC03 (2 mL) and the phases were separated phases. The aqueous phase was extracted with EtOAc (1 mL). The combined organic phases were washed with brine (1 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (2 mm thickness, Rf = 0.61) eluting with 1 : 1 EtOAc/hexanes to provide the title compound (44 mg; 35%).
[001087] Step B: Preparation of fert-butyl 2-(aminomethyl)-4- (methoxymethyl)benzylcarbamate : A flask was charged with tert-butyl 2-cyano-4- (methoxymethyl)benzylcarbamate (44 mg, 0.16 mmol), MeOH (2 mL) and cobalt chloride hexahydrate (76 mg, 0.32 mmol). The flask was degassed by vacuum purge with N2 three times. The flask was cooled in an ice bath under N2 and NaBEU (60 mg, 1.6 mmol) was added. The mixture was stirred for 5 minutes in ice bath and then at ambient temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NH4CI (3 mL), then concentrated under vacuum. The crude material was diluted with aqueous 2N NaOH (10 mL) and DCM (10 mL). The biphasic mixture was filtered through GF/F paper, rinsing the solids with multiple portions of DCM. The phases were separated and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organic phases were dried (MgS04), filtered, and concentrated to provide the title compound (29 mg; 62%).
[001088] Step C: Preparation of tert-butyl 2-((3-(l',4-dimethyl-l-phenyl-lH,l'H-[3,4'- bipyrazol]-5-yl)ureido)methyl)-4-(methoxymethyl)benzylcarbamate: Prepared from tert-butyl 2-(aminomethyl)-4-(methoxymethyl)benzylcarbamate (29 mg, 0.10 mmol) and phenyl (Γ,4- dimethyl-l-phenyl-lH, H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 39 mg, 0.10 mmol) according to the procedure described for Example 116, Step C. Yield: 53 mg (89%).
[001089] Step D: Preparation of 1 -(2-( aminomethylV5-( methoxymethyl )benzylV3 -( 1 '.4- dimethyl-l-phenyl-lH, H-[3,4'-bipyrazol]-5-yl)urea: A flask was charged with tert-butyl 2- ((3-( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 'H-[3,4'-bipyrazol]-5-yl)ureido)methyl)-4- (methoxymethyl)benzylcarbamate (51 mg, 0.091 mmol), DCM (1 mL) and 2,2,2- trifluoroacetic acid (1 mL). The mixture was stirred at ambient temperature for an hour and then concentrated under vacuum. The mixture was partitioned between DCM (5 mL) and saturated aqueous NaHC03 (5 mL). The resulting suspension was diluted with EtOH (1 mL) and 2N NaOH (2 mL) was added. The phases were separated and the aqueous phase was extracted with DCM (2 x 5 mL). The combined organic phases were dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (0.5 mm thickness, Rf = 0.15) eluting with 20% MeOH/DCM to provide the title compound (22 mg; 51%). MS m/z (APCI-pos) M+l = 460.3.
Example 119
Figure imgf000278_0001
1 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 ,H-r3.4'-bipyrazol1-5-ylV3-(5-rmethoxymethylV2-(,((2.2.2- trifluoroethyl)amino)methyl)benzvPurea
[001090] Step A: A vial was charged with anhydrous DMF (0.5 mL), l-(2- (aminomethyl)-5-(methoxymethyl)benzyl)-3-( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 Ή-[3,4'- bipyrazol]-5-yl)urea (Example 118, Step D; 20 mg, 0.044 mmol), triethylamine (12 ί, 0.087 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (7 μί, 0.05 mmol). The mixture was stirred overnight at ambient temperature. The mixture was partitioned between EtOAc (2 mL) and water (2 mL). The phases were separated and the aqueous phase was extracted with EtOAc (1 mL). The combined organic phases were washed with water (2 mL) and brine (1 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (0.5 mm thickness, Rf = 0.46) eluting with 10% MeOH/DCM to provide the title compound (13 mg; 54%). MS m/z (APCI-pos) M+l = 542.3.
Figure imgf000279_0001
1 -(2-cyclobutyl-5 -(methoxymethyl)benzyl)-3 -(2-phenyl-4,6-dihydro-2H-thieno [3 ,4- c]pyrazol-3 -yDurea
[001091] A vial was charged with phenyl (2-phenyl-4,6-dihydro-2H-thieno[3,4- c]pyrazol-3-yl)carbamate (Intermediate PI 30, Step B; 20 mg, 0.059 mmol), 1,2- dichloroethane (0.5 mL), (2-cyclobutyl-5-(methoxymethyl)phenyl)-methanamine (Preparation B; 16 mg, 0.077 mmol), and N-ethyl-N-isopropylpropan-2-amine (31 μί, 0.18 mmol). The mixture was stirred overnight at ambient temperature. The crude material was purified by preparative TLC (0.5 mm thickness, Rf = 0.66) eluting with 10% MeOH/DCM to provide the title compound (16 mg; 59%). MS m/z (APCI-pos) M+l = 449.2.
Example 121
Figure imgf000279_0002
l-(2-cyclobutyl-5-(methoxymethyl)benzyl)-3-(5.5-dioxido-2-phenyl-4,6-dihydro-2H- thieno [3 ,4-c]pyrazol-3 -yPurea
[001092] Prepared from (2-cyclobutyl-5-(methoxymethyl)phenyl)-methanamine (Preparation B; 14 mg, 0.070 mmol) and phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H- thieno[3,4-c]pyrazol-3-yl)carbamate (Intermediate PI 30, Step C; 20 mg, 0.054 mmol) according to the procedure described for Example 120. Yield: 19 mg (69%). MS m/z (APCI- neg) M-l = 479.2. Example 122
Figure imgf000280_0001
1 -(2-cyclobutyl-5-(methoxymethyl)benzyl)-3 -(4-methyl-5 -oxo-2-phenyl-2,5 -dihydro- 1 H- pyrazol-3 - vDurea
[001093] Step A: Preparation of 5-isocyanato-4-niethyl-l -phenyl- lH-pyrazol-3(2H)- one: A vial was charged with 5-amino-4-methyl-l-phenyl-lH-pyrazol-3(2H)-one (Intermediate PI 35, Step A; 50 mg, 0.264 mmol), DMF (0.5 mL), N-ethyl-N- isopropylpropan-2-amine (1 15 iL, 0.661 mmol), and lastly di(lH-imidazol-l-yl)methanone (94 mg, 0.58 mmol). he mixture was stirred at ambient temperature overnight. The crude reaction mixture was used in the next step without workup or purification.
[001094] Step B: Preparation of l-(2-cvclobutyl-5-(methoxymethvnbenzvn-3-(4- methyl-5-oxo-2-phenyl-2,5-dihydro-lH-pyrazol-3-ynurea: To one half of the reaction mixture from Example 122, Step A was added (2-cyclobutyl-5-(methoxymethyl)phenyl)- methanamine (Preparation B; 35 mg, 0.17 mmol). The mixture was stirred overnight at ambient temperature. The mixture was partitioned between EtOAc and water. The biphasic mixture was filtered, rinsing multiple times with 30% MeOH/DCM. The phases were separated and the aqueous phase was extracted with EtOAc. The crude material was purified by preparative TLC (0.5 mm thickness) eluting with 10% MeOH/DCM. Fractions containing the product were combined and further purified by preparative reverse phase HPLC (column: YMC ODS-AQ, 250 x 20 mm). Fractions containing the product were concentrated and azeotroped with CH3CN (3 x 5 mL). The resulting solids were dissolved in 20% MeOH/DCM and washed with saturated aqueous NaHC03 and the aqueous phase was extracted with 20% MeOH/DCM. The combined organic phases were were dried (MgS04), filtered, and concentrated to provide the title compound (2 mg; 3%). MS m/z (APCI-pos) M+l = 421.2. Example 123
Figure imgf000281_0001
1 -(2-cvclobutyl-5-((methylthio)methvnbenzvn-3-( 1 ',4-dimethyl-l -phenyl- 1 H, 1 Ή-Γ3.4'- bipyrazol]-5-yl)urea
[001095] Step A: Preparation of 2-bromo-5-(bromomethyl)benzonitrile: A flask was charged with DCM (5 mL) and 2-bromo-5-(hydroxymethyl)benzonitrile (Preparation L, Step A; 200 mg, 0.943 mmol). The mixture was cooled in an ice bath under N2 and PBr3 (180 μί, 1.9 mmol) was added. The mixture was stirred an ice bath for 1 hour. The mixture was poured onto ice. The phases were separated and the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with saturated aqueous NaHC03 (10 mL), then dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (1 mm thickness, Rf = 0.59) eluting with 25% EtOAc/hexanes to provide the title compound (71 mg; 27%).
[001096] Step B: Preparation of 2-bromo-5-((methylthio)methyl)benzonitrile: A flask was charged with 2-bromo-5-(bromomethyl)benzonitrile (76 mg, 0.28 mmol), anhydrous DMF (1 mL) and sodium methanethiolate (23 mg, 0.33 mmol). The mixture was stirred at ambient temperature overnight under N2. The mixture was partitioned between EtO Ac/water. The phases were separated and the aqueous phase was extracted with EtO Ac. The combined organic phases were dried over MgS04, filtered, and concentrated. The crude material was purified by preparative TLC (1 mm thickness, Rf = 0.60) eluting with 25% EtOAc/hexanes to provide the title compound (43 mg; 63%).
[001097] Step C: Preparation of 2-cyclobutyl-5-((methylthio)methyl)benzonitrile: Prepared from 2-bromo-5-((methylthio)methyl)benzonitrile (43 mg, 0.18 mmol) according to the procedure described in Example 116, Step F. Yield: 20 mg; 51%).
[001098] Step D: Preparation of (2-cvclobutyl-5-
((methylthio)methyl)phenyl)methanamine: Prepared from 2-cyclobutyl-5- ((methylthio)methyl)benzonitrile (20 mg, 0.092 mmol) according to the procedure described in Example 117, Step G. Yield: 20 mg; 69%). [001099] Step E: Preparation of 1 -(2-cyclobutyl-5-i(methylthio)methyl)benzviy3-i 1 '.4- dimethyl- 1 -phenyl- 1 H, 1 Ή- [3 ,4'-bipyrazol1 -5-yl)urea: Prepared (2-cyclobutyl-5-
((methylthio)methyl)phenyl)methanamine (20 mg, 0.088 mmol) and phenyl (l',4-dimethyl-l- phenyl-lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 30 mg, 0.080mmol) according to the procedure described for Example 1 16, Step C. The crude material was purified by preparative reverse phase HPLC (column: YMC ODS-AQ, 250 x 20 mm). Fractions containing product were concentrated, and the resulting solids were dissolved in 20% MeOH/DCM, washed with saturated aqueous NaHC03, and extracted aqueous with 20% MeOH/DCM. The combined organic layers were dried (MgS04), filtered, and concentrated to provide the title compound (9 mg; 21%). MS m/z (APCI-pos) M+l = 501.2.
Example 124
Figure imgf000282_0001
(5^-l-(2-cyclobutyl-5-(methoxymethyl)benzvn-3-(3-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)-4-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001100] Step A: A flask was charged with (S)-3-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)-4-methyl-l -phenyl- lH-pyrazol-5-amine (Intermediate P209; 50 mg, 0.16 mmol) and DCM (0.5 mL), followed by addition of N-ethyl-N-isopropylpropan-2-amine (86 μί, 0.49 mmol) and triphosgene (24 mg, 0.082 mmol). The mixture was stirred for 15 minutes at ambient temperature, and then (2-cyclobutyl-5-(methoxymethyl)phenyl)methanamine (Preparation B; 34 mg, 0.16 mmol) was added, followed by further addition of N-ethyl-N- isopropylpropan-2-amine (86 μΙ_, 0.49 mmol). The mixture was stirred over the weekend at ambient temperature for convenience. The crude material was purified by preparative TLC (1 mm thickness, Rf = 0.65) eluting with 5% MeOH (containing 7N NH3) in DCM to provide the title compound (33 mg; 37%). MS m/z (APCI-pos) M+l = 535.3. Example 125
Figure imgf000283_0001
(i?yi-(2-cyclobutyl-5-(methoxymrt^
pheny -1 H-pyrazol-5-vPurea
[001101] Step A: A flask was charged with (S)-l-(2-cyclobutyl-5- (methoxymethyl)benzyl)-3-(3-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-4-methyl-l- phenyl- lH-pyrazol-5-yl)urea (Example 123; 30 mg, 0.056 mmol), THF (2 mL), and IN aqueous HC1 (2 mL). The mixture was stirred at ambient temperature for 3 hours, and then concentrated under vacuum. The mixture was partitioned between EtOAc (10 mL) and saturated aqueous NaHC03 (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (10 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (0.5 mm thickness), eluting with 10% MeOH/DCM to provide the title compound (18 mg; 62%). MS m/z (APCI-pos) M+l = 495.2.
Example 126
Figure imgf000283_0002
l-(2-cyclobutyl-5-(methoxymethyl)benzvn-3-(4-methyl-3-((5-methyl-l,3,4-oxadiazol-2- yPmethoxy)- 1 -phenyl- 1 H-pyrazol-5-yl)urea
[001102] Prepared from 4-methyl-3-((5-methyl-l,3,4-oxadiazol-2-yl)methoxy)-l- phenyl-lH-pyrazol-5-amine (Intermediate P140; 36 mg, 0.13 mmol) and (2-cyclobutyl-5- (methoxymethyl)phenyl)methanamine (Preparation B; 26 mg, 0.13 mmol) according to the procedure for Example 123. Yield: 29 mg (42%). MS m/z (APCI-pos) M+l = 517.2.
Example 127
Figure imgf000284_0001
1 -( 2-cyclobutyl-5-(methylthio)benzylV 3 -( 1 ',4-dimethyl- 1 -phenyl- 1 H.1 Ή- Γ3.4'-bipyrazol] - 5- vDurea
[001103] Step A: Preparation of 2-amino-5-thiocyanatobenzonitrile: A flask was charged with 2-aminobenzonitrile (4.00 g, 33.9 mmol), MeOH (20 mL) and sodium thiocyanate (3.02 g, 37.2 mmol). The flask was cooled in an ice bath and bromine (1.75 mL, 33.9 mmol) dissolved in MeOH (5 mL) was added dropwise over 20 minutes. During the last few minutes of the addition a thick precipitate formed which stopped stirring. Additional MeOH (10 mL) was added and the remainder of the bromine was added to the thick suspension. The mixture was stirred in ice bath for 30 minutes, then neutralized by pouring into saturated aqueous NaHC03 (30 mL). The mixture was extracted into EtOAc (2 x 30 mL). The organic phase was washed with brine (30 mL), dried (MgS04), filtered, and concentrated. The crude material was triturated with 5% MeOH/DCM (20 mL) with sonication, and the resulting solids were filtered, rinsing with DCM to provide the title compound as an off-white solid. Yield: 3.56 g (54%).
[001104] Step B: Preparation of 2-amino-5-(methylthio)benzonitrile: A flask was charged with MeOH (20 mL) and sodium hydroxide (0.85 g, 21 mmol) dissolved in water (3 mL). To this was added 2-amino-5-thiocyanatobenzonitrile (3.56 g, 20.3 mmol). A yellow suspension resulted. The mixture was stirred at ambient temperature for 30 minutes. The flask was cooled in an ice bath and NaBH4 (0.38 g, 10 mmol) was added. The resulting yellow suspension was stirred for 30 minutes in the ice bath. Diethyl sulfate (2.9 mL, 22 mmol) was added dropwise. The mixture was stirred for 15 minutes in the ice bath then for 1 hour at ambient temperature. The mixture was concentrated under vacuum and the resulting solids were partitioned between diethyl ether (40 mL) and water (40 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (20 mL). The combined organic phases were washed with brine (40 mL), dried (MgS04), filtered, and concentrated. The crude material was purified on a Redi-Sep 220 silica gel column, eluting with a gradient of 10%-30% EtOAc/hexanes to provide 3.38 g of a 60:40 mixture of 2-amino-5- (ethylthio)benzonitrile and 2-amino-5-(methylthio)benzonitrile, respectively. The mixture was used in the next step without purification.
[001105] Step C: Preparation of 2-bromo-5-(methylthio)benzonitrile: To an open round bottomed flask containing a stirred suspension of a 60:40 mixture of 2-amino-5- (ethylthio)benzonitrile and 2-amino-5-(methylthio)benzonitrile from Step B (3.38 g, 19.0 mmol) in dioxane (10 mL) was added 48% aqueous hydrogen bromide (43 mL, 379 mmol). The mixture was cooled in an ice bath and sodium nitrite (1.44 g, 20.9 mmol) dissolved in water (5 mL) was added dropwise over a 20 minute period, maintaining internal temperature below 3 °C and monitoring gas evolution. The mixture was stirred in the ice bath for 30 minutes, then carefully poured into a stirred mixture of copper(I) bromide (3.54 g, 24.7 mmol) and 48% aqueous HBr (20 mL) that was cooled in an ice bath. The mixture was stirred for 15 minutes in the ice bath, then at ambient temperature for 1 hour, and then heated to 50 °C for 1 hour. After cooling to ambient temperature, The mixture was diluted with water (75 mL) and extracted with 10% EtOAc in diethyl ether (2 x 75 mL). The combined organic extracts were washed with 10% aqueous sodium thiosulfate solution (75 mL) and saturated aqueous Ν¾0 (75 mL), dried (MgS04), filtered, and concentrated. The crude material was purified on a Redi-Sep 330 silica gel column, eluting with a gradient of 5%-10% EtOAc/hexanes. 2-Bromo-5-(ethylthio)benzonitrile (1.8 g) eluted first, followed by 2-bromo- 5 -(methyl thio)benzonitrile (830 mg). Impure 2-bromo-5-(ethylthio)benzonitrile was repurified by Redi-Sep 220 silica gel column eluting with a gradient of 5%-7.5% EtOAc/hexanes to obtain 1.3 g (27% yield) of 2-bromo-5-(ethylthio)benzonitrile. Impure 2- bromo-5-(methylthio)benzonitrile was passed through a Redi-Sep 220 silica gel column eluting with a gradient of 7.5%-10% EtOAc/hexanes to obtain 500 mg (10% yield) of 2- bromo-5-(methylthio)benzonitrile.
[001106] Step D: Preparation of 2-cvclobutyl-5-(methylthio)benzonitrile: Prepared from 2-bromo-5-(methylthio)benzonitrile (100 mg, 0.44 mmol) according to the procedure described in Example 117, Step F. Yield: 25 mg (22%).
[001107] Step E: Preparation of (2-cyclobutyl-5-(methylthio)phenyl methanamine: Prepared from 2-cyclobutyl-5-(methylthio)benzonitrile (25 mg, 0.12 mmol) according to the procedure described in Example 117, Step G. Yield: 26 mg (69%).
[001108] Step F: Preparation of l-(2-cyclobutyl-5-(methylthio)benzvn-3-(l'.4-dimethyl- 1 -phenyl- 1 H, 1 'H-[3,4'-bipyrazol]-5-yOurea: Prepared 2-cyclobutyl-5- (methylthio)phenyl)methanamine (25 mg, 0.12 mmol) and phenyl (l',4-dimethyl-l-phenyl- lH,l'H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 38 mg, 0.10 mmol) according to the procedure described for Example 116, Step C. The crude material was purified by preparative reverse phase HPLC (column: YMC ODS-AQ, 250 x 20 mm). Fractions containing product were concentrated. The resulting solids were dissolved in 20% MeOH/DCM and washed with saturated aqueous NaHC03. The aqueous layer was extracted with 20% MeOH/DCM (2x), and the combined organic extracts were dried (MgS04), filtered, and concentrated to provide the title compound (3 mg; 6%). MS m/z (APCI-pos) M+l = 487.2.
Example 128
Figure imgf000286_0001
1 -(,2-cvclobutyl-5 -f ethylthio)benzyl)-3 -( 1 ',4-dimethyl- 1 -phenyl- 1 H.1 Ή- Γ3 ,4'-bipyrazon-5- yPurea
[001109] Step A: Preparation of 2-cvclobutyl-5-(ethylthio)benzonitrile: Prepared from 2-bromo-5-(ethylthio)benzonitrile (from Example 127, Step C; 100 mg, 0.41 mmol) according to the procedure described in Example 117, Step F. Yield: 33 mg (26%).
[001110] Step B: Preparation of (2-cyclobutyl-5-(ethylthio phenyl)methanamine: Prepared from 2-cyclobutyl-5-(ethylthio)benzonitrile (33 mg, 0.15 mmol) according to the procedure described in Example 1 17, Step G. Yield: 35 mg (67%).
[001111] Step C: Preparation of 1 -i2-cvclobutyl-5-(ethylthio)benzyl)-3-( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 'H-[3,4'-bipyrazol]-5-yl)urea: Prepared 2-cyclobutyl-5-
(ethylthio)phenyl)methanamine (34 mg, 0.15 mmol) and phenyl (1',4-dimethyl-l-phenyl- lH,rH-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 48 mg, 0.13 mmol) according to the procedure described for Example 116, Step C. The crude material was purified by preparative reverse phase HPLC (column: YMC ODS-AQ, 250 x 20 mm). Fractions containing product were concentrated. The resulting solids were dissolved in 20% MeOH/DCM and washed with saturated aqueous NaHC03. The aqueous phase was extracted with 20% MeOH/DCM (2x), and the combined organic extracts were dried (MgS04), filtered, and concentrated to provide the title compound (3 mg; 5%). MS m/z (APCI-pos) M+l = 501.2. Example 129
Figure imgf000287_0001
1 -( 1 '.4-dimethyl- 1 -phenyl- 1 H.1 Ή- [3 ,4'-bipyrazol]-5-yl)-3 -(" 1 -( 3 -imethoxymethyl)phenyl)-2- phenylethyDurea
[001112] Step A: Preparation of l-(3-(methoxymethyl)phenyl)-2-phenylethanone: A thick walled glass pressure vessel was charged with l-(3-bromophenyl)-2-phenylethanone (500 mg, 1.82 mmol), potassium methoxymethyl trifluoroborate (552 mg, 3.63 mmol), PdCi2(dppf) dichloromethane adduct (148 mg, 0.182 mmol), cesium carbonate (1776 mg, 5.45 mmol) and 1 : 1 dioxane/water (5 mL). The mixture was sparged with N2 for several minutes, then heated to 100 °C overnight. After cooling to ambient temperature, the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined organic phases were washed with brine (20 mL), dried (MgS04), filtered, and concentrated. The crude material was purified on Redi-Sep 80 silica gel column, eluting with a gradient of 5%-20% EtOAc/hexanes, then by preparative TLC (2 x 2 mm thick plates, Rf = 0.49), eluting with 2% MeOH/DCM to provide the title compound (133 mg; 30%).
[001113] Step B: Preparation of l-(3-(methoxymethyl)phenyl)-2-phenylethanone oxime: A flask equipped with a reflux condenser was charged with l-(3- (methoxymethyl)phenyl)-2-phenylethanone (133 mg, 0.553 mmol), EtOH (2 mL) and hydroxylamine hydrochloride (115 mg, 1.66 mmol). The mixture was heated to reflux for 4 hours. After cooling to ambient temperature, the reaction mixture was partitioned between 1 :1 water/saturated NaHC03 (20 mL) and EtOAc (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with brine (20 mL), dried (MgS04), filtered, and concentrated. Recovered 131 mg of the crude desired product which was used in the next step without purification.
[001114] Step C: Preparation of l-(3-(methoxymethyl)phenyl)-2-phenylethanamine: A flask was charged with l-(3-(methoxymethyl)phenyl)-2-phenylethanone oxime (131 mg, 0.513 mmol), zinc (250 mg, 3.8 mmol) and neat acetic acid (2 mL). The mixture was heated to 70 °C for 3 hours and then concentrated under vacuum. The residue was diluted with 2N aqueous NaOH (5 mL) and EtOAc (5 mL). The solution was filtered mixture through GF/F paper, rinsing multiple times with EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined organic phases were washed with brine (10 mL), dried (MgS04), filtered, and concentrated. The crude material was purified by preparative TLC (1 mm thickness, Rf = 0.31) eluting with 5% MeOH (containing 7N NH3) in DCM. Yield: 16 mg (12%).
[001115] Step D: Preparation of 1 -(1 '.4-dimethyl- 1 -phenyl- ILL 1 'H-i3,4'-bipyrazol1-5- yl)-3 -( 1 -(3-(methoxymethyl)phenyl)-2-phenylethyl)urea: Prepared l-(3-
(methoxymethyl)phenyl)-2-phenylethanamine (16 mg, 0.067 mmol) and phenyl ( ,4- dimethyl-l-phenyl-lH, H-[3,4'-bipyrazol]-5-yl)carbamate (Intermediate 5; 25 mg, 0.067 mmol) according to the procedure described for Example 1 16, Step C. Yield: 23 mg (63%). MS m/z (APCI-pos) M+l = 521.3.
Example 130
Figure imgf000288_0001
1 -(5-(methoxymethyl -2-(trifluoromethoxy)benzyl)-3-(4-methyl- 1 -phenyl-3-(quinuclidin-3- yloxy)- 1 H-pyrazol-5-yl)urea
[001116] Step A: Preparation of quinuclidin-3-yl methanesulfonate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro-4- (hydroxymethyl)piperidine-l-carboxylate with quinuclidin-3-ol to give quinuclidin-3-yl methanesulfonate (100%).
[001117] Step B: Preparation of 4-methyl-l-phenyl-3-(quinuclidin-3-yloxy)-lH- pyrazol-5-amine: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with quinuclidin-3-yl methanesulfonate to give 4-methyl-l-phenyl-3-(quinuclidin-3-yloxy)-lH-pyrazol-5 -amine (27%).
[001118] Step C: Preparation of l-(5-(methoxymethyl)-2-(trifluoromethoxy)benzyl)-3- (4-methyl-l-phenyl-3-(quinuclidin-3-yloxy)-lH-pyrazol-5-yl)urea: Prepared according to the procedure of Example 1, substituting 4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH- pyrazol-5-amine with 4-methyl-l-phenyl-3-(quinuclidin-3-yloxy)-lH-pyrazol-5-amine and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2- (trifluoromethoxy)phenyl)methanamine to give the title compound (21%). MS (APCI) m/z = 560.3 (M+H).
Example 131
Figure imgf000289_0001
(S -l-(5-(methoxymethylV2-(trifluoromethoxy)benzylV3-(4-methyl-3-((5-oxopyrrolidin-2- vPmethoxy)- 1 -phenyl- 1 H-pyrazol-5-yQurea
[001119] Step A: Preparation of (S)-(5-oxopyrrolidin-2-yl)methyl methanesulfonate: Prepared according to the procedure of Example 72, Step B, substituting tert-butyl 4-fluoro- 4-(hydroxymethyl)piperidine-l-carboxylate with (S)-5-(hydroxymethyl)pyrrolidin-2-one to give (S)-(5-oxopyrrolidin-2-yl)methyl methanesulfonate (25%).
[001120] Step B: Preparation of (S)-5-(((5-amino-4-methyl-l-phenyl-lH-pyrazol-3- yl)oxy)methyl)pyrrolidin-2-one: Prepared according to the procedure of Example 67, Step A, substituting tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate with (S)-(5- oxopyrrolidin-2-yl)methyl methanesulfonate to give (S)-5-(((5-amino-4-methyl-l -phenyl- 1H- pyrazol-3-yl)oxy)methyl)pyrrolidin-2-one (32%).
[001121] Step C: Preparation of (S)-l-(5-(methoxymethyl)-2-
(trifluoromethoxy)benzyl)-3-(4-methyl-3-((5-oxopyrrolidin-2-yl)methoxy)- 1 -phenyl- 1 H- pyrazol-5-yl)urea: Prepared according to the procedure of Example 1, substituting 4-methyl- 3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-amine with (S)-5-(((5-amino-4-methyl-l- phenyl- 1 H-pyrazol-3-yl)oxy)methyl)pyrrolidin-2-one and (2-cyclopropyl-5-
(methoxymethyl)phenyl)methanamine with (5-(methoxymethyl)-2-
(trifluoromethoxy)phenyl)methanamine to give the title compound (25%). MS (APCI) m/z = 546.2 (M-H). Example 132
Figure imgf000290_0001
1 -( 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 'H-r3,4'-bipyrazoll-5-yl)-3-(2.2.2-trifluoro- 1 -(3- (methoxymethyl)phenyl)ethyl)urea
[001122] Step A: Preparation of 2,2,2-trifluoro-l-(3-(methoxymethyl)phenyl)ethanone: A flask equipped with a nitrogen inlet was charged with l-bromo-3- (methoxymethyl)benzene (1.00 g, 4.974 mmol) and dry THF (50 mL). The mixture was cooled to -78 °C and n-BuLi (2.19 mL, 5.471 mmol, 2.5 M in hexanes) was added by syringe over a 10 minute period, resulting in a light yellow solution. The mixture was stirred at -78 °C for 45 minutes, and 2,2,2-trifluoro-l-(piperidin-l-yl)ethanone (0.991 g, 5.471 mmol) was added by syringe over a 5 minute period. Once addition was complete, the mixture was allowed to warm to ambient temperature, and then quenched with saturated ammonium chloride solution. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was passed through an 80 g Redi Sep column, eluting with 3 : 1 Hexane/ethyl acetate, to give 485 mg of an oil (1 :1 product/starting material).
[001123] Step B: Preparation of 2,2,2-trifluoro-l-(3-(methoxymethyl)phenyl)ethanone oxime: A round bottom flask equipped with a condenser was charged with 2,2,2-trifluoro-l- (3-(methoxymethyl)phenyl)ethanone (0.485 g, 2.22 mmol) and 22 mL of ethanol. To this was added hydroxylamine hydrochloride (0.154 g, 2.22 mmol) and the mixture was warmed to 65 °C for 16 hours, then concentrated under reduced pressure. The resulting crude material was taken up in EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 200 mg of an oil.
[001124] Step C: Preparation of 2,2,2-trifluoro-l-(3-
(methoxymethyl)phenyl)ethanamine: A round bottom flask equipped with a condenser was charged with 2,2,2-trifluoro-l-(3-(methoxymethyl)phenyl)ethanone oxime (0.200 g, 0.858 mmol) and 8 mL of acetic acid. To this was added zinc dust (0.280 g, 4.29 mmol) and the mixture was warmed to 70 °C for 5 hours, then filtered through GF/F filter paper. The filtrate was concentrated under reduced pressure and the resulting crude product was taken up in EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 138 mg of the title compound as an oil.
[001125] Step D: Preparation of l-(l',4-dimethyl-l-phenyl-lH,l'H-[3,4'-bipyrazol]-5- yl)-3-(2,2,2-trifluoro-l-(3-(methoxymethyl)phenyl)ethyl)urea: Prepared according to the procedure of Example 2, substituting phenyl (3 -ethoxy-4-methyl-l -phenyl- lH-pyrazol-5- yl)carbamate with phenyl (r,4-dimethyl-l-phenyl-lH,rH-[3,4'-bipyrazol]-5-yl)carbamate and (2-cyclopropyl-5-(methoxymethyl)phenyl)methanamine with 2,2,2-trifluoro-l-(3- (methoxymethyl)phenyl)ethanamine to give the title compound (12%). MS (APCI) m/z = 499.2 (M-H).

Claims

What is claimed is:
1. A compound of Formula I-C
Figure imgf000292_0001
I-C
or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:
X is O, S, NH or N-CN;
Ring A is formula A-1 or A-2
Figure imgf000292_0002
A-1 A-2
wherein the dashed lines are optional double bonds;
n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A is formula A-2;
G1, G2 and G3 are independently CRX or N, wherein no more than 2 of G1, G2 and G3 can be N;
each Rx is independently H, halogen, (l-4C)alkyl or (l-4C)alkoxy;
R1 is H, halogen, (l-3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(l-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(l-3C)alkyl (optionally substituted with 1-5 fluoros), (l-4C)alkyl (optionally substituted with 1-5 fluoros), CH3CH2NRy, CF3CH2NRy, HCF2CH2NRy, H2CFCH2NRy, CH3NRyCH2, RyRyNCH2CH2, RyRyNCH2CFH, or
RyRyNCH2CF2;
each Ry is independently H or methyl;
when n is 0, R is selected from the group consisting of H, halogen, (l-6C)alkyl
[optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH20-, amino(l-3C)alkyl,
CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyc3, hetCycaCH2, Cyca, hetAr1 and Ar1, and
when n is 1, R is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, methyl and methoxy.
hetCyc3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (1- 6C)alkoxy or (l-6C)alkyl [optionally substituted with 1-3 fluoros];
Cyca is a (3-6C)cycloalkyl optionally substituted with (l-4C)alkoxy, (l-4C)alkyl, F or
OH;
hetAr1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1 -2 groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, (l-4C)sulfanyl, hydroxy(l-4C)alkyl, (1- 6C)alkyl and CN;
Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl, or CF3, and
Rb is H, methyl or ethyl,
or Ra and Rb together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl ring;
Rc is H, methyl or ethyl
Rd is CF3CH2CH2, phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethy 1 ;
Ring C is formula C-l or C-2
Figure imgf000294_0001
C-l C-2
R3 is (l-6C)alkyl, hydroxy(l-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl, a C5-C8 bridged cycloalkyl, or hetAr2;
Ar2 is phenyl optionally substituted with one or more groups independently selected from halogen and (l-6C)alkyl;
hetCyc1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
R4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l- 6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l- 6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl,
aminocarbonyl(l -6C)alkyl, (1 -3C)alkylsulfonamido(l -6C)alkyl, sulfamido(l -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy,
monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafluoro(2- 6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy,
dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l- 6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy,
hydroxytrifluoro(l -6C)alkoxy, ( 1 -3C)alkylsulfonamido( 1 -6C)alkoxy, (1-3 C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl )amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1 - 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc3, halogen, CN, trifiuoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr5, Ar4-0-, hetCyc4-0-, Cyc'-O-, or aminohydroxy(l-6C)alkoxy; hetCyc2 is a 4-6 membered heterocyclic ring having 1 -2 ring heteroatoms
independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, 1-4C alkoxy)carbonyl, (l-6C)acyl, halogen and oxo;
hetCyc is a 4-7 membered heterocycle having 1 -2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents
independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1- 4C alkoxy)carbonyl;
hetCyc4 is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
Cyc1 is a 3-6 membered carbocycle optionally substituted with an amino group; hetAr3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;
Ar is phenyl optionally substituted with (l-4C)alkoxy;
hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l- 6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C
cycloalkyl)amino ;
hetAr5 is a group selected from the structures:
Figure imgf000295_0001
where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;
Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1- 3C alkoxy)(l-3C alkyl)OC(=0)-;
R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l- 4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy); or
R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
R4 and R5 together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=0)0-, (l-6C)acyl, (l-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(=0) or S02;
R3a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1- 6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen;
R4a is hydrogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (1- 6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1- 6C alkyl)amino, di(l-6C alkyl)amino and (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl; and
R5a is halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1- 6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (l-6C)alkyl and halogen.
2. A compound according to claim 1, wherein X is O.
3. A compound according to claim 1, wherein X is S.
4. A compound according to any one of claims 1 to 3, wherein Ring A is A-l .
5. A compound according to claim 4, wherein G1, G2 and G3 are CRX.
6. A compound according to claim 4, wherein:
G1 is N and G2 and G3 are CRX; or
G1 and G3 are CRX and G2 is N; or
G1 and G2 are CRX and G3 is N.
7. A compound according to claim 4, wherein:
G1 and G2 are N and G3 is CRX; or
G2 and G3 are N and G1 is CRX; or
G1 and G3 are N and G2 is CRX.
8. A compound according to any one of claims 1 to 7, wherein Rx is H or F.
9. A compound according to any one of claims 1 to 8, where n is 0 and R2 is selected from the group consisting of H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(l-4C)alkyl, (3-6C cycloalkyl)CH20-, amino(l-3C)alkyl, CF3CH2NHCH2, HCF2CH2NHCH2, a C5-C8 bridged cycloalkyl, hetCyca, hetCycaCH2, Cyca, hetAr1 and Ar1.
10. A compound according to claim 9, wherein R is selected from H, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy [optionally substituted with 1-5 fluoros], (3-6C cycloalkyl)CH20-, hetCyc3, and Cyca.
11. A compound according to any one of claims 1-8, where n is 1 and R2 is selected from the group consisting of H, halogen, CF3, F2CH, FCH2, methyl and methoxy.
12. A compound according to claim 11, wherein Rc is H and Rd is CF3CH2CH2, phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl.
13. A compound according to claim 12, wherein Rc is H and Rd is phenyl or phenylCH2- wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl.
14. A compound according to any one of claims 1-1 1, wherein R1 is (1- 3C)alkoxy(l-3C)alkyl (optionally substituted with 1-5 fluoros).
15. A compound according to claims 1-3, wherein Ring A is A-2.
16. A compound according to any one of claims 1-15, wherein Ra is H, (1- 3C)alkyl, cyclopropyl, cyclobutyl or CF3, and Rb is H, methyl or ethyl.
17. A compound claim 16, wherein Ra is H, (l-3C)alkyl, cyclopropyl, cyclobutyl or CF3 and Rb is H.
18. A compound claim 17, wherein Ra and Rb are H.
19. A compound according to any one of claims 1-18, wherein Ring C is formula
C-l .
20. A compound according to claim 19, wherein:
R4 is OH, (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l- 6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, hydroxy(l- 6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl(l-6C)alkyl, (l-3C)alkylsulfonamido(l-6C)alkyl, sulfamido(l-6C)alkyl, hydroxycarbonyl(l -6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy, monofluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, tetrafluoro(2- 6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc2(l- 6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(l-6C)alkoxy, hydroxycarbonyl(l-6C)alkoxy, aminocarbonyl(l- 6C)alkoxy, hetCyc2C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro(l -6C)alkoxy, ( 1 -3C)alkylsulfonamido( 1 -6C)alkoxy, ( 1 -3C)alkylamido( 1 - 6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc2C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1- 4C alkylcarboxy)(l-6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1- 3C alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr5, Ar4-0-, hetCyc4-0-, Cyc^O-, or aminohydroxy(l-6C)alkoxy; and R5 is (l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (l-4C)alkoxy, hydroxy(l- 4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(-O)-, (l-6C)alkylthio, (3- 4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy).
21. A compound according to claim 20, wherein R4 is selected from (1- 6C)alkoxy, cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, hetAr4 and hetAr5.
22. A compound according to claim 21, wherein R4 is (l-6C)alkoxy.
23. A compound according to claim 21 , wherein R4 is hetAr4 or hetAr5.
24. A compound according to any one of claims 1-23, wherein R5 is (l-6C)alkyl.
25. A compound according to any one of claims 1-24, wherein:
R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (l-6C)alkyl, or
R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said ring nitrogen atom is optionally substituted with (1-6C alkyl)C(=0)0-, or (l-6C)acyl, and said sulfur ring atom is optionally oxidized to S(=0) or S02.
26. A compound according to any one of claims 1-25, wherein R3 is selected from Ar2 and hetAr2.
27. A compound according to claim 26, wherein R3 is Ar2.
28. A compound according to claim 1, selected from a compound of Examples 1-
132.
29. A pharmaceutical composition, which comprises a compound of Formula I as defined in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
30. A method for treating a disease or disorder selected from pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.
31. The method of claim 29, wherein the method is a method of treating pain.
32. The method of claim 29, wherein said cancer is a cancer having a dysregulation of TrkA.
33. The method of claim 32, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.
34. A compound of Formula I as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.
35. Use of a compound of Formula I as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.
36. A process for the preparation of a compound of claim 1 , which comprises:
(a) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
Figure imgf000300_0001
II
with a corresponding compound having the formula III
Figure imgf000301_0001
III
in the presence carbonyldiimidazole or triphosgene and a base; or
(b) for a compound of Formula I where X is S, coupling a corresponding compound having the formula II
Figure imgf000301_0002
II
with a corresponding compound having the formula III
Figure imgf000301_0003
III
in the presence di(lH-imidazol-2-yl)methanethione and a base; or
(c) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
Figure imgf000301_0004
II
with a corresponding compound having the formula IV
Figure imgf000302_0001
IV
where L1 is a leaving group, in the presence of a base; or
(d) for a compound of Formula I where X is O, coupling a corresponding compound having the formula V
Figure imgf000302_0002
where L is a leaving group, with a corresponding compound having the formula III
Figure imgf000302_0003
III
in the presence of a base; or
(e) for a compound of Formula I where X is O, activating a corresponding compound having the formula VI
Figure imgf000302_0004
VI with diphenylphosphoryl azide followed by coupling the activated intermediate with a corresponding compound having the formula III
Figure imgf000303_0001
III
in the presence a base; or
(f) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II
Figure imgf000303_0002
II
with a corresponding compound having the formula VII
Figure imgf000303_0003
VII
in the presence of a base; or
(g) for a compound of Formula I where X is O, coupling a corresponding compound having the formula VIII
Figure imgf000304_0001
VIII
with a corresponding compound having the formula HI
Figure imgf000304_0002
III
in the presence of a base; and
optionally removing protecting groups and optionally preparing a pharmaceutically acceptable salt thereof.
PCT/US2013/069750 2012-11-13 2013-11-12 N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors WO2014078331A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/442,576 US9969694B2 (en) 2012-11-13 2013-11-12 N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261725933P 2012-11-13 2012-11-13
US61/725,933 2012-11-13

Publications (1)

Publication Number Publication Date
WO2014078331A1 true WO2014078331A1 (en) 2014-05-22

Family

ID=49667603

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/069750 WO2014078331A1 (en) 2012-11-13 2013-11-12 N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors

Country Status (2)

Country Link
US (1) US9969694B2 (en)
WO (1) WO2014078331A1 (en)

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
WO2017011776A1 (en) 2015-07-16 2017-01-19 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
WO2017075107A1 (en) 2015-10-26 2017-05-04 Nanda Nisha Point mutations in trk inhibitor-resistant cancer and methods relating to the same
US9718822B2 (en) 2010-05-20 2017-08-01 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9782415B2 (en) 2009-07-09 2017-10-10 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
WO2017176744A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2017176751A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9795611B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2018071454A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
WO2018071447A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10005783B2 (en) 2008-10-22 2018-06-26 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2018170381A1 (en) 2017-03-16 2018-09-20 Andrews Steven W Macrocyclic compounds as ros1 kinase inhibitors
US10160727B2 (en) 2014-08-06 2018-12-25 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TrkA inhibitory activity
EP3330256A4 (en) * 2015-07-07 2019-03-27 Shionogi & Co., Ltd. HETEROCYCLIC DERIVATIVE HAVING TrkA-INHIBITING ACTIVITY
CN109575006A (en) * 2018-12-30 2019-04-05 中南民族大学 A kind of diazole pyrazole amide analog derivative and its microwave attenuation materials method and application
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T Crystalline forms
WO2019084285A1 (en) 2017-10-26 2019-05-02 Qian Zhao Formulations of a macrocyclic trk kinase inhibitor
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
WO2019191659A1 (en) 2018-03-29 2019-10-03 Loxo Oncology, Inc. Treatment of trk-associated cancers
US10533006B2 (en) 2016-02-04 2020-01-14 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
WO2020028258A1 (en) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Spray-dried dispersions and formulations of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1h-pyrazole-4-carboxamide
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
EP3722441A1 (en) 2015-06-01 2020-10-14 Loxo Oncology Inc. Method of diagnosing a cancer for a treatment with a trk inhibitor
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117460731A (en) * 2021-06-11 2024-01-26 劲方医药科技(上海)有限公司 Heterocyclic lactams, process for their preparation and their use in medicine
CN115448864B (en) * 2022-08-26 2023-12-22 上海方予健康医药科技有限公司 Preparation method of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012188A1 (en) * 1999-08-12 2001-02-22 Pharmacia & Upjohn S.P.A. 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
WO2006070198A1 (en) * 2004-12-30 2006-07-06 Astex Therapeutics Limited Pyrazole derivatives as that modulate the activity of cdk, gsk and aurora kinases
WO2008124323A1 (en) 2007-04-03 2008-10-16 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
WO2010033941A1 (en) * 2008-09-22 2010-03-25 Array Biopharma Inc. Substituted imidazo[1,2b]pyridazine compounds as trk kinase inhibitors
WO2012158413A2 (en) * 2011-05-13 2012-11-22 Array Biopharma Inc. Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as trka kinase inhibitors

Family Cites Families (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU679887B2 (en) 1995-09-11 1997-07-10 Nihon Nohyaku Co., Ltd. Azole derivatives, their use, production and usage
CA2206201A1 (en) 1996-05-29 1997-11-29 Yoshiaki Isobe Pyrazole derivatives and their pharmaceutical use
US6083986A (en) 1996-07-26 2000-07-04 Icagen, Inc. Potassium channel inhibitors
US5998424A (en) 1997-06-19 1999-12-07 Dupont Pharmaceuticals Company Inhibitors of factor Xa with a neutral P1 specificity group
JP2001521934A (en) 1997-11-03 2001-11-13 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Aromatic heterocyclic compounds as anti-inflammatory drugs
WO1999032110A1 (en) 1997-12-22 1999-07-01 Bayer Corporation INHIBITION OF p38 KINASE ACTIVITY USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US6197798B1 (en) 1998-07-21 2001-03-06 Novartis Ag Amino-benzocycloalkane derivatives
CN1326848C (en) 1998-12-25 2007-07-18 帝国脏器制药株式会社 Aminopyrazole derivatives
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
US6410533B1 (en) 2000-02-10 2002-06-25 Genzyme Corporation Antibacterial compounds
AU2001273129A1 (en) 2000-06-30 2002-01-14 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloaklyl-piperidines as modulators of chemokine receptor activity
WO2002088101A2 (en) 2001-04-27 2002-11-07 Vertex Pharmaceuticals Incorporated Inhibitors of bace
GB0110901D0 (en) 2001-05-02 2001-06-27 Smithkline Beecham Plc Novel Compounds
ES2338539T3 (en) 2001-11-01 2010-05-10 Icagen, Inc. PIRAZOLAMIDS FOR USE IN PAIN TREATMENT.
WO2003045920A1 (en) 2001-11-27 2003-06-05 Merck & Co., Inc. 4-aminoquinoline compounds
SE0104248D0 (en) 2001-12-14 2001-12-14 Astrazeneca Ab Method of treatment
JP4498133B2 (en) 2002-07-02 2010-07-07 シェーリング コーポレイション Novel neuropeptide YY5 receptor antagonist
RU2338555C2 (en) 2002-10-08 2008-11-20 Ринат Ньюросайенс Корп. Method of treatment of postoperative pain by administering of antagonist of factor of growth of nerves and compositions containing factor of growth of nerves
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
WO2005024755A2 (en) 2002-12-31 2005-03-17 Deciphera Pharmaceuticals, Llc. Medicaments for the treatment of neurodegenerative disorders or diabetes
US20040171075A1 (en) 2002-12-31 2004-09-02 Flynn Daniel L Modulation of protein functionalities
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
SI2017265T1 (en) 2003-06-12 2011-09-30 Abbott Lab Fused compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
CA2545711A1 (en) 2003-11-13 2005-06-02 Ambit Biosciences Corporation Urea derivatives as kinase modulators
US20080220497A1 (en) 2003-12-24 2008-09-11 Flynn Daniel L Modulation of protein functionalities
JP4573223B2 (en) 2004-01-23 2010-11-04 東レ・ファインケミカル株式会社 Process for producing optically active trans-4-amino-1-benzyl-3-pyrrolidinol
ATE517885T1 (en) 2004-04-30 2011-08-15 Bayer Healthcare Llc SUBSTITUTED PYRAZOLYL UREA DERIVATIVES FOR THE TREATMENT OF CANCER
JP2008524213A (en) 2004-12-20 2008-07-10 アストラゼネカ・アクチエボラーグ Novel pyrazole derivatives and their use as modulators of nicotinic acetylcholine receptors
JP5197016B2 (en) 2004-12-23 2013-05-15 デシファラ ファーマスーティカルズ， エルエルシー Enzyme modulators and therapy
CA2592116A1 (en) 2004-12-23 2006-08-03 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
GB0510141D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B3
WO2007059202A2 (en) 2005-11-15 2007-05-24 Bayer Healthcare Ag Pyrazolyl urea derivatives useful in the treatment of cancer
US7514435B2 (en) 2005-11-18 2009-04-07 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
JP2009518298A (en) 2005-12-01 2009-05-07 バイエル ヘルスケア リミティド ライアビリティ カンパニー Urea compounds useful for cancer treatment
WO2008016811A2 (en) 2006-07-31 2008-02-07 Neurogen Corporation Aminopiperidines and realted compounds
US7605160B2 (en) 2006-08-09 2009-10-20 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
US7897762B2 (en) 2006-09-14 2011-03-01 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of proliferative diseases
US8188113B2 (en) 2006-09-14 2012-05-29 Deciphera Pharmaceuticals, Inc. Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US7790756B2 (en) 2006-10-11 2010-09-07 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
MX2009011343A (en) 2007-04-20 2009-11-05 Deciphera Pharmaceuticals Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases.
WO2008150899A1 (en) 2007-05-29 2008-12-11 Emory University Combination therapies for treatment of cancer and inflammatory diseases
ITMI20071731A1 (en) 2007-09-06 2009-03-07 Univ Degli Studi Genova NEW UREIC DERIVATIVES OF 1H-PIRAZOL-4-CARBOXYLIC ACID WITH INHIBITIVE ACTIVITY TOWARDS NEUTRROPHILES CHEMOTASSASSES
MX2010012457A (en) 2008-05-13 2010-12-07 Irm Llc Fused nitrogen containing heterocycles and compositions thereof as kinase inhibitors.
USRE48334E1 (en) 2008-09-19 2020-12-01 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound and use of same
JP2012505173A (en) 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー Pyrrolidine N-benzyl derivative
BRPI0919873B8 (en) 2008-10-22 2021-05-25 Array Biopharma Inc substituted pyrazol[1,5-a]pyrimidine compounds as trk kinase inhibitors, their preparation processes and pharmaceutical compositions
ES2605811T3 (en) 2008-11-19 2017-03-16 Merial, Inc. Dimeric 1-arylpyrazole derivatives
WO2010077680A2 (en) 2008-12-08 2010-07-08 Vm Discovery Inc. Compositions of protein receptor tyrosine kinase inhibitors
WO2010075376A2 (en) 2008-12-23 2010-07-01 Abbott Laboratories Anti-viral compounds
CA2753061C (en) 2009-02-19 2016-08-09 Alexandros Makriyannis Novel hetero pyrrole analogs acting on cannabinoid receptors
WO2010125799A1 (en) 2009-04-27 2010-11-04 塩野義製薬株式会社 Urea derivative having pi3k inhibitory activity
AR077468A1 (en) 2009-07-09 2011-08-31 Array Biopharma Inc PIRAZOLO COMPOUNDS (1,5-A) PYRIMIDINE SUBSTITUTED AS TRK-QUINASA INHIBITORS
WO2011032291A1 (en) 2009-09-18 2011-03-24 Zalicus Pharmaceuticals Ltd . Selective calcium channel modulators
LT3205654T (en) 2010-05-20 2019-05-27 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
EP2770987B1 (en) 2011-10-27 2018-04-04 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
WO2013096226A1 (en) 2011-12-19 2013-06-27 Abbvie Inc. Trpv1 antagonists
US9181261B2 (en) 2012-05-22 2015-11-10 Merck Sharp & Dohme Corp. TrkA kinase inhibitors, compositions and methods thereof
JP6280554B2 (en) 2012-09-28 2018-02-14 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Novel compounds that are ERK inhibitors
US9226922B2 (en) 2012-09-28 2016-01-05 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078417A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
HUE038512T2 (en) 2012-11-13 2018-10-29 Array Biopharma Inc N-pyrrolidinyl, n'-pyrazolyl- urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
HUE031557T2 (en) 2012-11-13 2017-07-28 Array Biopharma Inc Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078372A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2015039333A1 (en) 2013-09-22 2015-03-26 Merck Sharp & Dohme Corp. TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012188A1 (en) * 1999-08-12 2001-02-22 Pharmacia & Upjohn S.P.A. 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
WO2006070198A1 (en) * 2004-12-30 2006-07-06 Astex Therapeutics Limited Pyrazole derivatives as that modulate the activity of cdk, gsk and aurora kinases
WO2008124323A1 (en) 2007-04-03 2008-10-16 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
WO2010033941A1 (en) * 2008-09-22 2010-03-25 Array Biopharma Inc. Substituted imidazo[1,2b]pyridazine compounds as trk kinase inhibitors
WO2012158413A2 (en) * 2011-05-13 2012-11-22 Array Biopharma Inc. Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as trka kinase inhibitors

Non-Patent Citations (65)

* Cited by examiner, † Cited by third party
Title
"Protecting Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC.
ANSEL, HOWARD C. ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPINCOTT, WILLIAMS & WILKINS
BARDELLI, A., SCIENCE, vol. 300, 2003, pages 949
BEDIA KOÇYIGIT KAYMAKÇIOGLU ET AL: "Synthesis and biological evaluation of new N-substituted-N'-(3,5-di/1,3,5-trimethylpyrazole-4-yl)thiourea/urea derivatives", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 26, no. 1, 1 September 2005 (2005-09-01), pages 97 - 103, XP055093589, ISSN: 0928-0987, DOI: 10.1016/j.ejps.2005.05.005 *
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 12, 2004, pages 3345 - 3356
BRODEUR, G. M., NAT. REV. CANCER, 2003, pages 203 - 216
BRUNO O ET AL: "1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 17, no. 9, 1 May 2009 (2009-05-01), pages 3379 - 3387, XP026022780, ISSN: 0968-0896, [retrieved on 20090325], DOI: 10.1016/J.BMC.2009.03.035 *
CATTANEO, A., CURRENT OPINION IN MOLECULAR THERAPEUTICS, vol. 12, no. 1, 2010, pages 94 - 106
CHAMBERS L J ET AL: "Synthesis and structure@?activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, GB, vol. 20, no. 10, 15 May 2010 (2010-05-15), pages 3161 - 3164, XP027036811, ISSN: 0960-894X, [retrieved on 20100430] *
DAVIDSON. B. ET AL., CLIN. CANCER RES., vol. 9, 2003, pages 2248 - 2259
DE ARELLANO ET AL., FERTILITY AND STERILITY, vol. 95, no. 3, 2011, pages 1123 - 1126
DE ARELLANO, M.L. ET AL., REPRODUCTIVE SCIENCES, vol. 18, no. 12, 2011, pages 1202 - 1210
DELAFOY, L. ET AL., PAIN, vol. 105, 2003, pages 489 - 497
DI MOLA, F. F, GUT, vol. 46, no. 5, 2000, pages 670 - 678
DOU, Y.-C., ARCHIVES OF DERMATOLOGICAL RESEARCH, vol. 298, no. 1, 2006, pages 31 - 37
DU, J. ET AL., WORLD JOURNAL OF GASTROENTEROLOGY, vol. 9, no. 7, 2003, pages 1431 - 1434
EGUCHI, M. ET AL., BLOOD, vol. 93, no. 4, 1999, pages 1355 - 1363
ERIC ADRIAENSSENS, E. ET AL., CANCER RES, vol. 68, no. 2, 2008, pages 346 - 351
EUTHUS, D.M. ET AL., CANCER CELL, vol. 2, no. 5, 2002, pages 347 - 348
EXPERT OPIN. THER. PATENTS, vol. 19, no. 3, 2009, pages 305 - 319
FAUCHAIS, A.L. ET AL., SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, vol. 38, no. 1, 2009, pages 50 - 57
FREUND-MICHEL, V; FROSSARD, N., PHARMACOLOGY & THERAPEUTICS, vol. 117, no. 1, 2008, pages 52 - 76
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS & WILKINS
GRECO, A. ET AL., MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 321, no. 1, 2010, pages 44 - 49
GRUBER-OLIPITZ, M. ET AL., JOURNAL OF PROTEOME RESEARCH, vol. 7, no. 5, 2008, pages 1932 - 1944
GWAK, Y. S. ET AL., NEUROSCI. LETT., vol. 336, 2003, pages 117 - 120
HERZBERG, U. ET AL., PAIN, vol. 79, 1997, pages 265 - 274
HU VIVIAN Y, THE JOURNAL OF UROLOGY, vol. 173, no. 3, 2005, pages 1016 - 21
J. HETEROCYCLIC; CHEMISTRY, vol. 47, 2010, pages 287 - 291
J. ORG. CHEM., vol. 43, 1978, pages 2879 - 2882
JAGGAR, S. I. ET AL., BR. J ANAESTH., vol. 83, 1999, pages 442 - 448
JIN, W. ET AL., CARCINOGENESIS, vol. 31, no. 11, 2010, pages 1939 - 1947
K. ASAUMI ET AL., BONE, vol. 26, no. 6, 2000, pages 625 - 633
KIM, H.C. ET AL., DIABETIC MEDICINE, vol. 26, no. 12, 2009, pages 1228 - 1234
KOUDIH, R. ET AL., EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, 2012, pages 408 - 415
LAMB, K. ET AL., NEUROGASTROENTEROL. MOTIL., vol. 15, 2003, pages 355 - 361
LI, L. ET AL., MOL. CELL. NEUROSCI., vol. 23, 2003, pages 232 - 250
LI, Y.-G. ET AL., CHINESE JOURNAL OF CANCER PREVENTION AND TREATMENT, vol. 16, no. 6, 2009, pages 428 - 430
LIU, H.-T. ET AL., BJU INTERNATIONAL, vol. 106, no. 11, 2010, pages 1681 - 1685
MA, Q. P.; WOOLF, C. J., NEUROREPORT, vol. 8, 1997, pages 807 - 810
MCMAHON, S.B. ET AL., NAT. MED, vol. 1, 1995, pages 774 - 780
MELO-JORGE, M ET AL., CELL HOST & MICROB, vol. 1, no. 4, 2007, pages 251 - 261
MEYER, J. ET AL., LEUKEMIA, 2007, pages 1 - 10
MILLER, L.J. ET AL., UROLOGY, vol. 59, no. 4, 2002, pages 603 - 608
NAKAGAWARA, A., CANCER LETTERS, vol. 169, 2001, pages 107 - 114
NEUROREPORT, vol. 8, pages 1613 - 1618
ORG. LETT., vol. 14, no. 12, 2012, pages 3138 - 3141
OSSIPOV, M.H., CURRENT PAIN AND HEADACHE REPORTS, vol. 15, no. 3, 2011, pages 185 - 192
PATAPOUTIAN, A. ET AL., CURRENT OPINION IN NEUROBIOLOGY, vol. 11, 2001, pages 272 - 280
PIEROTTIA, M.A.; GRECO A., CANCER LETTERS, vol. 232, 2006, pages 90 - 98
RAMER, M. S.; BISBY, M. A., EUR. J NEUROSCI., vol. 11, 1999, pages 837 - 846
RAYCHAUDHURI, S. P. ET AL., J INVESTIGATIVE DERMATOLOGY, vol. 122, no. 3, 2004, pages 812 - 819
RICCI A. ET AL., AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, vol. 25, no. 4, pages 439 - 446
ROWE, RAYMOND C.: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS
SHELTON, D. L. ET AL., PAIN, vol. 116, 2005, pages 8 - 16
SINISCALCO, D. ET AL., CURRENT NEUROPHARMACOLOGY, vol. 9, no. 4, 2011, pages 523 - 529
THEODOSIOU, M. ET AL., PAIN, vol. 81, 1999, pages 245 - 255
TRUZZI, F. ET AL., DERMATO-ENDOCRINOLOGY, vol. 3, no. 1, 2008, pages 32 - 36
VAN HENDE ET AL., J. ORG. CHEM., vol. 74, 2009, pages 2250 - 2253
WADHWA, S. ET AL., JOURNAL OF BIOSCIENCES, vol. 28, no. 2, 2003, pages 181 - 188
WANG T ET AL: "Trk kinase inhibitors as new treatments for cancer and pain", EXPERT OPINION ON THERAPEUTIC PATENTS, INFORMA HEALTHCARE, GB, vol. 19, no. 3, 1 March 2009 (2009-03-01), pages 305 - 319, XP002557234, ISSN: 1354-3776, DOI: 10.1517/13543770902721261 *
WATANABE, T. ET AL., BJU INTERNATIONAL, vol. 108, no. 2, 2011, pages 248 - 251
WOOLF, C.J. ET AL., NEUROSCIENCE, vol. 62, 1994, pages 327 - 331
YILMAZ, T. ET AL., CANCER BIOLOGY AND THERAPY, vol. 10, no. 6, 2010, pages 644 - 653
ZAHN, P.K. ET AL., J. PAIN, vol. 5, 2004, pages 157 - 163

Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10011604B2 (en) 2008-09-22 2018-07-03 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9796723B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US10590139B2 (en) 2008-09-22 2020-03-17 Array Biopharma Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9795611B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US11267818B2 (en) 2008-10-22 2022-03-08 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10005783B2 (en) 2008-10-22 2018-06-26 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10774085B2 (en) 2008-10-22 2020-09-15 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US10047097B2 (en) 2008-10-22 2018-08-14 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US9796724B2 (en) 2009-07-09 2017-10-24 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9782415B2 (en) 2009-07-09 2017-10-10 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US10758542B2 (en) 2009-07-09 2020-09-01 Array Biopharma Inc. Substituted pyrazolo[l,5-a]pyrimidine compounds as Trk kinase inhibitors
US10251889B2 (en) 2009-07-09 2019-04-09 Array BioPharm Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9750744B2 (en) 2010-05-20 2017-09-05 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9902741B2 (en) 2010-05-20 2018-02-27 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9718822B2 (en) 2010-05-20 2017-08-01 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9840519B2 (en) 2010-05-20 2017-12-12 Array Biopharma, Inc. Macrocyclic compounds as TRK kinase inhibitors
US10323022B2 (en) 2011-05-13 2019-06-18 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9878997B2 (en) 2011-05-13 2018-01-30 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10851080B2 (en) 2012-11-13 2020-12-01 Array Biopharma Inc. Methods of treatment using pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10889589B2 (en) 2012-11-13 2021-01-12 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
US10532985B2 (en) 2014-08-06 2020-01-14 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TRKA inhibitory activity
US10160727B2 (en) 2014-08-06 2018-12-25 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TrkA inhibitory activity
US10285993B2 (en) 2014-11-16 2019-05-14 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10799505B2 (en) 2014-11-16 2020-10-13 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10813936B2 (en) 2014-11-16 2020-10-27 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-YL)-pyrazolo[1,5-A]pyrimidin-3-YL)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10172861B2 (en) 2014-11-16 2019-01-08 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
EP3722441A1 (en) 2015-06-01 2020-10-14 Loxo Oncology Inc. Method of diagnosing a cancer for a treatment with a trk inhibitor
US10640495B2 (en) 2015-07-07 2020-05-05 Shionogi & Co., Ltd. Heterocycle derivatives having TrkA inhibitory activity
EP3330256A4 (en) * 2015-07-07 2019-03-27 Shionogi & Co., Ltd. HETEROCYCLIC DERIVATIVE HAVING TrkA-INHIBITING ACTIVITY
US10174027B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2017011776A1 (en) 2015-07-16 2017-01-19 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10138243B2 (en) 2015-07-16 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10174028B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10655186B2 (en) 2015-10-26 2020-05-19 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10724102B2 (en) 2015-10-26 2020-07-28 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
WO2017075107A1 (en) 2015-10-26 2017-05-04 Nanda Nisha Point mutations in trk inhibitor-resistant cancer and methods relating to the same
US10907215B2 (en) 2015-10-26 2021-02-02 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10378068B2 (en) 2015-10-26 2019-08-13 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10370727B2 (en) 2015-10-26 2019-08-06 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10533006B2 (en) 2016-02-04 2020-01-14 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
US11008320B2 (en) 2016-02-04 2021-05-18 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
US10781210B2 (en) 2016-02-04 2020-09-22 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
US11191766B2 (en) 2016-04-04 2021-12-07 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10668072B2 (en) 2016-04-04 2020-06-02 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10137127B2 (en) 2016-04-04 2018-11-27 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
WO2017176744A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11484535B2 (en) 2016-04-04 2022-11-01 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
WO2017176751A1 (en) 2016-04-04 2017-10-12 Loxo Oncology, Inc. Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10588908B2 (en) 2016-04-04 2020-03-17 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US10555944B2 (en) 2016-10-10 2020-02-11 Eli Lilly And Company Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018071447A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US11998545B2 (en) 2016-10-10 2024-06-04 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10441581B2 (en) 2016-10-10 2019-10-15 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11648243B2 (en) 2016-10-10 2023-05-16 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
EP4144735A1 (en) 2016-10-10 2023-03-08 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
WO2018071454A1 (en) 2016-10-10 2018-04-19 Andrews Steven W Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10953005B1 (en) 2016-10-10 2021-03-23 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10137124B2 (en) 2016-10-10 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10881652B2 (en) 2016-10-10 2021-01-05 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
EP3753939A1 (en) 2016-10-10 2020-12-23 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172845B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172851B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
US11851434B2 (en) 2017-01-18 2023-12-26 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyrazine compounds as ret kinase inhibitors
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US11168090B2 (en) 2017-01-18 2021-11-09 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
WO2018170381A1 (en) 2017-03-16 2018-09-20 Andrews Steven W Macrocyclic compounds as ros1 kinase inhibitors
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T Crystalline forms
WO2019084285A1 (en) 2017-10-26 2019-05-02 Qian Zhao Formulations of a macrocyclic trk kinase inhibitor
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
US11472802B2 (en) 2018-01-18 2022-10-18 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
US11603374B2 (en) 2018-01-18 2023-03-14 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
WO2019191659A1 (en) 2018-03-29 2019-10-03 Loxo Oncology, Inc. Treatment of trk-associated cancers
WO2020028258A1 (en) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Spray-dried dispersions and formulations of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1h-pyrazole-4-carboxamide
US11964988B2 (en) 2018-09-10 2024-04-23 Array Biopharma Inc. Fused heterocyclic compounds as RET kinase inhibitors
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
CN109575006A (en) * 2018-12-30 2019-04-05 中南民族大学 A kind of diazole pyrazole amide analog derivative and its microwave attenuation materials method and application
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use

Also Published As

Publication number Publication date
US20160272592A1 (en) 2016-09-22
US9969694B2 (en) 2018-05-15

Similar Documents

Publication Publication Date Title
WO2014078331A1 (en) N-(arylalkyl)-n&#39;-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
AU2017221802B2 (en) Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US10323022B2 (en) Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9822118B2 (en) Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078322A1 (en) Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078328A1 (en) N-bicyclic aryl,n&#39;-pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078325A1 (en) N-(monocyclic aryl),n&#39;-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078417A1 (en) Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078378A1 (en) Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13795949

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 14442576

Country of ref document: US

122 Ep: pct application non-entry in european phase

Ref document number: 13795949

Country of ref document: EP

Kind code of ref document: A1