WO2009007753A2 - 4- (3-aminopyrazole) -pyrimidine derivativee and their use as tyrosine kinase inhibitors for the treatment of cancer - Google Patents

4- (3-aminopyrazole) -pyrimidine derivativee and their use as tyrosine kinase inhibitors for the treatment of cancer Download PDF

Info

Publication number
WO2009007753A2
WO2009007753A2 PCT/GB2008/050553 GB2008050553W WO2009007753A2 WO 2009007753 A2 WO2009007753 A2 WO 2009007753A2 GB 2008050553 W GB2008050553 W GB 2008050553W WO 2009007753 A2 WO2009007753 A2 WO 2009007753A2
Authority
WO
WIPO (PCT)
Prior art keywords
heterocyclyl
carbocyclyl
occurrence
alkyl
optionally
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2008/050553
Other languages
French (fr)
Other versions
WO2009007753A3 (en
Inventor
Huiping Guan
Stephanos Ioannidis
Michelle Lamb
Bo Peng
Mei Su
Tao Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
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 AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2009007753A2 publication Critical patent/WO2009007753A2/en
Publication of WO2009007753A3 publication Critical patent/WO2009007753A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention relates to novel compounds, their pharmaceutical compositions and methods of use.
  • the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these compounds in the manufacture of medicaments for the treatment and prevention of myeloproliferative disorders and cancers.
  • JAK Janus-associated kinase
  • STAT signal transducers and activators of transcription
  • the JAK family consists of four non-receptor tyrosine kinases Tyk2, JAKl, JAK2, and JAK3, which play a critical role in cytokine- and growth factor mediated signal transduction.
  • Cytokine and/or growth factor binding to cell-surface receptor(s) promotes receptor dimerization and facilitates activation of receptor-associated JAK by autophosphorylation.
  • Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STATl, 2, 3, 4, 5a, 5b and 6).
  • Receptor- bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus.
  • the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including, but not limited to, genes encoding apoptosis inhibitors (e.g. BcI-XL, McI-I) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).
  • apoptosis inhibitors e.g. BcI-XL, McI-I
  • cell cycle regulators e.g. Cyclin D1/D2, c-myc
  • JAK2 JAK2 kinase domain with an oligomerization domain
  • TEL- JAK2 JAK2 kinase domain with an oligomerization domain
  • Bcr-JAK2 oligomerization domain
  • PCM1-JAK2 PCM1-JAK2
  • V617F valine-to- phenylalanine
  • the present invention relates to compounds of Formula (I):
  • the compounds of Formula (I) are believed to possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body.
  • the invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man.
  • the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer.
  • the properties of the compounds of Formula (I) are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinases are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplasia syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma,
  • the present invention relates to compounds of Formula (I):
  • Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ;
  • X is selected from -O- and -S-;
  • R 1 is selected from H, -CN, Ci ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -C(O)H, -C(O)R lb , -C(O) 2 R la , -C(0)N(R la ) 2 , -0C(0)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(0)N(R la ) 2 , -OC(O)R lb , -S(O)R lb , -S(O) 2 R lb , -S(O) 2 N(R la
  • R la in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 ;
  • R lb in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 ;
  • R 2 is selected from H, halo, -CN, Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -C(O)H, -C(O)R 2b
  • R 2a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;
  • R 2b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 20 ;
  • R 3 is selected from H, halo, -CN, Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3a , -N(R 3a )C(O) 2 R 3a , -N(R 3a )C(O)N(R 3a ) 2 , -OC(O)R 3b
  • R 3b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ;
  • R 4 is selected from H, -CN, Ci ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O)N(R 4a ) 2 , -OC(O)R 4b , -S(O)R 4b , -S(O) 2 R 4b , -S(O) 2 R 4b , -S(O) 2 N(R 4
  • R 4a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 40 ;
  • R 4b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 5 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 5a , -SR 5a , -N(R 5a ) 2 , -N(R 5a )C(O)R 5b , -N(R 5a )N(R 5a ) 2 , -NO 2 , -C(O)H, -C(O)R 5b , -C(O) 2 R 53 , -C(O)N(R 5a ) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a , -N(R 5a )C(O) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R
  • R 5b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 50 ;
  • R 10 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 10a , -SR 1Oa , -N(R 10a ) 2 , -N(R 10a )C(O)R 10b , -N(R 10a )N(R 10a ) 2 , -NO 2 , -C(O)H, -C(O)R 10b , -C(O) 2 R 10a , -C(O)N(R 10a ) 2 , -OC(O)N(R 10a ) 2 , -N(R 10a )C(O) 2 R 10a , -N(R 10a )C(O) 2 , -S(O)R 10b , -S(O)R 10b ,
  • R 1Ob in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R a ;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 20a ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -NO 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a , -N(R 20a )C(O) 2 , -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2
  • R 20a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;
  • R 20b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R b R 30 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 3Oa , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 3Oa )N(R 3Oa ) 2 , -NO 2 , -C(O)H, -C(O)R 30b , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 , -OC(O)N(R 30a ) 2 , -N(R 30a )C(O) 2 R 30a , -N(R 30a )C(O) 2 R 30a , -N(R 30a )C(O) 2 R 30a , -
  • R 30a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R c ;
  • R 30b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 40 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b ,
  • R 40a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R d ;
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 50 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 50a , -SR 5Oa , -N(R 50a ) 2 , -N(R 50a )C(O)R 50b , -N(R 50a )N(R 50a ) 2 , -NO 2 , -C(O)H, -C(O)R 50b , -C(O) 2 R 50a , -C(O)N(R 50a ) 2 , -OC(O)N(R 50a ) 2 , -N(R 50a )C(O) 2 R 50a , -N(R 50a )C(O) 2 R 50a , -N(R 50a )C(O) 2 , -OC(O)N(R 50a
  • R 50b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R e ; R a , R b , R c , R d , and R e in each occurrence are independently selected from halo, -CN, Ci_6alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR m , -SR m , -N(R m ) 2 , -N(R m )C(O)R n , -N(R m )N(R m ) 2 , -NO 2 , -C(O)H, -C(O)R", -C(O) 2 R 111 , -C(O)N(R m ) 2 , -OC(O)N(R m ) 2 , -N(R m )C(O) 2 R m , -N(R m )C(0)N(R m ) 2 ,
  • R" in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl.
  • Ci- 4 alkyl includes Cialkyl (methyl), C 2 alkyl (ethyl), Csalkyl (propyl and isopropyl) and C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and ⁇ -butyl).
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • alkenyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond.
  • C2-6alkenyl includes, but is not limited to, groups such as C 2 - 5 alkenyl, C 2 - 4 alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
  • alkynyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond.
  • C2-6alkynyl includes, but is not limited to, groups such as C 2 - 5 alkynyl, C 2 - 4 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
  • Halo refers to fluoro, chloro, bromo and iodo. In one aspect, the term “halo” may refer to fluoro, chloro, and bromo. In another aspect, the term “halo” may refer to fluoro and chloro. In still another aspect, the term “halo” may refer to fluoro.
  • Carbocyclyl - refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • Carbocyclyl include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl.
  • “carbocyclyl” may refer to cyclopropyl.
  • Carbocyclyl may be "3- to 6-membered carbocyclyl.”
  • the term “3- to 6-membered carbocyclyl” refers to a saturated, partially saturated, or unsaturated monocyclic carbon ring containing 3 to 6 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • 3- to 6-membered carbocyclyl include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl, cyclopentenyl, cyclohexyl, and phenyl.
  • "3- to 6-membered carbocyclyl” may be cyclopropyl.
  • carbocyclyl and “3- to 6-membered carbocyclyl” may be “3- to 5-membered carbocyclyl.”
  • the term “3- to 5- membered carbocyclyl” refers to a saturated or partially saturated monocyclic carbon ring containing 3 to 5 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • 3- to 5-membered carbocyclyl include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl, and cyclopentenyl.
  • "3- to 5-membered carbocyclyl” may be cyclopropyl.
  • Heterocyclyl refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • heterocyclyl include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydrofuranyl, tetra
  • heterocyclyl may be “5- or 6-memberedd heterocyclyl.”
  • heterocyclyl refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • “5- or 6-membered heterocyclyl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • "5- or 6-membered heterocyclyl” include, but are not limited to, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholino, oxazolyl, 2- oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thi
  • heterocyclyl and “5- or 6-membered heterocyclyl” may be “6-membered heterocycyl.”
  • the term “6-membered heterocyclyl” refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • “6-membered heterocyclyl” groups may be carbon or nitrogen linked.
  • Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperidinyl, morpholino, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
  • heterocyclyl may be “6-membered heteroaryl.”
  • heteroaryl is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms.
  • 6-membered heteroaryl groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
  • 6-membered heteroaryl include, but are not limited to, pyrazinyl, pyridazinyl, pyrimidinyl, and pyridinyl.
  • heterocyclyl may be “4- to 6- membered non-aromatic heterocyclyl.”
  • the term "4- to 6-Membered Non- Aromatic Heterocyclyl” refers to a non-aromatic, monocyclic ring containing 4 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • “4- to 6-membered non-aromatic heterocyclyl” groups may be carbon or nitrogen linked.
  • Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "4- to 6-membered non-aromatic heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, oxetanyl, oxoimidazolidinyl, 3-oxo-l-piperazinyl, 2-oxopyrrolidinyl, oxo-1,3- thiazolidinyl, 2-oxotetrahydrofuranyl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, , tetrahydrofuranyl, tetrahydropyranyl, , thiazo
  • 6-Membered Non- Aromatic ⁇ eterocvclyl 6-Membered Non- Aromatic ⁇ eterocvclyl -
  • heterocyclyl "5- or 6-membered heterocyclyl,” “6-membered heterocyclyl,” and “4- to 6-membered non-aromatic heterocyclyl” may be “6-membered non-aromatic heterocyclyl.”
  • the term “6-membered non- aromatic heterocyclyl” is intended to refer to a saturated or partially saturated, monocyclic, non- aromatic heterocyclyl ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -C ⁇ 2- group can optionally be replaced by a -C(O)-.
  • 6-membered non-aromatic heterocyclyl groups may be carbon or nitrogen linked. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • Illustrative examples of "6-membered non- aromatic heterocyclyl” include 3,5-dioxopiperidinyl, morpholinyl, piperazinyl, piperidyl, 2H- pyranyl, tetrahydropyranyl, and thiomorpholinyl.
  • the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
  • Effective Amount means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.
  • Optionally substituted indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
  • a particular group when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted.
  • the particular group may bear one substituent.
  • the particular substituent may bear two substituents.
  • the particular group may bear three substituents.
  • the particular group may bear four substituents.
  • the particular group may bear one or two substituents.
  • the particular group may be unsubstituted, or may bear one or two substituents.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • protecting group is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.
  • suitable protecting groups for a hydroxy group include, but are not limited to, an acyl group; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl.
  • the deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • suitable protecting groups for an amino group include, but are not limited to, acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • alkanoyl groups such as acetyl
  • alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl
  • arylmethoxycarbonyl groups such as benzyloxycarbonyl
  • aroyl groups such benzoyl.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a ⁇ -butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persul
  • basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others.
  • Non-toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • Some compounds of Formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
  • the invention further relates to any and all tautomeric forms of the compounds of Formula (I).
  • Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ; and R 5 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 5a , -SR 5a , -N(R 5a ) 2 , -N(R 5a )C(O)R 5b , -C(O)H, -C(O)R 5b , -C(O) 2 R 53 , -C(O)N(R 5a ) 2 , -OC(O)R 5a , -N(R 5a )C(O)N(R 5a ) 2 , -S(O)R 5b , -S(O) 2 R 5b , -S(O)(O
  • R 5a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 -6alkenyl C 2 -6alkynyl, carbocyclyl, and heterocyclyl in
  • R 5b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 50 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl,
  • R 50a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 50b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl.
  • Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ; and R 5 is halo.
  • Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with one or more R 5 ; and R 5 is halo.
  • Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl are substituted with at least one R 5 ;
  • R is halo
  • Ring A is selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl are optionally substituted with one or more R 5 ; and R 5 is halo.
  • Ring A is selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl are optionally substituted with one or more R 5 ; and R 5 is fluoro.
  • Ring A is selected from 3,5-difluoropyridinyl, 4-fluorophenyl, 5-fluoropyridin-2- yl, and 5-fluoropyrimidin-2-yl.
  • Ring A is 4-fluorophenyl.
  • Ring A is 5-fluoropyridin-2-yl.
  • Ring A is 5-fluoropyrimidin-2-yl.
  • Ring A is 3,5-difluoropyridinyl.
  • X is selected from -O- .
  • X is -S-.
  • R 1 is selected from H, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -C(O)H, -C(O)R lb , -C(O) 2 R 13 , -C(O)N(R la ) 2 , -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(O)N(R la ) 2 , -OC(O)R lb ,
  • Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ;
  • R 1Oa in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from Ci- 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl.
  • R 1 is selected from Ci_ 6 alkyl and -OR la ; and R la is Ci_ 6 alkyl.
  • R 1 is selected from C h alky 1, 3- to 6-membered carbocyclyl, and -OR la ;
  • R la is Ci_ 6 alkyl.
  • R 1 is Ci_ 6 alkyl.
  • R 1 is selected from -OR la ; and R la is Ci_ 6 alkyl.
  • R 1 is selected from cyclopropyl, methoxy, and methyl.
  • R 1 is selected from methyl and methoxy.
  • R 1 is methyl. In another aspect, R 1 is methoxy.
  • R 1 is cyclopropyl
  • R 2 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -NO 2 , -C(O)H, -C(O)R 2b , -C(O) 2 R 2a ,
  • Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 20 ;
  • R 2a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;
  • R 2b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl wherein said C h alky 1, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 20 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl,
  • RR 2200aa iinn eeaacchh ooccccuurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and he 2tteerrocyclyl;
  • RR 2200bb iinn eeaacchh occurrence is independently selected from C h alky!, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, and heterocyclyl.
  • R 2 is selected from H, halo, and Ci_ 6 alkyl.
  • R 2 is selected from H.
  • R 2 is selected from halo. In a further aspect, R 2 is selected from Ci_ 6 alkyl.
  • R 2 is selected from H, fluoro, chloro, and methyl.
  • R 2 is selected from fluoro.
  • R 2 is selected from chloro. In another aspect, R 2 is selected from methyl.
  • R 3 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -OC(O)R 3a , -N(R 3a )C(O)N(R 3a ) 2 , -S(O)R 3b , -S(O) 2 R 3b , -S(O) 2 N(R 3a ) 2 , and -N(R 3a )S(O) 2 R 3b , wherein said Ci- ⁇ alkyl, C 2
  • R 3a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ;
  • R 3b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ; R 30 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl,
  • R 3 is selected from H and heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R 30 ; and R 30 is C 1-6 alkyl.
  • R 3 is selected from H and 4- to 6-membered non-aromatic heterocyclyl.
  • R 3 is selected from H and 6-membered non-aromatic heterocyclyl.
  • W ,30" is C 1-6 alkyl.
  • R is piperazinyl, wherein said piperazinyl is optionally substituted with one or more R 30 ;
  • R 30 is C 1-6 alkyl.
  • R 3 is selected from H, morpholin-4-yl, piperazin-1-yl, and 4- methylpiperazin- 1 -yl.
  • R is H.
  • R 3 is morpholino
  • R is piperazin-1-yl.
  • R 3 is 4-methylpiperazin-l-yl.
  • R 3 is morpholin-4-yl.
  • R 4 is selected from H, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl,
  • Ci_ 6 alkyl, C 2 _ 6 alkenyl, and C 2 _ 6 alkynyl are optionally substituted with one or more R 40 ;
  • R 4a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 40 ;
  • R 4b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 40 ; R 40 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl,
  • R 40a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl.
  • R is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more R 40 ;
  • R 40 is -OR 40a ;
  • R 40a in each occurrence is independently selected from H and Ci_ 6 alkyl.
  • R 4 is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or m l o O rree RR 4400 ;; R 40 is -OR 40a ; and R 40a is C 1-6 alkyl.
  • R »4 4 is methyl
  • R 4 is selected from hydroxymethyl and methoxymethyl.
  • R 4 is selected from methyl, hydroxymethyl, and methoxymethyl.
  • R 4 is selected from methyl and methoxymethyl.
  • Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ;
  • X is selected from -O- and -S-;
  • R 1 is selected from H, -CN, Ci ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR la ,
  • Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 10 ;
  • R la in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 ;
  • R lb in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl wherein said C h alky 1, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 2 is selected from H, halo, -CN, Ci ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl,
  • R 2a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;
  • R 2b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl wherein said Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 3 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 ,
  • Ci_ 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ;
  • R 3a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ;
  • R 3b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ;
  • R 4 is selected from H, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, -N(R 4a )C(O)R 4b , -NO 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 43 , -C(O)N(R 4a ) 2 , -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O)N(R 4a ) 2 , -OC(O)R 4b , -S(O)R 4b , -S(O) 2 R 4b , -S(O) 2 N(R 4a ) 2 , and -N(R 4a )S(O) 2 R 4b , wherein said Ci- ⁇ alkyl, C 2 _ 6
  • R 4a in each occurrence is independently selected from H, C h alky 1, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 40 ;
  • R 4b in each occurrence is independently selected from C h alky!, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 40 ;
  • R 5 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 5a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 50 ;
  • R 5b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
  • R 50 ; R 10 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl,
  • R 1Oa in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl,
  • R 20a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, and heterocyclyl;
  • R 30 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 3Oa , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -C(O)H,
  • R 30a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _ 6 alkenyl,
  • R 40a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 50 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _ 6 alkenyl,
  • R 50a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 50b in each occurrence is independently selected from Ci- 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl.
  • Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ;
  • X is selected from -O- and -S-;
  • R 1 is selected from Ci_ 6 alkyl, and -0R la ; and R la is Ci_ 6 alkyl;
  • R 2 is selected from H, halo, and Ci_6alkyl
  • R 3 is selected from H and heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R 30 ;
  • R 4 is Ci- ⁇ alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more R 40 ;
  • R 5 is halo
  • R 30 is C 1-6 alkyl
  • R 40 is -OR 40a ;
  • R 40a in each occurrence is independently selected from H and Ci_ 6 alkyl.
  • Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl are substituted with at least one R 5 ;
  • X is selected from -O- and -S-;
  • R 1 is selected from Ci_6alkyl, 3- to 6-membered carbocyclyl, and -OR la ;
  • R la is C 1-6 alkyl
  • R 2 is selected from H, halo, and Ci_6alkyl
  • R 3 is selected from H and 4- to 6-membered non-aromatic heterocyclyl
  • R is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more R ;
  • R 5 is halo
  • R 40a is C 1-6 alkyl.
  • Ring A is selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl are optionally substituted with one or more R 5 ; and
  • X is selected from -O- and -S-;
  • R 1 is selected from C 1-6 alkyl, and -OR la ;
  • R la is Ci_ 6 alkyl;
  • R 2 is selected from H, halo, and Ci- ⁇ alkyl
  • R is selected from H, morpholino, and piperazinyl, wherein said morpholino and piperazinyl is optionally substituted with one or more R ;
  • R 4 is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more R 40 ;
  • R 5 is halo;
  • R 30 is C 1-6 alkyl
  • R 40 is -OR 40a ;
  • R 40a in each occurrence is independently selected from H and Ci_ 6 alkyl.
  • Ring A is selected from 3,5-difluoropyridinyl, 4-fluorophenyl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl;
  • X is selected from -O- and -S-;
  • R 1 is selected from methyl and methoxy;
  • R 2 is selected from H, fluoro, chloro, and methyl;
  • R 3 is selected from H, morpholin-4-yl, piperazin-1-yl, and 4-methylpiperazin-l-yl; and R 4 is selected from methyl, hydroxymethyl, and methoxymethyl.
  • the compound of Formula (I) is a compound of Formula (Ia):
  • Ring A, X, R 1 , R 2 , R 3 , and R 4 are as defined hereinabove.
  • the compound of Formula (I) is a compound of Formula (Ib):
  • Ring A, X, R 1 , R 2 , R 3 , and R 4 are as defined hereinabove.
  • the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • the present invention provides the following compounds of Formula (I), or a pharmaceutically acceptable salt thereof:
  • the present invention provides the following compounds of Formula (I), or a pharmaceutically acceptable salt thereof:
  • the compounds of Formula (I) have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinase are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic mye
  • Tyrosine kinase inhibitors particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.
  • the compounds of Formula (I) have been shown to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2, as determined by the JAK2 Assay described herein.
  • the compounds of Formula (I) should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2. These would be provided in commercial kits comprising a compound of this invention.
  • JAK2 kinase activity may be determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified
  • Luminescent Proximity Assay Alphascreen
  • JAK2 kinase activity a commercially available purified enzyme may be used.
  • the enzyme may be C-terminal His6-tagged, recombinant, human JAK2, amino acids 808-end, (Genbank Accession number NM 004972) expressed by baculovirus in Sf21 cells (Upstate Biotechnology MA).
  • ATP adenosine triphosphate
  • the kinase reaction may be stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the reaction may be performed in 384 well microtitre plates and the reaction products may be detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specif ⁇ c antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature.
  • Teween 20 is a registered trademark of ICI Americas, Inc.
  • the JAK inhibitory activity of the following examples was measured at the following IC50S.
  • a hyphen indicates that an IC50 value was not provided for that particular compound, and is not meant to imply that the particular compound does not possess IC50 activity.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and hematologic tumors), f ⁇ broproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma
  • a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancers solid and hematologic tumors
  • f ⁇ broproliferative and differentiative disorders psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man
  • said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing an anti-proliferative effect in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing a JAK inhibitory effect in a warmblooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating cancer in a warm-blooded animal comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti -proliferative effect, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a warm-blooded animal such as man.
  • the treatment (or prophylaxis) of cancer may particularly refer to the treatment (or prophylaxis) of mesoblastic nephroma, mesothelioma, acute myeloblasts leukemia, acute lymphocytic leukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukaemia, tumors of the central and peripheral nervous
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_-hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin.
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti -tumor agents:
  • antiproliferative/antineoplastic drags and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirabicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as
  • 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (AbI) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (GleevecTM); and any agents that modify STAT signalling; (v) antiangiogenic agents such as those which inhibit the effects of vascular endotheli
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine -transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drags thalidomide and lenalidomide [Revlimid ® ]; and (x) other treatment regimes including: dexamethasone, proteasome inhibitors (including bortezomib), isotretinoin (13-cis retinoic acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitors CEP-701 and CEP-2563, anti-Trk or anti
  • 131I-MIBG anti-G(D2) monoclonal antibody therapy with or without granulocyte- macrophage colony-stimulating factor (GM-CSF) following chemotherapy.
  • GM-CSF granulocyte- macrophage colony-stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of JAK2 in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • any of the alternate embodiments of the compounds of the invention described herein also apply.
  • the inhibition of JAK activity particularly refers to the inhibition of JAK2 activity.
  • the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.
  • compounds of Formula (I), or pharmaceutically acceptable salts thereof may be prepared by:
  • compounds of Formula (X), which are compounds of Formula (I) in which X is -S-, or pharmaceutically acceptable salts thereof, may be prepared by:
  • Process A - Compounds of Formula (A) and compounds of Formula (B) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • the reaction may advantageously occur in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction may be advantageously performed at a temperature in a range from 0 0 C to reflux. Heating the reaction may be particularly advantageous.
  • compounds of Formula (A) and compounds of Formula (B) may be reacted together under standard Buchwald conditions (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066), with a suitable base.
  • suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ⁇ -butoxide.
  • Such a reaction may advantageously occur in the presence of a palladium catalyst such as palladium acetate.
  • solvents suitable for such a reaction include toluene, benzene, dioxane, and xylene.
  • the -NH- moiety of the compound of Formula (B) may advantageously be protected with a suitable protecting group, examples of which include protecting groups such as tert-butoxycarbonyl.
  • Process B - Compounds of Formula (D) and compounds of Formula (B) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
  • L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
  • Compounds of Formula (B) and compounds of Formula (E) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid-2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid-2-one.
  • the reaction advantageously will take place in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction is advantageously performed at a temperature in a range from 0 C to reflux.
  • Compounds of Formula (C) may be reacted with Na 2 S in a solvent such as DMF.
  • temperatures are given in degrees Celsius ( 0 C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 0 C;
  • a "Gilson column” refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H 2 OMeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturer's instructions, obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A;
  • "Biotage” refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12g, 4Og, 80 g etc.), used according to the manufacturer's instructions, obtained from Biotage Inc, 1725 Discovery Drive Charlotteville,
  • SFC super critical fluid chromatography
  • Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psi) and temperatures to 80 0 C;
  • the following abbreviations may be used: BINAP 2,2'-bis(diphenylphosphino)-l,l '-binapthyl
  • a 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd 2 (dba) 3 (0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol).
  • the flask was evacuated and backfilled with N 2 , and anhydrous DMAc.
  • the vial was mounted onto a Personal Chemistry microwave reactor and heated at 100 0 C for 10 hours.
  • the reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer was obtained and evaporated to dryness.
  • Example 2(a) First Eluting Compound 5-Chloro-2-ri-(4-fluorophenyl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine, Enantiomer A
  • the first eluting compound (52 mg) had retention time of 8.65 minutes.
  • Example 2(b) Second Eluting Compound 5-Chloro-2-r(l-(4-fluorophenyl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine, Enantiomer B
  • the second eluting compound (49 mg) had a retention time of 11.61 minutes.
  • Enantiomeric excess for each enantiomer of Example 2 was estimated to be > 99%, using area percentage at 210nm.
  • the first eluting compound had a retention time of 11.00 min.
  • the second eluting compound had a retention time of 13.71 minutes.
  • Enantiomeric excess for each enantiomer of Example 3 was estimated to be > 98%, using area percentage at 220 nm.
  • Example 4
  • Oven 40 0 C Outlet: 100 bar Post purification purity check Chiral SFC using ultraviolet diode array Column: AD-H, 250 x 4.6mm Conditions: 20% isopropanol, 0.1% dimethylethylamine Flow rate: 3 ml/min; 15 minutes Oven: 35°C
  • Example 4(a) First Eluting Compound 5-Fluoro-2-[l-(5-fluoropyridin-2-yl N )ethoxyl-N-(5-methyl-lH-pyrazol-3-yl N )pyrimidin-4-amine, Enantiomer A
  • the first eluting compound had a retention time of 4.80 minutes.
  • Example 4(b) Second Eluting Compound 5-Fluoro-2-[l-(5-fluoropyridin-2-yl N )ethoxyl-N-(5-methyl-lH-pyrazol-3-yl N )pyrimidin-4-amine, Enantiomer B
  • the second eluting compound had a retention time of 6.59 minutes.
  • Enantiomeric excess for each enantiomer of Example 4 was estimated to be > 98%, using area percentage at 254 nm.
  • the first eluting compound had a retention time of 3.34 minutes.
  • the second eluting compound had a retention time of 5.99 minutes..
  • Enantiomeric excess for each enantiomer of Example 5 was estimated to be > 98%, using area percentage at 254 nm.
  • a microwave tube was charged with 6-chloro-2-(l-(5-fluoropyridin-2-yl)ethoxy)-N-(5-methoxy- lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 11, 129mg, 0.35mmol), n-BuO ⁇ (2.5mL), morpholine (0.062mL, 0.71mmol), DIPEA (0.092mL, 0.53mmol).
  • the reaction mixture was heated under microwave condition to 160 0 C for 6hrs. Evaporation of the volatiles under reduced pressure afforded an oil. Purification by Gilson (0-60% MeCN/water, 0.1% TFA) provided the title product (37mg, white solid) as a mixture of enantiomers.
  • Modifier / additive 25 % Methanol Flow rate (ml/min): 60
  • Modifier / additive 20 % Isopropanol/ 0.4 % dimethylethylamine Flow rate (ml/min): 60 Oven ( 0 C): 40 Outlet Pressure (bar): 100 Wavelength (nm) : 254 nm Post purification purity check
  • Modifier / additive 20 % Isopropanol/ 0.4 % dimethylethylamine Flow rate (ml/min): 5
  • the first eluting comound had a retention time of 20.54 minutes.
  • the second eluting compound had a retention time of 24.11 minutes.
  • Enantiomeric excess for each enantiomer of Example 8 was estimated to be > 98%, using area percentage at 254 nm.
  • Modifier / additive 20 % Isopropanol/ 0.1 % dimethylethylamine
  • Enantiomer A The first eluting comound had a retention time of 1.62 minutes.
  • Enantiomeric excess for each enantiomer of Example 9 was estimated to be > 98%, using area percentage at 254 nm.

Landscapes

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

Abstract

The present invention relates to compounds of Formula (I) and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds provide a treatment for myeloproliferative disorders and cancer.

Description

Chemical Compounds 916-1
Field of the Invention
The present invention relates to novel compounds, their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these compounds in the manufacture of medicaments for the treatment and prevention of myeloproliferative disorders and cancers.
Background of the Invention The JAK (Janus-associated kinase)/STAT (signal transducers and activators of transcription) signalling pathway is involved in a variety of hyperproliferative and cancer related processes including cell-cycle progression, apoptosis, angiogenesis, invasion, metastasis and evasion of the immune system (Haura et al, Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al, Cancer and Metastasis Reviews, 2003, 22, 423-434).
The JAK family consists of four non-receptor tyrosine kinases Tyk2, JAKl, JAK2, and JAK3, which play a critical role in cytokine- and growth factor mediated signal transduction. Cytokine and/or growth factor binding to cell-surface receptor(s), promotes receptor dimerization and facilitates activation of receptor-associated JAK by autophosphorylation. Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STATl, 2, 3, 4, 5a, 5b and 6). Receptor- bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus. Once in the nucleus, the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including, but not limited to, genes encoding apoptosis inhibitors (e.g. BcI-XL, McI-I) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).
Over the past decade, a considerable amount of scientific literature linking constitutive JAK and/or STAT signalling with hyperproliferative disorders and cancer has been published. Constitutive activation of the STAT family, in particular STAT3 and STAT5, has been detected in a wide range of cancers and hyperproliferative disorders (Haura et al, Nature Clinical Practice Oncology, 2005, 2(6), 315-324). Furthermore, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders (Tibes et al., Annu Rev Pharmacol Toxicol 2550, 45, 357-384; Choudhary et al., International Journal of Hematology 2005, 82(2), 93-99; Sordella et al., Science 2004, 305, 1163-1167). In addition, impairment of negative regulatory proteins, such as the suppressors of cytokine signalling (SOCS) proteins, can also influence the activation status of the JAK/STAT signalling pathway in disease (JC Tan and Rabkin R, Pediatric Nephrology
2005, 20, 567-575).
Several mutated forms of JAK2 have been identified in a variety of disease settings. For example, translocations resulting in the fusion of the JAK2 kinase domain with an oligomerization domain, TEL- JAK2, Bcr-JAK2 and PCM1-JAK2, have been implicated in the pathogenesis of various hematologic malignancies (SD Turner and Alesander DR, Leukemia,
2006, 20, 572-582). More recently, a unique acquired mutation encoding a valine-to- phenylalanine (V617F) substitution in JAK2 was detected in a significant number of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis patients and to a lesser extent in several other diseases. The mutant JAK2 protein is able to activate downstream signalling in the absence of cytokine stimulation, resulting in autonomous growth and/or hypersensitivity to cytokines and is believed to play a role in driving these diseases (MJ Percy and McMullin MF, Hematological Oncology 2005, 23(3-4), 91-93).
Summary of the Invention
The present invention relates to compounds of Formula (I):
Figure imgf000004_0001
or pharmaceutically acceptable salts thereof.
The compounds of Formula (I) are believed to possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man. Also in accordance with the present invention the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer.
The properties of the compounds of Formula (I) are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinases, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplasia syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.
Furthermore, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia; particularly myeloma, leukemia, ovarian cancer, breast cancer and prostate cancer.
Detailed Description of the Invention
The present invention relates to compounds of Formula (I):
Figure imgf000005_0001
or pharmaceutically acceptable salts thereof, wherein
Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ; X is selected from -O- and -S-;
R1 is selected from H, -CN, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -C(O)H, -C(O)Rlb, -C(O)2Rla, -C(0)N(Rla)2, -0C(0)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(0)N(Rla)2, -OC(O)Rlb, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R10;
Rla in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
Rlb in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10; R2 is selected from H, halo, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R20;
R2a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ; R2b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R20;
R3 is selected from H, halo, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -OC(O)N(R3a)2, -N(R3a)C(O)2R3a, -N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3a), and -C(R3a)=N(OR3a), wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R30; R3a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R3b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R4 is selected from H, -CN, Ci^alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R40;
R4a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R40; R4b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R40;
R5 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR5a, -SR5a, -N(R5a)2, -N(R5a)C(O)R5b, -N(R5a)N(R5a)2, -NO2, -C(O)H, -C(O)R5b, -C(O)2R53, -C(O)N(R5a)2, -OC(O)N(R5a)2, -N(R5a)C(O)2R5a, -N(R5a)C(O)N(R5a)2, -OC(O)R5b, -S(O)R5b, -S(O)2R5b, -S(O)2N(R5a)2, -N(R5a)S(O)2R5b, -C(R5a)=N(R5a), and -C(R5a)=N(OR5a), wherein said C1-6alkyl, C2-6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R5 ; R5a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R5b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R10 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR1Oa, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -OC(O)R10b, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R1Oa)=N(R1Oa), and -C(R10a)=N(OR10a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Ra; R1Oa in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Ra;
R1Ob in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Ra;
R20 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a), wherein said C1-6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rb;
R20a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;
R20b in each occurrence is independently selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
Rb; R30 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR3Oa, -N(R30a)2, -N(R30a)C(O)R30b, -N(R3Oa)N(R3Oa)2, -NO2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -OC(O)N(R30a)2, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, -OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R3Oa)=N(R3Oa), and -C(R30a)=N(OR30a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rc;
R30a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rc; R30b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
Rc;
R40 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b,
-N(R40a)N(R40a)2, -NO2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rd;
R40a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R d ; R40b in each occurrence is independently selected from Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
Rd;
R50 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR50a, -SR5Oa, -N(R50a)2, -N(R50a)C(O)R50b, -N(R50a)N(R50a)2, -NO2, -C(O)H, -C(O)R50b, -C(O)2R50a, -C(O)N(R50a)2, -OC(O)N(R50a)2, -N(R50a)C(O)2R50a, -N(R50a)C(O)N(R50a)2, -OC(O)R50b, -S(O)R50b, -S(O)2R50b, -S(O)2N(R50a)2, -N(R50a)S(O)2R50b, -C(R5Oa)=N(R5Oa), and -C(R50a)=N(OR50a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Re; R50a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Re;
R50b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
Re; Ra, Rb, Rc, Rd, and Re in each occurrence are independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -ORm, -SRm, -N(Rm)2, -N(Rm)C(O)Rn, -N(Rm)N(Rm)2, -NO2, -C(O)H, -C(O)R", -C(O)2R111, -C(O)N(Rm)2, -OC(O)N(Rm)2, -N(Rm)C(O)2Rm, -N(Rm)C(0)N(Rm)2, -OC(O)R", -S(O)R", -S(O)2R", -S(O)2N(Rm)2, -N(Rm)S(O)2R", -C(Rm)=N(Rm), and -C(Rm)=N(0Rm); Rm in each occurrence is independently selected from H, Chalky 1, carbocyclyl, and heterocyclyl; and
R" in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl.
In this specification the prefix Cx_y as used in terms such as Cx_yalkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, Ci-4alkyl includes Cialkyl (methyl), C2alkyl (ethyl), Csalkyl (propyl and isopropyl) and C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and ϊ-butyl).
Alkyl - As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
Alkenyl - As used herein, the term "alkenyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C2-6alkenyl" includes, but is not limited to, groups such as C2-5alkenyl, C2-4alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
Alkynyl - As used herein, the term "alkynyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C2-6alkynyl" includes, but is not limited to, groups such as C2-5alkynyl, C2-4alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
Halo - As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo. In one aspect, the term "halo" may refer to fluoro, chloro, and bromo. In another aspect, the term "halo" may refer to fluoro and chloro. In still another aspect, the term "halo" may refer to fluoro.
Carbocyclyl - As used herein, the term "carbocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH2- groups may be optionally replaced with a corresponding number of -C(O)- groups. Illustrative examples of "carbocyclyl" include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl. In one aspect, "carbocyclyl" may refer to cyclopropyl.
3- to 6-Membered Carbocvclyl - In one aspect, "carbocyclyl" may be "3- to 6-membered carbocyclyl." As used herein, the term "3- to 6-membered carbocyclyl" refers to a saturated, partially saturated, or unsaturated monocyclic carbon ring containing 3 to 6 ring atoms, of which one or more -CH2- groups may be optionally replaced with a corresponding number of -C(O)- groups. Illustrative examples of "3- to 6-membered carbocyclyl" include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl, cyclopentenyl, cyclohexyl, and phenyl. In one aspect, "3- to 6-membered carbocyclyl" may be cyclopropyl.
3- to 5-Membered Carbocvclyl - In one aspect, "carbocyclyl" and "3- to 6-membered carbocyclyl" may be "3- to 5-membered carbocyclyl." As used herein, the term "3- to 5- membered carbocyclyl" refers to a saturated or partially saturated monocyclic carbon ring containing 3 to 5 ring atoms, of which one or more -CH2- groups may be optionally replaced with a corresponding number of -C(O)- groups. Illustrative examples of "3- to 5-membered carbocyclyl" include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl, and cyclopentenyl. In one aspect, "3- to 5-membered carbocyclyl" may be cyclopropyl.
Heterocyclyl - As used herein, the term "heterocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thiophenyl, pyridine-N-oxidyl and quinoline-N-oxidyl. 5- or 6-Membered Heterocyclyl - In one aspect, "heterocyclyl" may be "5- or 6-memberedd heterocyclyl." As used herein, the term "5- or 6-membered heterocyclyl" refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "5- or 6-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "5- or 6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholino, oxazolyl, 2- oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thiophenyl, pyridine-N-oxidyl.
6-Membered Ηeterocvclyl - In one aspect, "heterocyclyl" and "5- or 6-membered heterocyclyl" may be "6-membered heterocycyl." As used herein, the term "6-membered heterocyclyl" refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "6-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperidinyl, morpholino, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
6-Membered Ηeteroaryl - In one aspect, "heterocyclyl", "5- or 6-membered heterocyclyl," and "6-membered heterocyclyl" may be "6-membered heteroaryl." As used herein, the term "6- membered heteroaryl" is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms. Unless otherwise specified, "6-membered heteroaryl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
Illustrative examples of the term "6-membered heteroaryl" include, but are not limited to, pyrazinyl, pyridazinyl, pyrimidinyl, and pyridinyl.
4- to 6- Membered Non- Aromatic Heterocvclyl - In one aspect, "heterocyclyl" may be "4- to 6- membered non-aromatic heterocyclyl." The term "4- to 6-Membered Non- Aromatic Heterocyclyl" refers to a non-aromatic, monocyclic ring containing 4 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "4- to 6-membered non-aromatic heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "4- to 6-membered non-aromatic heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, oxetanyl, oxoimidazolidinyl, 3-oxo-l-piperazinyl, 2-oxopyrrolidinyl, oxo-1,3- thiazolidinyl, 2-oxotetrahydrofuranyl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, , tetrahydrofuranyl, tetrahydropyranyl, , thiazolidinyl, and thiomorpholinyl.
6-Membered Non- Aromatic Ηeterocvclyl - In one aspect, "heterocyclyl", "5- or 6-membered heterocyclyl," "6-membered heterocyclyl," and "4- to 6-membered non-aromatic heterocyclyl" may be "6-membered non-aromatic heterocyclyl." As used herein, the term "6-membered non- aromatic heterocyclyl" is intended to refer to a saturated or partially saturated, monocyclic, non- aromatic heterocyclyl ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CΗ2- group can optionally be replaced by a -C(O)-. Unless otherwise specified, "6-membered non-aromatic heterocyclyl" groups may be carbon or nitrogen linked. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of "6-membered non- aromatic heterocyclyl" include 3,5-dioxopiperidinyl, morpholinyl, piperazinyl, piperidyl, 2H- pyranyl, tetrahydropyranyl, and thiomorpholinyl.
Where a particular R group (e.g. Rla, R10, etc.) is present in a compound of Formula (I) more than once, it is intended that each selection for that R group is independent at each occurrence of any selection at any other occurrence. For example, the -N(R)2 group is intended to encompass: 1) those -N(R)2 groups in which both R substituents are the same, such as those in which both R substituents are, for example, Ci_6alkyl; and 2) those -N(R)2 groups in which each R substituent is different, such as those in which one R substituent is, for example, H, and the other R substituent is, for example, carbocyclyl.
Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
Effective Amount - As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
In particular, an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.
Leaving Group - As used herein, the phrase "leaving group" is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, and alcohol nucleophile, or a thiol nucleophile. Examples of suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.
Optionally substituted - As used herein, the phrase "optionally substituted," indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
In one aspect, when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted. In another aspect, the particular group may bear one substituent. In another aspect, the particular substituent may bear two substituents. In still another aspect, the particular group may bear three substituents. In yet another aspect, the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents.
Pharmaceutically Acceptable - As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Protecting Group - As used herein, the term "protecting group" is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.
Illustrative examples of suitable protecting groups for a hydroxy group include, but are not limited to, an acyl group; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl. The deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
Illustrative examples of suitable protecting groups for an amino group include, but are not limited to, acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ϊ-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl. The deprotection conditions for the above amino protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a ϊ-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
With reference to substituent R for illustrative purposes, the following substituent definitions have the indicated meanings:
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
The compounds discussed herein in many instances were named and/or checked with ACD/Name by ACD/Labs®.
Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
Some compounds of Formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers. The invention further relates to any and all tautomeric forms of the compounds of Formula (I).
It is also to be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
Ring A
In one aspect, Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ; and R5 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR5a, -SR5a, -N(R5a)2, -N(R5a)C(O)R5b, -C(O)H, -C(O)R5b, -C(O)2R53, -C(O)N(R5a)2, -OC(O)R5a, -N(R5a)C(O)N(R5a)2, -S(O)R5b, -S(O)2R5b, -S(O)2N(R5a)2, and -N(R5a)S(O)2R5b, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R5a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2-6alkenyl C2-6alkynyl, carbocyclyl, and heterocyclyl in
50 each occurrence are optionally and independently substituted with one or more R
R5b in each occurrence is independently selected from Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R50;
R50 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR50a, -SR5Oa, -N(R50a)2, -N(R50a)C(O)R50b,
-N(R50a)N(R50a)2, -NO2, -C(O)H, -C(O)R50b, -C(O)2R50a, -C(O)N(R50a)2, -OC(O)N(R50a)2, -N(R50a)C(O)2R50a, -N(R50a)C(O)N(R50a)2, -OC(O)R50b, -S(O)R50b, -S(O)2R50b, -S(O)2N(R50a)2,
-N(R50a)S(O)2R50b, -C(R5Oa)=N(R5Oa), and -C(R50a)=N(OR50a);
R50a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; and
R50b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl.
In another aspect, Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ; and R5 is halo.
In still another aspect, Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with one or more R5; and R5 is halo.
In yet another aspect, Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl are substituted with at least one R5; and
R is halo.
In a further aspect, Ring A is selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl are optionally substituted with one or more R5; and R5 is halo. In still a further aspect, Ring A is selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl are optionally substituted with one or more R5; and R5 is fluoro.
In one aspect, Ring A is selected from 3,5-difluoropyridinyl, 4-fluorophenyl, 5-fluoropyridin-2- yl, and 5-fluoropyrimidin-2-yl.
In another aspect, Ring A is 4-fluorophenyl.
In still another aspect, Ring A is 5-fluoropyridin-2-yl.
In yet another aspect, Ring A is 5-fluoropyrimidin-2-yl.
In a further aspect, Ring A is 3,5-difluoropyridinyl.
X
In one aspect, X is selected from -O- .
In another aspect, X is -S-.
In one aspect, R1 is selected from H, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -C(O)H, -C(O)Rlb, -C(O)2R13, -C(O)N(Rla)2, -OC(O)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -OC(O)Rlb,
-S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ;
Rla in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10; Rlb in each occurrence is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10; R10 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR1Oa, -N(R10a)2, -N(R10a)C(O)R10b, -C(O)H, -C(O)R10b, -C(O)2R103, -C(O)N(R10a)2, -OC(O)R10b, -N(R10a)C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, and -N(R10a)S(O)2R10b;
R1Oa in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; and
R1Ob in each occurrence is independently selected from Ci-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl.
In another aspect, R1 is selected from Ci_6alkyl and -ORla; and Rla is Ci_6alkyl.
In still another aspect, R1 is selected from Chalky 1, 3- to 6-membered carbocyclyl, and -ORla; and
Rla is Ci_6alkyl.
In yet another aspect, R1 is Ci_6alkyl.
In a further aspect, R1 is selected from -ORla; and Rla is Ci_6alkyl.
In still a further aspect, R1 is selected from cyclopropyl, methoxy, and methyl.
In yet a further aspect, R1 is selected from methyl and methoxy.
In one aspect, R1 is methyl. In another aspect, R1 is methoxy.
In still another aspect, R1 is cyclopropyl.
R2.
In one aspect, R2 is selected from H, halo, -CN, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -NO2, -C(O)H, -C(O)R2b, -C(O)2R2a,
-C(O)N(R2a)2, -OC(O)R2b, -N(R2a)C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, and
-N(R2a)S(O)2R2b, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R20;
R2a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;
R2b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl wherein said Chalky 1, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R20;
R20 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -C(O)H,
--CC((OO))RR2200bb,, --CC((OO))22RR2200aa,, --CC((OO))NN((RR2200aa))22,, --OC(O)R20b, -N(R20a)C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b,
-S(O)2N(R2200aa)\2, and j -N Λ.τ(rRr> 2200aa)\Scv(O/~»)\2R r>220
^2IN (^ 0bb;.
RR2200aa iinn eeaacchh ooccccuurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and he 2tteerrocyclyl; and
RR2200bb iinn eeaacchh , occurrence is independently selected from Chalky!, C2_6alkenyl, C2_6alkynyl, and heterocyclyl.
In another aspect, R2 is selected from H, halo, and Ci_6alkyl.
In still another aspect, R2 is selected from H.
In yet another aspect, R2 is selected from halo. In a further aspect, R2 is selected from Ci_6alkyl.
In still a further aspect, R2 is selected from H, fluoro, chloro, and methyl.
In yet a further aspect, R2 is selected from fluoro.
In one aspect, R2 is selected from chloro. In another aspect, R2 is selected from methyl.
E!
In one aspect, R3 is selected from H, halo, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -OC(O)R3a, -N(R3a)C(O)N(R3a)2, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, and -N(R3a)S(O)2R3b, wherein said Ci-βalkyl, C2_6alkenyl, and C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ;
R3a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R3b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30; R30 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR3Oa, -N(R30a)2, -N(R30a)C(O)R30b, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -OC(O)R30a, -N(R30a)C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, and -N(R30a)S(O)2R30b; R30a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; and R30b in each occurrence is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl.
In another aspect, R3 is selected from H and heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R30; and R30 is C1-6alkyl.
In still another aspect, R3 is selected from H and 4- to 6-membered non-aromatic heterocyclyl.
In yet another aspect, R3 is selected from H and 6-membered non-aromatic heterocyclyl.
In a further aspect, R3 is selected from H, morpholino, and piperazinyl, wherein said morpholino and piperazinyl are optionally substituted with one or more R 30 ;. and
W ,30" is C1-6alkyl.
In still a further aspect, R is piperazinyl, wherein said piperazinyl is optionally substituted with one or more R30; R30 is C1-6alkyl.
In yet a further aspect, R3 is selected from H, morpholin-4-yl, piperazin-1-yl, and 4- methylpiperazin- 1 -yl.
In one aspect, R is H.
In another aspect, R3 is morpholino.
In still another aspect, R is piperazin-1-yl.
In yet another aspect, R3 is 4-methylpiperazin-l-yl.
In one aspect, R3 is morpholin-4-yl. E!
In one aspect, R4 is selected from H, -CN, Ci_6alkyl, C2-6alkenyl, and C2-6alkynyl,
-N(R4a)C(O)R4b, -NO2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, and
-N(R4a)S(O)2R4b, wherein said Ci_6alkyl, C2_6alkenyl, and C2_6alkynyl are optionally substituted with one or more R40;
R4a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R40;
R4b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R40; R40 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -NO2,
-C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)R40a, -N(R40a)C(O)N(R40a)2, -S(O)R40b,
-S(O)2R40b, -S(O)2N(R40a)2, and -N(R40a)S(O)2R40b;
R40a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; and
R40b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl.
In another aspect, R is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more R40;
R40 is -OR40a; and
R40a in each occurrence is independently selected from H and Ci_6alkyl.
In still another aspect, R4 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or m loOrree RR4400;; R40 is -OR40a; and R40a is C1-6alkyl.
In still another aspect, R »44 is methyl.
In yet another aspect, R4 is selected from hydroxymethyl and methoxymethyl.
In a further aspect, R4 is selected from methyl, hydroxymethyl, and methoxymethyl.
In still a further aspect, R4 is selected from methyl and methoxymethyl.
Ring A, X, R1. R2, R3, and R4
In one aspect, Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ;
X is selected from -O- and -S-; R1 is selected from H, -CN, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla,
-SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -C(O)H, -C(O)Rlb, -C(O)2Rla,
-C(O)N(Rla)2, -OC(O)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -OC(O)Rlb, -S(O)Rlb,
-S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said
Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R10;
Rla in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
Rlb in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl wherein said Chalky 1, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R10;
R2 is selected from H, halo, -CN, Ci^alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl,
-OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -NO2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -OC(O)R2b, -N(R2a)C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, and -N(R2a)S(O)2R2b, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 20. R2a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ; R2b in each occurrence is independently selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R20;
R3 is selected from H, halo, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2,
-OC(O)R3a, -N(R3a)C(O)N(R3a)2, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, and -N(R3a)S(O)2R3b, wherein said Ci_6alkyl, C2-6alkenyl, and C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ; R3a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R3b in each occurrence is independently selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Chalky 1, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R4 is selected from H, -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, -N(R4a)C(O)R4b, -NO2, -C(O)H, -C(O)R4b, -C(O)2R43, -C(O)N(R4a)2, -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, and -N(R4a)S(O)2R4b, wherein said Ci-βalkyl, C2_6alkenyl, and C2_6alkynyl are optionally substituted with one or more R40;
R4a in each occurrence is independently selected from H, Chalky 1, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R40; R4b in each occurrence is independently selected from Chalky!, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R40;
R5 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR5a, -SR5a, -N(R5a)2, -N(R5a)C(O)R5b, -C(O)H,
-C(O)R5b, -C(O)2R53, -C(O)N(R5a)2, -OC(O)R5a, -N(R5a)C(O)N(R5a)2, -S(O)R5b, -S(O)2R5b, -S(O)2N(R5a)2, and -N(R5a)S(O)2R5b, wherein said d_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R5a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R5b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more
R50; R10 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR1Oa, -N(R10a)2, -N(R10a)C(O)R10b, -C(O)H,
-C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -OC(O)R10b, -N(R10a)C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b,
-S(O)2N(R10a)2, and -N(R10a)S(O)2R10b;
R1Oa in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R1Ob in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R20 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -OC(O)R20b, -N(R20a)C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b,
-S(O)2N(R20a)2, and -N(R20a)S(O)2R20b;
R20a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R20b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, and heterocyclyl;
R30 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR3Oa, -N(R30a)2, -N(R30a)C(O)R30b, -C(O)H,
-C(O)R30b, -C(O)2R303, -C(O)N(R30a)2, -OC(O)R30a, -N(R30a)C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b,
-S(O)2N(R30a)2, and -N(R30a)S(O)2R30b;
R30a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R30b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R40 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -NO2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)R40a, -N(R40a)C(O)N(R40a)2, -S(O)R40b,
-S(O)2R40b, -S(O)2N(R40a)2, and -N(R40a)S(O)2R40b;
R40a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R40b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R50 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR50a, -SR5Oa, -N(R50a)2, -N(R50a)C(O)R50b,
-N(R50a)N(R50a)2, -NO2, -C(O)H, -C(O)R50b, -C(O)2R50a, -C(O)N(R50a)2, -OC(O)N(R50a)2,
-N(R50a)C(O)2R50a, -N(R50a)C(O)N(R50a)2, -OC(O)R50b, -S(O)R50b, -S(O)2R50b, -S(O)2N(R50a)2, -N(R50a)S(O)2R50b, -C(R5Oa)=N(R5Oa), and -C(R50a)=N(OR50a);
R50a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; and
R50b in each occurrence is independently selected from Ci-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl.
In another aspect, Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ; and
X is selected from -O- and -S-;
R1 is selected from Ci_6alkyl, and -0Rla; and Rla is Ci_6alkyl;
R2 is selected from H, halo, and Ci_6alkyl; R3 is selected from H and heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R30;
R4 is Ci-βalkyl, wherein said Ci_6alkyl is optionally substituted with one or more R40;
R5 is halo;
R30 is C1-6alkyl;
R40 is -OR40a; and
R40a in each occurrence is independently selected from H and Ci_6alkyl.
Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl are substituted with at least one R5;
X is selected from -O- and -S-;
R1 is selected from Ci_6alkyl, 3- to 6-membered carbocyclyl, and -ORla;
Rla is C1-6alkyl;
R2 is selected from H, halo, and Ci_6alkyl; R3 is selected from H and 4- to 6-membered non-aromatic heterocyclyl;
R is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more R ;
R5 is halo;
R40 is -OR40a; and
R40a is C1-6alkyl.
In still another aspect, Ring A is selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl are optionally substituted with one or more R5; and
X is selected from -O- and -S-;
R1 is selected from C1-6alkyl, and -ORla; Rla is Ci_6alkyl;
R2 is selected from H, halo, and Ci-βalkyl;
R is selected from H, morpholino, and piperazinyl, wherein said morpholino and piperazinyl is optionally substituted with one or more R ;
R4 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more R40; R5 is halo;
R30 is C1-6alkyl; R40 is -OR40a; and
R40a in each occurrence is independently selected from H and Ci_6alkyl.
In yet another aspect, Ring A is selected from 3,5-difluoropyridinyl, 4-fluorophenyl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl; X is selected from -O- and -S-; R1 is selected from methyl and methoxy; R2 is selected from H, fluoro, chloro, and methyl;
R3 is selected from H, morpholin-4-yl, piperazin-1-yl, and 4-methylpiperazin-l-yl; and R4 is selected from methyl, hydroxymethyl, and methoxymethyl.
In a further aspect, Ring A is selected from 3,5-difluoropyridinyl, 4-fluorophenyl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl; X is selected from -O- and -S-; R1 is selected from cyclopropyl, methyl, and methoxy; R2 is selected from H, fluoro, chloro, and methyl; R3 is selected from H and morpholin-4-yl; and R4 is selected from methyl and methoxymethyl.
In one aspect, the compound of Formula (I) is a compound of Formula (Ia):
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, X, R1, R2, R3, and R4 are as defined hereinabove.
In another aspect, the compound of Formula (I) is a compound of Formula (Ib):
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, X, R1, R2, R3, and R4 are as defined hereinabove.
In one aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
In still another aspect, the present invention provides the following compounds of Formula (I), or a pharmaceutically acceptable salt thereof:
5-Chloro-2- { [( I1S)- 1 -(4-fluorophenyl)ethyl]thio} -N-(5 -methyl- lH-pyrazol-3 -yl)pyrimidin-4- amine;
5-Chloro-2-[(l.S)-l-(4-fluorophenyl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine; 5-Chloro-2-[(l1S)-l-(5-fluoropyridin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine;
5-Fluoro-2-[(l1S)-l-(5-fluoropyridin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine; 5-Chloro-2-[(l1S)-l-(5-fluoropyrimidin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine;
5-Chloro-N-(5-cyclopropyl-lH-pyrazol-3-yl)-2-[(l1S)-l-(4-fluorophenyl)ethoxy]pyrimidin-4- amine; 2-[(l1S)-l-(5-Fluoropyridin-2-yl)ethoxy]-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4- ylpyrimidin-4- amine ;
5-Chloro-2-[(li?)-l-(5-fluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-lH-pyrazol-3- yl)pyrimidin-4- amine ;
5-Chloro-2-[(li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-lH-pyrazol-3- yl)pyrimidin-4-amine;
2-[(l1S)-l-(5-Fluoropyridin-2-yl)ethoxy]-5-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine;
2-[(l1S)-l-(5-Fluoropyrimidin-2-yl)ethoxy]-5-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine; and 2-[(l1S)-l-(5-Fluoropyrimidin-2-yl)ethoxy]-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4- ylpyrimidin-4-amine.
In yet another aspect, the present invention provides the following compounds of Formula (I), or a pharmaceutically acceptable salt thereof:
5-Chloro-2- { [( Ii?)- 1 -(4-fluorophenyl)ethyl]thio } -N-(5 -methyl- lH-pyrazol-3 -yl)pyrimidin-4- amine;
5-Chloro-2-[(li?)-l-(4-fluorophenyl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine;
5-Chloro-2-[(li?)-l-(5-fluoropyridin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine;
5-Fluoro-2-[(li?)-l-(5-fluoropyridin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine;
5-Chloro-2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine; 5-Chloro-N-(5-cyclopropyl-lH-pyrazol-3-yl)-2-[(li?)-l-(4-fluorophenyl)ethoxy]pyrimidin-4- amine; 2-[(li?)-l-(5-Fluoropyridin-2-yl)ethoxy]-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4- ylpyrimidin-4- amine ;
5-Chloro-2-[(l1S)-l-(5-fluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-lH-pyrazol-3- yl)pyrimidin-4- amine ; 5-Chloro-2-[(l1S)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-lH-pyrazol-3- yl)pyrimidin-4- amine ;
2-[(li?)-l-(5-Fluoropyridin-2-yl)ethoxy]-5-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine;
2-[(li?)-l-(5-Fluoropyrimidin-2-yl)ethoxy]-5-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine; and
2-[(li?)-l-(5-Fluoropyrimidin-2-yl)ethoxy]-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4- ylpyrimidin-4-amine.
Utility JAK2
The compounds of Formula (I) have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinase, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases. The compounds of Formula (I) have been shown to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2, as determined by the JAK2 Assay described herein.
The compounds of Formula (I) should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2. These would be provided in commercial kits comprising a compound of this invention.
JAK2 kinase activity may be determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified
Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
To measure JAK2 kinase activity, a commercially available purified enzyme may be used. The enzyme may be C-terminal His6-tagged, recombinant, human JAK2, amino acids 808-end, (Genbank Accession number NM 004972) expressed by baculovirus in Sf21 cells (Upstate Biotechnology MA). After incubation of the kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 60 minutes at room temperature, the kinase reaction may be stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA). The reaction may be performed in 384 well microtitre plates and the reaction products may be detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specifϊc antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature. "Tween 20" is a registered trademark of ICI Americas, Inc.
JAK2 Hu Phos AScrn CRICso ENZ 5PT JAK2 ASl JAK2 Mean ICso (uM) Assay
Figure imgf000037_0001
Figure imgf000038_0001
Although the pharmacological properties of the compounds of the Formula (I) may vary with structural change, typical compounds of the Formula (I) are believed to possess JAK inhibitory activity at IC50 concentrations (concentrations to achieve 50% inhibition) or doses at a level below 10 μM.
When tested in an assay based on the in-vitro assay described above, the JAK inhibitory activity of the following examples was measured at the following IC50S. A hyphen indicates that an IC50 value was not provided for that particular compound, and is not meant to imply that the particular compound does not possess IC50 activity.
Figure imgf000038_0002
Figure imgf000039_0001
Thus, in one aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
In another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
In still another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
In yet another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man.
In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of an anti-proliferative effect, in a warm-blooded animal such as man.
In still a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of a JAK inhibitory effect.
In yet a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In one aspect, there is provided a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In another aspect, there is provided a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In still another aspect, there is provided a method for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In yet another aspect, there is provided a method for producing an anti-proliferative effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided a method for producing a JAK inhibitory effect in a warmblooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In still a further aspect, there is provided a method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In yet a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
In one aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
In another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man.
In still another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti -proliferative effect, in a warm-blooded animal such as man.
In yet another further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.
In a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as man.
In still a further aspect, where reference is made to the treatment (or prophylaxis) of cancer, it may particularly refer to the treatment (or prophylaxis) of mesoblastic nephroma, mesothelioma, acute myeloblasts leukemia, acute lymphocytic leukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukaemia, tumors of the central and peripheral nervous system, melanoma, fibrosarcoma including congenital fibrosarcoma and osteosarcoma. More particularly it refers to prostate cancer. In addition, more particularly it refers to SCLC, NSCLC, colorectal cancer, ovarian cancer and / or breast cancer. In a further aspect it may refer to hormone refractory prostate cancer.
In yet a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_-hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti -tumor agents:
(i) antiproliferative/antineoplastic drags and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirabicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin); and proteosome inhibitors (for example bortezomib [Velcade®]); and the agent anegrilide [Agrylin®]; and the agent alpha-interferon; (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , famesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine
(gefitinib, AZDl 839), N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (AbI) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (Gleevec™); and any agents that modify STAT signalling; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine -transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drags thalidomide and lenalidomide [Revlimid®]; and (x) other treatment regimes including: dexamethasone, proteasome inhibitors (including bortezomib), isotretinoin (13-cis retinoic acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies, targeted radiation therapy with 13 ll-metaiodobenzylguanidine
(131I-MIBG), anti-G(D2) monoclonal antibody therapy with or without granulocyte- macrophage colony-stimulating factor (GM-CSF) following chemotherapy.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
In addition to its use in therapeutic medicine, compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of JAK2 in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant invention, any of the alternate embodiments of the compounds of the invention described herein also apply.
In one aspect, the inhibition of JAK activity particularly refers to the inhibition of JAK2 activity.
Process
If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.
It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5X Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991) and as described hereinabove.
Compounds of Formula (I) may be prepared in a variety of ways. The Processes and Scheme shown below illustrate some methods for synthesizing compounds of Formula (I) and intermediates which may be used for the synthesis of compounds of Formula (I) (wherein Ring A, X, R1, R2, R3, and R4, unless otherwise defined, are as defined hereinabove). Where a particular solvent or reagent is shown in a Scheme or referred to in the accompanying text, it is to be understood that the chemist of ordinary skill in the art will be able to modify that solvent or reagent as necessary. The Processes and Schemes are not intended to present an exhaustive list of methods for preparing the compounds of Formula (I); rather, additional techniques of which the skilled chemist is aware may be also be used for the compounds' synthesis. The claims are not intended to be limited to the structures shown in the Processes and Scheme.
The skilled chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples and Schemes herein, to obtain necessary starting materials and products. In one aspect, compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be prepared by:
1) Process A - reacting a compound of Formula (A):
Figure imgf000051_0001
with a compound of Formula (B):
Figure imgf000051_0002
2) Process B - reacting a compound of Formula (C):
Figure imgf000051_0003
with a compound of Formula (D):
Figure imgf000051_0004
and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
In another aspect, compounds of Formula (X), which are compounds of Formula (I) in which X is -S-, or pharmaceutically acceptable salts thereof, may be prepared by:
Process C - reacting a compound of Formula (F) :
Figure imgf000052_0001
Formula (F)
with a compound of Formula (G):
Figure imgf000052_0002
and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove. For each of Processes A, B, and C, it is to be understood that protecting groups may be used as necessary. Leaving groups suitable for use in Processes A, B, and C include halo groups such as chloro. The Processes are discussed in more detail below.
Process A - Compounds of Formula (A) and compounds of Formula (B) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one. The reaction may advantageously occur in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide. The reaction may be advantageously performed at a temperature in a range from 00C to reflux. Heating the reaction may be particularly advantageous.
In another aspect, compounds of Formula (A) and compounds of Formula (B) may be reacted together under standard Buchwald conditions (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066), with a suitable base. Examples of suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ϊ-butoxide. Such a reaction may advantageously occur in the presence of a palladium catalyst such as palladium acetate. Examples of solvents suitable for such a reaction include toluene, benzene, dioxane, and xylene. The -NH- moiety of the compound of Formula (B) may advantageously be protected with a suitable protecting group, examples of which include protecting groups such as tert-butoxycarbonyl.
Process B - Compounds of Formula (D) and compounds of Formula (B) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
Compounds of Formula (A) may be prepared according to Scheme 1 :
Scheme 1
Figure imgf000054_0001
wherein in each occurrence may be the same or different, and is a leaving group as described hereinabove.
Compounds of Formula (D) and compounds of Formula (E) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
Compounds of Formula (C) may be prepared according to Scheme 2:
Scheme 2
Figure imgf000054_0002
wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove. Compounds of Formula (B) and compounds of Formula (E) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid-2-one. The reaction advantageously will take place in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide. The reaction is advantageously performed at a temperature in a range from 0 C to reflux.
Compounds of Formula (F) may be prepared according to Scheme 3:
Scheme 3
Figure imgf000055_0001
Compounds of Formula (C) may be reacted with Na2S in a solvent such as DMF.
Examples
The invention will now be further described with reference to the following illustrative Examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (0C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 0C;
(ii) organic solutions were dried over anhydrous magnesium sulfate unless other wise stated; evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 - 30 mmHg) with a bath temperature of up to 60 0C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of reactions was followed by TLC or liquid chromatography/mass spectroscopy and reaction times are given for illustration only; (v) final products have satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectra data; (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in DMSO-dβ unless otherwise stated;
(viii) chemical symbols have their usual meanings; (ix) solvent ratio was given in volume : volume (v/v) terms; (x) "ISCO" refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12 g, 40 g etc.), used according to the manufacturer's instructions, obtained from ISCO, Inc, 4700 Superior Street Lincoln, NE, USA;
(xi) A "Gilson column" refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H2OMeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturer's instructions, obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A; (xii) "Biotage" refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12g, 4Og, 80 g etc.), used according to the manufacturer's instructions, obtained from Biotage Inc, 1725 Discovery Drive Charlotteville,
Virginia 22911, USA;
(xiii) "SFC (super critical fluid chromatography)" refers to Analytical SFC (ASC-1000 Analytical SFC System with a diode array detector) and/or Preparative SFC (APS-
1000 AutoPrep Preparative SFC), used according to the manufacturer's instruction, obtained from SFC Mettler Toledo AutoChem, Inc. 7075 Samuel Morse Drive
Columbia MD 21046, USA.;
(xiv) Chiralcel OJ® and Chiralcel AD-H®, Chiralcel AD-S® or Chiralpak® columns are used according to the manufacturer's instruction, and are obtained from Chiral
Technologies,Inc. 800NorthFivePointsRoad WestChester, PA 19380, USA; (xv) Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psi) and temperatures to 80 0C; (xvi) the following abbreviations may be used: BINAP 2,2'-bis(diphenylphosphino)-l,l '-binapthyl
BOC2O di-fert-butyl-dicarbonate
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMF N,N-dimethylformamide DMAP 4-dimethylaminopyridine
DMSO dimethylsulfoxide dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene e.e. enantiomeric excess
EtOAc ethyl acetate Et2O diethyl ether
GC gas chromatography
Intermediate 1 2-Chloro-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine
To a solution of 5-methyl-lH-pyrazol-3-amine (612 mg, 6.0 mmol) in absolute EtOH (10 ml) was added triethylamine (1.1 ml) and 2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound as a solid (679 mg). LC-MS: 228 [M+Η].
Intermediate 2
2,,5-Dichloro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine To a solution of 5-methyl-lH-pyrazol-3-amine (2.78 g, 27.3 mmol) in absolute EtOH (30 ml) was added triethylamine (5 ml) and 2,4,5-trichloropyrimidine (5.0 g, 27.3 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound (4.1 g). LC-MS: 245 [M+H]+.
Intermediate 3 l-(5-Fluoropyridin-2-yl)ethanol
To a solution of 5-fluoropyridine-2-carbaldehyde (2.5 g) in Et2O (50 ml) at 00C was added drop- wise a solution of MeMgBr (8 ml, 3.0M in Et2O). The resulting solution was stirred at this temperature for 30 minutes and then it was allowed to warm to ambient temperature over 1 hour. The mixture was quenched with a solution of saturated NH4Cl^q) and extracted with Et2O. The organic extracts dried and evaporation gave the title compound (2.6 g). 1H NMR O 8.43 (s, IH), 7.69 (m, IH), 7.55 (m, IH), 5.40 (d, IH), 4.71 (m, IH), 1.33 (d, 3H).
Intermediate 4 5-Fluoropyrimidine-2-carbonitrile
A 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd2(dba)3 (0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol). The flask was evacuated and backfilled with N2, and anhydrous DMAc. The vial was mounted onto a Personal Chemistry microwave reactor and heated at 100 0C for 10 hours. The reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer was obtained and evaporated to dryness. The dried residue was purified by silica gel chromatography (By ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a creamy solid (1.50 g, 80%). GC-MS: 123 [M]+. 1H NMR (CDCl3) δ: 8.80 (s, 2H).
Intermediate 5 l-(5-Fluoropyrimidin-2-yl)ethanone
To a solution of 5-fluoropyrimidine-2-carbonitrile (Intermediate 4, 2.5 g) in Et2O (50 ml) at 00C was added drop-wise a solution of MeMgBr (12 ml, 3.0M in Et2O). The resulting solution was stirred at this temperature for 30 minutes, and was then allowed to warm to ambient temperature overnight. The mixture was quenched with a solution of saturated NH4Cl(aq) and extracted with Et2O. The organic extracts dried and evaporation gave a colored residue. Purification by column chromatography (ISCO, 3% MeOH/DCM) to afford the title compound (800 mg). 1H NMR (CDCl3) δ 8.75 (s, 2H), 2.77 (s, 3H).
Intermediate 6 l-(5-Fluoropyrimidin-2-yl)ethanol
To a solution of l-(5-fluoropyrimidin-2-yl)ethanone (Intermediate 5, 800 mg) in MeOH (40 ml) at 00C was added portion-wise NaBH4 (12 ml, 3.0M in Et2O). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between H2O and DCM. The organic layer was washed with saturated NH4Cl(aq) solution, H2O and brine. The organic extracts dried and evaporation gave the tile compound (330 mg). 1H NMR (CDCl3) δ 8.59 (s, 2H), 4.96 (m, IH), 3.79 (br s, IH), 1.54 (d, 3H).
Intermediate 7
5-Chloro-4-r(5-methyl-lH-pyrazol-3-yl)aminolpyrimidine-2-thiol
To a solution of 2,5-dichloro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 2, 730 mg) in DMF (10 ml) was added Na2S (246 mg) and the resulting solution was heated to 800C for 2 hours. The mixture was evaporated and used in the next step (synthesis of Example 1) without any further purification. LC-MS: 449 [dimer+Η]+.
Intermediate 8
2,5-Dichloro-N-(5-cvclopropyl-lH-pyrazol-3-yl)pyrimidin-4-amine 5-Methyl-lH-pyrazol-3-amine and 2,4,5-trichloropyrimidine were reacted using a procedure similar to the one described for the synthesis of Intermediate 2, providing the title compound. LC-MS: 271 [M+Η]+.
Intermediate 9 5-Methoxy- lH-pyrazol-3 -amine
To a solution of 3-amino-5-hydroxypyrazole (50.00 g) in CH2Cl2 (800 ml) was added triphenylphosphine (155.64 g) and the resulting mixture was cooled to 00C. Diisopropyl azodicarboxylate (117.64 ml) was added drop- wise over a period of 35 minutes (temp<2°C) to give a dark brown, mobile slurry. The reaction mixture was then stirred at 00C for 1 hour. A beige precipitate came out of solution after 20 minutes. MeOH (50 ml) was then added drop- wise over a period of 15 minutes at 00C as the slurry thinned considerably to give a lighter yellow slurry. The reaction mixture was then stirred at 00C for 1 hour. The reaction was warmed slowly to ambient temperature over a period of 2 hours. The reaction mixture was then stirred at ambient temperatures for 22 hours. The reaction mixture was filtered to remove undissolved solids. The filtrate was dried over MgSO4, and concentrated under reduced pressure to give a yellow-orange oil. Purification by column chromatography (5%-> 10% MeOH/CEkCb) afforded the title compound as a waxy solid. 1H NMR (300 MHz) δ: 4.67 (s, 1 H) 3.61 (s, 3 H). LC-MS: 114 [M+H]+.
Intermediate 10
2,6-Dichloro-N-(5-methoxy-lH-pyrazol-3-yl)pyrimidin-4-amine
To a solution of 2,4,6-trichloropyrimidine (4.81 g) in EtOH (75 ml) were added DIPEA (7.3 mL) and 5-methoxy-lH-pyrazol-3-ylamine (Intermediate 9, 3.0g). The resulting solution was stirred at room temperature for 4 hours. The title compound was obtained by filtration, washed with EtOH (1OmL) and dried o/n in a vacuum oven (4.7g). LC-MS: 261 [M+Η] +.
Intermediate 11
6-Chloro-2-(l-(5-fluoropyridin-2-yl)ethoxy)-N-(5-methoxy-lH-pyrazol-3-yl)pyrimidin-4-amine 2,6-Dichloro-N-(5-methoxy-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 10) and l-(5- fluoropyridin-2-yl)ethanol (Intermediate 3) were reacted using procedure similar to the one described for the synthesis of Example 2, providing the title compound as a mixture of enantiomers.
LC-MS: 365 [M+Η] +. 2-Chloro-6-(l-(5-fluoropyridin-2-yl)ethoxy)-N-(5-methoxy-lΗ-pyrazol-3-yl)pyrimidin-4-amine was isolated as a by-product in this reaction. Intermediate 12 l-(5-Fruoropyridin-2-yl)-2-methoxyethanone
To a solution of 2-bromo-5-fluoropyridine (15.O g, 85.23 mmol) in methyl t-butyl ether (250 ml) at -78 0C was added tert-butyllithium (60.2 ml, 102.28 mmol) with caution.
After the addition of the organolithium was completed, the resulting black solution was stirred at -78 0C for 15 minutes whereupon methyl 2-methoxyacetate (8.43 ml, 85.23 mmol) in 10 ml MTBE was added to the solution. The mixture was stirred for 3 hours at -78 0C whereupon saturated NH4Cl was added in order to quench the reaction. The mixture was partitioned between EtOAc and brine and the organic extract was dried and evaporated under reduced pressure. Purification by column chromatography (20% ->40% EtOAc/hexanes) gave the titled compound as a yellowish solid 6.19 g (43% yield). LCMS: 170 [M+H]+.
Intermediate 13 l-(5-Fluoropyridin-2-yl)-2-methoxyethanol
In a 50OmL round-bottomed flask, l-(5-fluoropyridin-2-yl)-2-methoxyethanone (Intermediate
12, 6.19 g, 36.59 mmol) was dissolved in MeOH (183 ml) to give a yellow solution at 0 0C.
Sodium borohydride (1.383 g, 36.59 mmol) was added to the above solution at 00C. The reaction was allowed to warm up to rt and stirred for 30 min. Concentration under reduced pressure removed the MeOH, and to the residue was added sat. NaHCO3, and extracted with EtOAc. The crude was added to a silica gel column and was eluted with EtOAc/DCM (20->50%). The title compound was obtained yellow oil 5.6 Ig (90% yield).
LCMS: 172 [M+H]+.
Intermediate 14
2-Chloro-5 -methyl-N-(5 -methyl- lH-pyrazol-3-yl)pyrimidin-4-amine
2,4-Dichloro-5-methylpyrimidine (2.395 g, 14.69 mmol), 5 -methyl- lH-pyrazo 1-3 -amine (1.710 g,
17.61 mmol), and DIPEA (3.80 g, 29.39 mmol) in ethanol (20 ml) was heated at 6O0C over the weekend. LCMS indicated complete reaction. Solvent was removed under reduced pressure and the residue was purified by ISCO (5%MeOH/0.5% NH4OH in CH2Cl2. 2.5g (76%) of the title compound was isolated.
1H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (s, 1 H) 9.30 (s, 1 H) 7.97 (s, 1 H) 6.37 (s, 1 H) 2.25 (s, 3 H) 2.13 (s, 3 H). LCMS: 224 [M+H]+.
Example 1
5-Chloro-2-{ri-(4-fluorophenyl)ethyllthio}-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine
Figure imgf000062_0001
To a solution of 5-chloro-4-[(5-methyl-lH-pyrazol-3-yl)amino]pyrimidine-2-thiol (Intermediate 7, 100 mg) in DMF (10 ml) was added Et3N (0.8 ml) and l-(4-fluorophenyl)ethyl methanesulfonate (420 mg, readily prepared from the reaction of l-(4-fluorophenyl)ethanol and methanesulphonyl chloride in DMF, in the presence OfEt3N, for 30 minutes and used without any further purification). The resulting mixture was heated to 800C for 2 hours. The solvent was evaporated and the residue was partitioned between H2O and DCM. The organic layer was washed with saturated NEUCl^ solution, H2O and brine. The organic extracts were dried and evaporation gave a colored residue. Purification using a Gilson column (5%->95% MeCN/H2O) afforded the title compound (17.6 mg) as a mixture of enantiomers. The title compound obtained via this method of purification may be in the form of the trifluoroacetic acid salt. 1H NMR δ 9.42 (s, IH), 8.37 (s, IH), 7.54 (m, 2H), 7.25 (m, 2H), 6.40 (s, IH), 4.82 (m, IH), 2.27 (s, 3H), 1.56 (d, 3H). LC-MS: 362 [M-H]+. Example 2
5-Chloro-2-ri-(4-fluorophenylN)ethoxy1-N-(5-methyl-lH-pyrazol-3-ylN)pyrimidin-4-amine
Figure imgf000063_0001
To a solution of 2,5-dichloro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 2, 121.5 mg) and l-(4-fluorophenyl)ethanol (210 mg) in ?-BuOΗ was added sodium ϊ-butoxide (96 mg). The resulting mixture was heated at 900C overnight. The mixture was partitioned between Η2O and DCM. The organic layer was washed with saturated NH4Cl^q) solution, H2O and brine. Purification by column chromatography (ISCO, 40% EtOAc/hexanes) afforded the title compound (125 mg) as a mixture of enantiomers. 1H NMR (CDCl3) δ 8.10 (s, IH), 7.90 (s,lH), 7.39 (m, 2H), 7.01 (m, 2H), 6.45 (s, IH), 6.01 (m, IH), 2.37 (s, 3H), 1.64 (d, 3H). LC-MS: 348 [M+H]+.
The R and S enantiomers of the title compound were separated using a Gilson system.
Column and solvent conditions
Column: Chiralcel OJ®, 250 x 20mm, lOμ
Conditions: 50% hexane, 50% (EtOH/MeOH 1 : 1 v/v), 0.1% diethylamine
Flow rate: lOml/min
Post purification purity check
Chiral Gilson system using ultraviolet diode array
Column: Chiralcel OJ®, 250 x 4.6mm, lOμ Conditions: 50% hexane, 50% (EtOH/MeOH 1 : 1 v/v), 0.1% diethylamine Flow rate: 0.5 ml/min
Example 2(a), First Eluting Compound 5-Chloro-2-ri-(4-fluorophenyl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine, Enantiomer A The first eluting compound (52 mg) had retention time of 8.65 minutes.
Example 2(b), Second Eluting Compound 5-Chloro-2-r(l-(4-fluorophenyl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine, Enantiomer B The second eluting compound (49 mg) had a retention time of 11.61 minutes.
Enantiomeric excess for each enantiomer of Example 2 was estimated to be > 99%, using area percentage at 210nm.
Example 3
5-Chloro-2-ri-(5-fluoropyridin-2-ylN)ethoxy1-N-(5-methyl-lH-pyrazol-3-ylN)pyrimidin-4-amine
Figure imgf000064_0001
2,5-Dichloro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 2) and l-(5- fluoropyridin-2-yl)ethanol (Intermediate 3) were reacted using a procedure similar to the one described for the synthesis of Example 2, providing the title compound as a mixture of enantiomers.
1H NMR O 11.96 (s, IH), 8.60 (s, IH), 8.48 (s, IH), 8.12 (s, IH), 7.62 (m, IH), 6.14 (s, IH), 6.00 (m, IH), 2.25 (s, 3H), 1.59 (d, 3H). LC-MS: 349 [M+H]+.
The R and S enantiomers of the title compound were separated using a Gilson system.
Column and solvent conditions Column: Chiralcel OJ®, 250 x 20mm, lOμ
Conditions: 80% hexane, 20% (EtOH/MeOH 1 : 1 v/v), 0.1% diethylamine Flow rate: lOml/min
Post purification purity check Chiral Gilson system using ultraviolet diode array Column: Chiralcel OJ®, 250 x 4.6mm, lOμ
Conditions: 80% hexane, 20% (EtOH/MeOH 1 : 1 v/v), 0.1% diethylamine Flow rate: 0.5 ml/min
Example 3(a), First Eluting Compound
5-Chloro-2-ri-(5-fluoropyridin-2-yl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine,
Enantiomer A
The first eluting compound had a retention time of 11.00 min.
Example 3(b), Second Eluting Compound
5-Chloro-2-[l-(5-fluoropyridin-2-yl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine,
Enantiomer B
The second eluting compound had a retention time of 13.71 minutes.
Enantiomeric excess for each enantiomer of Example 3 was estimated to be > 98%, using area percentage at 220 nm. Example 4
5-Fluoro-2-ri-(5-fluoropyridin-2-ylN)ethoxy1-N-(5-methyl-lH-pyrazol-3-ylN)pyrimidin-4-amine
Figure imgf000066_0001
2-Chloro-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 1) and l-(5- fluoropyridin-2-yl)ethanol (Intermediate 3) were reacted with the procedure similar to the one described for the synthesis of Example 2, providing the title compound as a mixture of enantiomers.
1H NMR O 11.81 (s, IH), 9.40 (s, IH), 8.48 (s, IH), 7.99 (s, IH), 7.63 (m, IH), 7.44 (m, IH),
6.16 (s, IH), 5.98 (m, IH), 2.23 (s, 3H), 1.60 (d, 3H).
LC-MS: 333 [M+H]+.
The R and S enantiomers of the title compound were separated using the chiral SFC system.
Column and solvent conditions
Column: Chiralcel AD-H, 250 x 20mm
Modifier: 15% isopropanol, 0.1% dimethylethylamine; 5μ
Flow rate: 60ml/min
Oven: 400C Outlet: 100 bar Post purification purity check Chiral SFC using ultraviolet diode array Column: AD-H, 250 x 4.6mm Conditions: 20% isopropanol, 0.1% dimethylethylamine Flow rate: 3 ml/min; 15 minutes Oven: 35°C
Outlet: 120 bar
Example 4(a), First Eluting Compound 5-Fluoro-2-[l-(5-fluoropyridin-2-ylN)ethoxyl-N-(5-methyl-lH-pyrazol-3-ylN)pyrimidin-4-amine, Enantiomer A The first eluting compound had a retention time of 4.80 minutes.
Example 4(b), Second Eluting Compound 5-Fluoro-2-[l-(5-fluoropyridin-2-ylN)ethoxyl-N-(5-methyl-lH-pyrazol-3-ylN)pyrimidin-4-amine, Enantiomer B The second eluting compound had a retention time of 6.59 minutes.
Enantiomeric excess for each enantiomer of Example 4 was estimated to be > 98%, using area percentage at 254 nm.
Example 5
5-Chloro-2-ri-(5-fluoropyrimidin-2-yl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine
Figure imgf000068_0001
2,5-Dichloro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 2) and l-(5- fluoropyrimidin-2-yl)ethanol (Intermediate 6) were reacted using procedure similar to the one described for the synthesis of Example 2, providing the title compound as a mixture of enantiomers.
1H NMR O 8.58 (s, 2H), 8.00 (s, IH), 6.00 (s, IH), 5.91 (m, IH), 2.23 (s, 3H), 1.63 (d, 3H). LC-MS: 350 [M+H]+.
The R and S enantiomers of the title compound were separated using the chiral SFC system.
Column and solvent conditions
Column: Chiralcel AD-H, 250 x 20mm
Modifier: 30% isopropanol, 0.1% dimethylethylamine; 5μ
Flow rate: 60ml/min Oven: 400C
Outlet: 100 bar
Post purification purity check Chiral SFC using ultraviolet diode array Column: Chiralcel AD-H, 250 x 4.6mm
Conditions: 30% isopropanol, 0.1% dimethylethylamine Flow rate: 3 ml/min; 15 minutes Oven: 35°C Outlet: 120 bar
Example 5(a), First Eluting Compound
5-Chloro-2-ri-(5-fluoropyrimidin-2-yl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine, Enantiomer A
The first eluting compound had a retention time of 3.34 minutes.
Example 5(b), Second Eluting Compound
5-Chloro-2-ri-(5-fluoropyrimidin-2-yl)ethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine, Enantiomer B
The second eluting compound had a retention time of 5.99 minutes..
Enantiomeric excess for each enantiomer of Example 5 was estimated to be > 98%, using area percentage at 254 nm.
Example 6 5-Chloro-N-(5-cvclopropyl-lH-pyrazol-3-ylN)-2-ri-(4-fluorophenylN)ethoxy1pyrimidin-4-amine
Figure imgf000069_0001
To a suspension of NaH (60% in mineral oil, 80 mg, 2.05 mmol) in toluene (5 mL) at room temperature was added a solution of l-(4-fluorophenyl)ethanol (285 mg, 2.05 mmol) in toluene. The reaction mixture was stirred for 5 minutes (bubbling observed) and to it was added 2,5- dichloro-N-(5-cyclopropyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 8, 500 mg, 1.85 mmol). The reaction mixture was stirred at 11O0C in a microwave reactor for 4 hours. EtOAc and water were added to the mixture and two layers were separated. The organic layer was concentrated and reversed phased HPLC gave the desired product as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.06 (s, IH), 7.73 (br s, 1 H), 7.38 (m, 2 H), 7.00 (m, 2H), 6.26 (s, IH), 6.03 (m, IH), 1.86 (m, IH), 1.63 (m, 3H), 1.00 (m, 2H), 0.75 (m, 2H).
Example 7
2-ri-(5-Fluoropyridin-2-yl)ethoxyl-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin- 4-amine, TFA salt
Figure imgf000070_0001
A microwave tube was charged with 6-chloro-2-(l-(5-fluoropyridin-2-yl)ethoxy)-N-(5-methoxy- lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 11, 129mg, 0.35mmol), n-BuOΗ(2.5mL), morpholine (0.062mL, 0.71mmol), DIPEA (0.092mL, 0.53mmol). The reaction mixture was heated under microwave condition to 1600C for 6hrs. Evaporation of the volatiles under reduced pressure afforded an oil. Purification by Gilson (0-60% MeCN/water, 0.1% TFA) provided the title product (37mg, white solid) as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1 H) 7.59-7.70 (m, 2 H) 6.13 (q, 1 H) 5.69 (s, 1 H) 3.94(s, 3H) 3.67-3.72 (m, 4 H) 3.53-3.58(m, 4H) 1.73 (d, 3 H). LCMS: 416 [M+H]+.
The R and S enantiomers of the title compound were separated using the chiral SFC system. Column and solvent conditions
Column type/particle size: Chiralpak AD-H / 5 μ
Column dimensions (mm): 21x 250
Modifier / additive: 25 % Methanol Flow rate (ml/min): 60
Oven (0C): 40
Outlet Pressure (bar): 100
Wavelength (nm) : 254 nm
Example 7(a), First Eluting Compound
2-ri-(5-fluoropyridin-2-yl)ethoxyl-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin-
4-amine, Enantiomer A
1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1 H) 7.59-7.70 (m., 2 H) 6.13 (q, 1 H) 5.69 (s, 1 H)
3.94(s, 3H) 3.67-3.72 (m, 4 H) 3.53-3.58(m, 4H) 1.73 (d, 3 H) LC-MS: 416 [M+H]+.
Example 7(b), Second Eluting Compound
2-ri-(5-fluoropyridin-2-yl)ethoxyl-N-(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin- 4-amine, Enantiomer B 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1 H) 7.59-7.70 (m., 2 H) 6.13 (q, 1 H) 5.69 (s, 1 H) 3.94(s, 3H) 3.67-3.72 (m, 4 H) 3.53-3.58(m, 4H) 1.73 (d, 3 H) LC-MS: 416 [M+H]+.
Example 8 5-Chloro-2-ri-(5-fluoropyridin-2-yl)-2-methoxyethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin- 4- amine
Figure imgf000072_0001
Sodium tert-butoxide (359mg, 3.74mmol) was dissolved in t-BuOH (19mL) and heated to 600C to achieve complete disolution. l-(5-fluoropyridin-2-yl)-2-methoxyethanol (Intermediate 13,
640mg, 3.74mmol) was added and the resulting mixture was allowed to cool to room temperature. 2,5-Dichloro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 2) was added and the resulting solution was heated to 85°C for 5 hours. Evaporation of the volatiles under reduced pressure gave an oil. Purification by Gilson (5-95% MeCN/water, 0.1% TFA) provided the TFA salt of the title compound 610mg) as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.32 (bs, 1 H) 8.09(s, IH) 7.55-7.63 (m., 1 H) 7.35-7.43(m,
IH) 6.31 (t, 1 H) 6.22 (s, 1 H) 3.83-4.01 (m, 2 H) 3.42 (s, 3H) 2.34 (s, 3 H).
LC-MS: 379 [M+H]+.
The R and S enantiomers of the title compound were separated using the chiral SFC system.
Column and solvent conditions
Column type/particle size: Chiralcel OD-H / 5 μ
Column dimensions (mm): 21x 250
Modifier / additive: 20 % Isopropanol/ 0.4 % dimethylethylamine Flow rate (ml/min): 60 Oven (0C): 40 Outlet Pressure (bar): 100 Wavelength (nm) : 254 nm Post purification purity check
Column type/particle size: Chiralcel OD-H / 5 μ
Column dimensions (mm): 100 x 4.6
Modifier / additive: 20 % Isopropanol/ 0.4 % dimethylethylamine Flow rate (ml/min): 5
Oven (0C): 35
Outlet Pressure (bar): 120
Wavelength (nm) : 254 nm
Example 8(a), First Eluting Compound
5-chloro-2-ri-(5-fluoropyridin-2-yl)-2-methoxyethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-
4-amine, Enantiomer A
1H NMR (300 MHz, MeOD) δ ppm 8.32 (bs, 1 H) 8.09(s, IH) 7.55-7.63 (m., 1 H) 7.35-7.43(m,
IH) 6.31 (t, 1 H) 6.22 (s, 1 H) 3.83-4.01 (m, 2 H) 3.42 (s, 3H) 2.34 (s, 3 H). LC-MS: 379 [M+H]+.
The first eluting comound had a retention time of 20.54 minutes.
Example 8(b), Second Eluting Compound
5-chloro-2-[l-(5-fluoropyridin-2-yl)-2-methoxyethoxyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin- 4-amine, Enantiomer B
The second eluting compound had a retention time of 24.11 minutes.
1H NMR (300 MHz, MeOD) δ ppm 8.32 (bs, 1 H) 8.09(s, IH) 7.55-7.63 (m., 1 H) 7.35-7.43(m,
IH) 6.31 (t, 1 H) 6.22 (s, 1 H) 3.83-4.01 (m, 2 H) 3.42 (s, 3H) 2.34 (s, 3 H).
LC-MS: 379 [M+H]+.
Enantiomeric excess for each enantiomer of Example 8 was estimated to be > 98%, using area percentage at 254 nm.
Example 9 2-(l-(5-Fluoropyridin-2-yl)ethoxy)-5-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine
Figure imgf000074_0001
2-Chloro-5-methyl-N-(5 -methyl- lH-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 14, 334 mg, 1.49 mmol), l-(5-fluoropyridin-2-yl)ethanol (Intermediate 3, 420 mg, 2.98 mmol) were reacted using procedure similar to the one described for the synthesis of Example 2, providing the title compound as a mixture of enantiomers.
The R and S enantiomers of the title compound were separated using the chiral SFC system.
Column and solvent conditions Column type/particle size: Chiralpak AD-H / 5 μ
Column dimensions (mm): 2 Ix 250
Modifier / additive: 20 % Isopropanol/ 0.1 % dimethylethylamine
Flow rate (ml/min): 60
Oven (0C): 40 Outlet Pressure (bar): 100
Post purification purity check
Column type/particle size: Chiralpak AD-H / 5 μ
Column dimensions (mm): 100 x 4.6 Modifier / additive: 20 % Isopropanol/ 0.1 % dimethylethylamine
Flow rate (ml/min): 5
Oven (0C): 35
Outlet Pressure (bar): 120 Example 9(a), First Eluting Compound
2-(l-(5-Fluoropyridin-2-ylN)ethoxyN)-5-methyl-N-(5-methyl-lH-pyrazol-3-ylN)pyrimidin-4-amine,
Enantiomer A The first eluting comound had a retention time of 1.62 minutes.
1H NMR (400 MHz, DMSOd6) δ ppm 12.00 (s, 1 H) 8.76 (s, 1 H) 8.52 (d, 1 H) 7.80 (s, 1 H)
7.66 (td, 1 H) 7.36 - 7.44 (m, 1 H) 6.16 (s, 1 H) 5.97 (d, 1 H) 2.21 (s, 3 H) 2.02 (s, 3 H) 1.55 (d, 3
H).
LC-MS: 329 [M+H]+.
Example 9(b), Second Eluting Compound
2-(l-(5-fluoropyridin-2-yl)ethoxy)-5-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine,
Enantiomer B
The second eluting comound had a retention time of 2.22 minutes. 1H NMR (400 MHz, DMSOd6) δ ppm 12.00 (s, 1 H) 8.76 (s, 1 H) 8.52 (d, 1 H) 7.80 (s, 1 H)
7.66 (td, 1 H) 7.36 - 7.44 (m, 1 H) 6.16 (s, 1 H) 5.97 (d, 1 H) 2.21 (s, 3 H) 2.02 (s, 3 H) 1.55 (d, 3
H).
LC-MS: 329 [M+H]+.
Enantiomeric excess for each enantiomer of Example 9 was estimated to be > 98%, using area percentage at 254 nm.

Claims

Claims
What is claimed is:
1. A compound of Formula (I):
Figure imgf000076_0001
or a pharmaceutically acceptable salt thereof, wherein
Ring A is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R5; X is selected from -O- and -S-; R1 is selected from H, -CN, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl,
-ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -C(O)H, -C(O)Rlb, -C(O)2R13, -C(O)N(Rla)2, -OC(O)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -OC(O)Rlb, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R10;
Rla in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10; Rlb in each occurrence is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10; R2 is selected from H, halo, -CN, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -C(O)H, -C(O)R2b, -C(O)2R23, -C(O)N(R2a)2, -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R20;
R2a in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R20; R2b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R20;
R3 is selected from H, halo, -CN, Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -OC(O)N(R3a)2, -N(R3a)C(O)2R3a,
-N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3a), and -C(R3a)=N(OR3a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R30; R3a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R3b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
R4 is selected from H, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R40;
R4a in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R40; R4b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R40;
R5 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR5a, -SR5a, -N(R5a)2, -N(R5a)C(O)R5b, -N(R5a)N(R5a)2, -NO2, -C(O)H, -C(O)R5b, -C(O)2R5a, -C(O)N(R5a)2, -OC(O)N(R5a)2,
-N(R5a)C(O)2R5a, -N(R5a)C(O)N(R5a)2, -OC(O)R5b, -S(O)R5b, -S(O)2R5b, -S(O)2N(R5a)2, -N(R5a)S(O)2R5b, -C(R5a)=N(R5a), and -C(R5a)=N(OR5a), wherein said d_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50; R5a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R5b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R10 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR1Oa, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -OC(O)R10b, -S(O)R10b, -S(O)2R10b,
-S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R1Oa)=N(R1Oa), and -C(R10a)=N(OR10a), wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Ra; R1Oa in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Ra;
R1Ob in each occurrence is independently selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Ra; R20 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a), wherein said Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ; R20a in each occurrence is independently selected from H, Ci^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rb; R20b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rb; R30 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR3Oa, -N(R30a)2, -N(R30a)C(O)R30b,
-N(R3Oa)N(R3Oa)2, -NO2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -OC(O)N(R30a)2, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, -OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R3Oa)=N(R3Oa), and -C(R30a)=N(OR30a), wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rc;
R30a in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rc;
R30b in each occurrence is independently selected from Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rc;
R40 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b,
-S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a), wherein said Ci-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ; R40a in each occurrence is independently selected from H, Ci^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rd;
R40b in each occurrence is independently selected from Ci-βalkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Rd;
R50 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR50a, -SR5Oa, -N(R50a)2, -N(R50a)C(O)R50b, -N(R50a)N(R50a)2, -NO2, -C(O)H, -C(O)R50b, -C(O)2R50a, -C(O)N(R50a)2, -OC(O)N(R50a)2, -N(R50a)C(O)2R50a, -N(R50a)C(O)N(R50a)2, -OC(O)R50b, -S(O)R50b, -S(O)2R50b, -S(O)2N(R50a)2, -N(R50a)S(O)2R50b, -C(R5Oa)=N(R5Oa), and -C(R50a)=N(OR50a), wherein said Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Re;
R50a in each occurrence is independently selected from H, Ci^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Re; R50b in each occurrence is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more Re; Ra, Rb, Rc, Rd, and Re in each occurrence are independently selected from halo, -CN,
Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORm, -SRm, -N(Rm)2, -N(Rm)C(O)Rn, -N(Rm)N(Rm)2, -NO2, -C(O)H, -C(O)R", -C(O)2R1", -C(O)N(Rm)2, -OC(O)N(Rm)2, -N(Rm)C(O)2Rm, -N(Rm)C(0)N(Rm)2, -OC(O)R", -S(O)R", -S(O)2R", -S(O)2N(Rm)2, -N(Rm)S(O)2R", -C(Rm)=N(Rm), and -C(Rm)=N(0Rm); Rm in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl; and
R" in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl.
2. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein:
Ring A is selected from phenyl and 6-membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with one or more R ; and
R5 is halo.
3. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in either one of claims 1 or 2, wherein
R1 is selected from Ci_6alkyl, 3- to 6-membered carbocyclyl, and -0Rla; and Rla is Ci_6alkyl.
4. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 to 3, wherein
R2 is selected from H, halo, and Ci_6alkyl.
5. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 to 4, wherein R3 is selected from H and 4- to 6-membered non-aromatic heterocyclyl.
6. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 to 5, wherein
R4 is Ci-βalkyl, wherein said Ci_6alkyl is optionally substituted with one or more R40; and R40 is -OR40a; and R40a is C1-6alkyl.
7. A compound of Formula (I):
Figure imgf000082_0001
or a pharmaceutically acceptable salt thereof, wherein
Ring A is selected from 3,5-difluoropyridinyl, 4-fluorophenyl, 5-fluoropyridin-2-yl, and 5 - fluoropyrimidin-2 -y 1; X is selected from -O- and -S-;
R1 is selected from cyclopropyl, methyl, and methoxy; R2 is selected from H, fluoro, chloro, and methyl; R3 is selected from H and morpholin-4-yl; and R4 is selected from methyl and methoxymethyl.
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use as a medicament.
The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for the treatment of cancer.
10. A method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.
11. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the treatment of cancer in a warm-blooded animal such as man.
12. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
13. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, wherein said process is selected from: Process A - reacting a compound of Formula (A):
Figure imgf000083_0001
Formula (A) with a compound of Formula (B):
Figure imgf000083_0002
Formula (B); and Process B - reacting a compound of Formula (C):
Figure imgf000084_0001
with a compound of Formula (D):
F
Figure imgf000084_0002
and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula
(I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L in each occurrence may be the same or different, and is a leaving group..
PCT/GB2008/050553 2007-07-11 2008-07-09 4- (3-aminopyrazole) -pyrimidine derivativee and their use as tyrosine kinase inhibitors for the treatment of cancer Ceased WO2009007753A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94917107P 2007-07-11 2007-07-11
US60/949,171 2007-07-11

Publications (2)

Publication Number Publication Date
WO2009007753A2 true WO2009007753A2 (en) 2009-01-15
WO2009007753A3 WO2009007753A3 (en) 2009-03-26

Family

ID=40029126

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050553 Ceased WO2009007753A2 (en) 2007-07-11 2008-07-09 4- (3-aminopyrazole) -pyrimidine derivativee and their use as tyrosine kinase inhibitors for the treatment of cancer

Country Status (1)

Country Link
WO (1) WO2009007753A2 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2397482A1 (en) 2010-06-15 2011-12-21 Almirall, S.A. Heteroaryl imidazolone derivatives as jak inhibitors
US20150025095A1 (en) * 2012-02-17 2015-01-22 Abbvie Inc. Diaminopyrimidines And Uses Thereof
US12018015B2 (en) 2021-06-18 2024-06-25 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US12428427B2 (en) 2021-12-16 2025-09-30 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US12486274B2 (en) 2020-01-13 2025-12-02 Verge Analytics, Inc. Substituted pyrazolo-pyrimidines and uses thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6989385B2 (en) * 2000-12-21 2006-01-24 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
CN101208093A (en) * 2005-04-27 2008-06-25 阿斯利康(瑞典)有限公司 Use of pyrazole-pyrimidine derivatives in the treatment of pain
US20080287437A1 (en) * 2005-05-16 2008-11-20 Astrazeneca Ab Pyrazolylaminopyrimidine Derivatives Useful as Tyrosine Kinase Inhibitors
JP2009513615A (en) * 2005-10-28 2009-04-02 アストラゼネカ アクチボラグ 4- (3-Aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2397482A1 (en) 2010-06-15 2011-12-21 Almirall, S.A. Heteroaryl imidazolone derivatives as jak inhibitors
WO2011157397A1 (en) 2010-06-15 2011-12-22 Almirall, S.A. Heteroaryl imidazolone derivatives as jak inhibitors
US20150025095A1 (en) * 2012-02-17 2015-01-22 Abbvie Inc. Diaminopyrimidines And Uses Thereof
US9447051B2 (en) * 2012-02-17 2016-09-20 Abbvie Inc. Diaminopyrimidines and uses thereof
US12486274B2 (en) 2020-01-13 2025-12-02 Verge Analytics, Inc. Substituted pyrazolo-pyrimidines and uses thereof
US12018015B2 (en) 2021-06-18 2024-06-25 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US12534450B2 (en) 2021-06-18 2026-01-27 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US12428427B2 (en) 2021-12-16 2025-09-30 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

Also Published As

Publication number Publication date
WO2009007753A3 (en) 2009-03-26

Similar Documents

Publication Publication Date Title
AU2008247159B2 (en) 9-(pyrazol- 3 -yl) -9H- purine-2 -amine and 3-(pyrazol-3-yl) -3H-imidazo [4,5-B]pyridin-5-amine derivatives and their use for the treatment of cancer
WO2008132502A1 (en) Pyrazolyl-amino-substituted pyrimidines and their use for the treatment of cancer
US20100204246A1 (en) 5-aminopyrazol-3-yl-3h-imidazo (4,5-b) pyridine derivatives and their use for the treatment of cancer
US8461170B2 (en) Chemical compounds
AU2009259026B2 (en) Tricyclic 2,4-diamin0-L,3,5-triazine derivatives useful for the treatment of cancer and myeloproliferative disorders
WO2008117050A1 (en) Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer
WO2010020810A1 (en) 2-(imidaz0lylamin0)-pyridine derivatives and their use as jak kinase inhibitors
WO2009013545A2 (en) Chemical compounds
WO2009016410A2 (en) Chemical compounds 831
WO2010038060A1 (en) Heterocyclic jak kinase inhibitors
EP2152702B1 (en) Amino-thiazolyl- pyrimidine derivatives and their use for the treatment of cancer
WO2009027736A2 (en) 2,4 diaminopyrimid&#39;lnes for the treatment of myeloproliferative disorders and cancer
WO2009007753A2 (en) 4- (3-aminopyrazole) -pyrimidine derivativee and their use as tyrosine kinase inhibitors for the treatment of cancer
WO2009095712A2 (en) Chemical compounds
HK1141800A (en) 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer

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: 08776188

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08776188

Country of ref document: EP

Kind code of ref document: A2