WO2010020810A1 - 2-(imidaz0lylamin0)-pyridine derivatives and their use as jak kinase inhibitors - Google Patents

2-(imidaz0lylamin0)-pyridine derivatives and their use as jak kinase inhibitors Download PDF

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Publication number
WO2010020810A1
WO2010020810A1 PCT/GB2009/051032 GB2009051032W WO2010020810A1 WO 2010020810 A1 WO2010020810 A1 WO 2010020810A1 GB 2009051032 W GB2009051032 W GB 2009051032W WO 2010020810 A1 WO2010020810 A1 WO 2010020810A1
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Prior art keywords
methyl
heterocyclyl
imidazol
carbocyclyl
diamine
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PCT/GB2009/051032
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French (fr)
Inventor
Lynsie Almeida
Claudio Edmundo Chuaqui
Amy Guan
Stephanos Ioannidis
Michelle Lamb
Bo Peng
Qibin Su
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2010020810A1 publication Critical patent/WO2010020810A1/en

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    • 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
    • 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

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 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted on carbon with one or more R 6 , and wherein if said 5- or 6-membered heteroaryl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 6* ;
  • D is selected from N and C-R 3 ;
  • E is selected from N and C-R 4 , wherein at least one of D and E is carbon;
  • X is selected from -NH-, -O-, and -S-;
  • R la 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 on carbon with one or more R 10 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 10* ;
  • R lb in each occurrence is selected from Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optional
  • R 2 is selected from H, halo, -CN, C ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 3- to 6 membered carbocyclyl, 4- to 6-membered 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 , -N(R 2a )(OR 2a ), -ON(R 2a ) 2 , -C(O)H, -C(O)R 2b , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 , -C(O)N(R 2a )(OR 2a ), -OC(O)N(R 2a ) 2 , -N(R 2a )C(
  • R 3 is selected from H, halo, -CN, Ci- ⁇ alkyl, C2-6alkenyl, 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 , -N(R 3a )(OR 3a ), -O-N(R 3a ) 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -C(O)N(R 3a )(OR 3a ), -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -N(R 3
  • R 3a 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 on carbon with one or more R 30 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 30* ;
  • R 3b in each occurrence is 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 on carbon with one or more R 30 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substitute
  • R 4 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )(OR 4a ), -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -C(O)N(R 4a )(OR 4a ) -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N
  • 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 on carbon with one or more R 40 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 40* ;
  • R 4b in each occurrence is selected from Ci- ⁇ alkyl, C2-6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aUcyl, C2-6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 40*
  • R 5 is selected from H, halo, -CN, Ci_6alkyl, C 2- 6alkenyl, C 2- 6alkynyl, 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 , -N(R 5a )(OR 5a ), -O-N(R 5a ) 2 , -C(O)H, -C(O)R 5b , -C(O) 2 R 5a , -C(O)N(R 5a ) 2 , -C(O)N(R 5a )(OR 5a ) -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a , -N(R
  • R 5a 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 on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 50* ;
  • R 5b in each occurrence is selected from Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aUcyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted
  • R 6 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, carbocyclyl, heterocyclyl, -OR 6a , -SR 6a , -N(R 6a ) 2 , -N(R 6a )C(O)R 6b , -N(R 6a )N(R 6a ) 2 , -NO 2 , -N(R 6a )(OR 6a ), -O-N(R 6a ) 2 , -C(O)H, -C(O)R 6b , -C(O) 2 R 6a , -C(O)N(R 6a ) 2 , -C(O)N(R 6a )(OR 6a ) -OC(O)N(R 6a ) 2 , -N(R 6a )C(O) 2 R 6a
  • R 6a 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 on carbon with one or more R 60 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R 60* ;
  • R 6b in each occurrence is selected from Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aUcyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 60 , and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is
  • 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 , -N(R 10a )(OR 10a ), -O-N(R 10a ) 2 , -C(O)H, -C(O)R 10b , -C(O) 2 R 10a , -C(O)N(R 10a ) 2 , -C(O)N(R 10a )(OR 10a ), -OC(O)N(R 10a ) 2 , -N(R 10a )C(O) 2 R 10
  • 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 C 2 -6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, 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 , -N(R 20a )(OR 20a ), -O-N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -C(O)N(R 20a )(OR 20a ), -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a
  • 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, carbocyclyl, and heterocyclyl;
  • R 30 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 . 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 30a , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 30a )N(R 30a ) 2 , -NO 2 , -N(R 30a )(OR 30a ), -O-N(R 30a ) 2 , -C(O)H, -C(O)R 30b , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 , -C(O)N(R 30a )(OR 30a ), -OC(O)N(R 30a ) 2 , -N(R 30a )C(O) 2 R 30a
  • R 30a in each occurrence is independently selected from H, Ci- ⁇ alkyl, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from d_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a ) 2 , -NO 2 , -N(R 40a )(OR 40a ), -O-N(R 40a ) 2 , -C(O)H, -C(O)R 40b , -C(O) 2 R 40a , -C(O)N(R 40a ) 2 , -C(O)N(R 40a )(OR 40a ), -OC(O)N(R 40a ) 2 , -N(R 40a )C(O) 2 R 40a
  • R 40* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl,
  • R 40a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 50 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl,
  • R 50* in each occurrence is independently selected from -CN, Ci- ⁇ alkyl, carbocyclyl, heterocyclyl,
  • 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;
  • R 60 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl,
  • R 60* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl,
  • R 60a in each occurrence is independently selected from H, d_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 60b 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 C 4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-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.
  • C 2 _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.
  • C 2 _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 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.
  • 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 -CH 2 - 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, morpholinyl, 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, te
  • heterocyclyl may be “4- to 6-membered heterocyclyl.”
  • the term “4- to 6-membered heterocyclyl” refers to a saturated, partially saturated, or unsaturated, 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 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.
  • "4- to 6-membered heterocyclyl” include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxoimidazolidinyl, 3-oxo-l- piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydro furanyl, oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl,
  • heterocyclyl and “4- to 6-membered heterocyclyl” may be “5- or 6-membered heterocyclyl.”
  • 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 -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.
  • Illustrative examples of "5- or 6-membered heterocyclyl" include dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxoimidazolidinyl, 3-oxo-l- piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydro furanyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl,
  • 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, morpholinyl, piperazinyl, piperidinyl, 2H- pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
  • heterocyclyl may be “5- or 6-membered heteroaryl.”
  • heteroaryl is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen. 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 heteroaryl include furanyl, imidazolyl, isothiazolyl, isoxazole, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, pyrimidinyl, pyridinyl, pyrrolyl, 1,3,4- thiadiazolyl, thiazolyl, thiophenyl, and 4H-l,2,4-triazolyl.
  • 6-Membered ⁇ eteroaryl In one aspect, “heterocyclyl”, “4- to 6-membered heterocyclyl,” “5- or 6-membered heterocyclyl,” “6-membered heterocyclyl,” and “5- or 6-membered heteroaryl” may be “6-membered heteroaryl.”
  • the term “6-membered heteroaryl” is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms. 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.
  • heterocyclyl and “4- to 6-membered heterocyclyl,” may be “4 to 6-membered saturated heterocyclyl.”
  • the term “4- to 6-membered saturated heterocyclyl” refers to a saturated, 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 saturated 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 saturated heterocyclyl" include azetidinyl, 1,1-dioxidothiomorpholinyl, morpholinyl, oxetanyl, oxopiperazinyl, 2- oxopyrrolidinyl, oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, and thiomorpholinyl.
  • heterocyclyl may be “6-membered saturated heterocyclyl.”
  • the term “6-membered saturated heterocyclyl” refers to a saturated, 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. Unless otherwise specified, "6-membered saturated 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 saturated heterocyclyl" include 1,1-dioxidothiomorpholinyl, morpholinyl, oxopiperazinyl, piperazinyl, piperidyl, tetrahydropyranyl, and thiomorpholinyl.
  • 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.
  • 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.
  • 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.
  • suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.
  • 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 t-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • alkanoyl groups such as acetyl
  • alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and t-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 t-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
  • 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.
  • 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 centers and/or geometric isomeric centers (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 is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R 6 ; and R 6 is halo.
  • Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R 6 ; and R 6 is halo.
  • Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are substituted with at least one R 6 ; and R 6 is halo.
  • Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R 6 ; and R 6 is fluoro.
  • Ring A is selected from pyridin-2-yl and pyrimidin-2-yl, wherein said pyridin-2-yl and pyrimidin-2-yl are optionally substituted with one or more R 6 ; and R 6 is fluoro.
  • Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl.
  • D is C-R > 3 ;
  • E is selected from N and C-R 4 ;
  • R 3 is selected from H, halo, 5- or 6-membered heterocyclyl, and -NH 2 ;
  • R 4 is -CN.
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • R 3 is selected from H, 5- or 6-membered heterocyclyl, and -NH 2 ;
  • R 4 is -CN.
  • D is C-R 3 ;
  • R 3 is selected from H, 5- or 6-membered heterocyclyl, and -NH 2 .
  • D is C-R ;
  • E is C-R 4 ;
  • R 3 is selected from H, 5- or 6-membered heterocyclyl, and -NH 2 ;
  • R 4 is -CN.
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • R 3 is selected from H, morpholin-4-yl, and -NH 2 ;
  • R 4 is -CN.
  • D is C-R 3 ; E is selected from N and C-R 4 ; R 3 is H; and R 4 is -CN.
  • X is -NH-.
  • R 1* is Ci_ 6 alkyl.
  • R 1* is methyl
  • R 2 is selected from H, halo, Ci_6alkyl, and -OR 2a ; and R 2a is Ci_ 6 alkyl.
  • R 2 is selected from H, fluoro, chloro, methyl, and methoxy.
  • R 2 is halo
  • R 2 is selected from fluoro and chloro.
  • R 5 is Ci_ 6 alkyl, wherein said Ci_6alkyl is optionally substituted with one or more -OR 5a ; and R 5a is Ci_ 6 alkyl.
  • R 5 is selected from methyl and methoxy.
  • R 5 is selected from methyl and methoxymethyl.
  • Ring A is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R 6 ;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-
  • R 1* is Ci_ 6 alkyl
  • R 2 is selected from H, halo, C 1-6 alkyl, and -OR 2a ;
  • R 2a is Ci_ 6 alkyl
  • R 3 is selected from H, halo, 5- or 6-membered heterocyclyl, and -NH 2 ;
  • R 4 is -CN
  • R 5 is Ci_ 6 alkyl, wherein said C ⁇ alkyl is optionally substituted with one or more -OR 5a ;
  • R 5a is Ci_ 6 alkyl
  • R 6 is halo
  • Ring A is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R 6 ;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-
  • R 1* is Ci_ 6 alkyl
  • R 2 is selected from H, halo, d_ 6 alkyl, and -OR 2a ;
  • R 2a is Ci_ 6 alkyl
  • R 3 is selected from H, 5- or 6-membered heterocyclyl, and -NH 2 ;
  • R 4 is -CN
  • R 5 is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more -OR 5a ;
  • R 5a is Ci_ 6 alkyl
  • R 6 is halo
  • Ring A is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R 6 ;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-;
  • R 1* is Ci_ 6 alkyl;
  • R 2 is halo;
  • R 3 is H;
  • R 4 is -CN
  • R 5 is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more -OR 5a ;
  • R 5a is Ci_ 6 alkyl
  • R 6 is halo
  • Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R 6 ;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-
  • R 1* is methyl
  • R 2 is selected from fluoro and chloro
  • R 3 is H
  • R 4 is -CN
  • R 5 is selected from methyl and methoxy
  • R 6 is fluoro
  • Ring A is selected from pyridin-2-yl and pyrimidin-2-yl, wherein said pyridin-2-yl and pyrimidin-2-yl are optionally substituted with one or more R 6 ;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-
  • R 1* is Ci_ 6 alkyl
  • R 2 is selected from H, halo, d_ 6 alkyl, and -OR 2a ;
  • R 2a is Ci_ 6 alkyl
  • R 3 is selected from H, halo, 6-membered heterocyclyl, and -NH 2 ;
  • R 4 is -CN;
  • R 5 is Ci_ 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more -OR 5a ;
  • R 5a is Ci_ 6 alkyl;
  • R 6 is halo
  • Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-
  • R 2 is selected from fluoro and chloro
  • R 3 is H
  • R 4 is -CN
  • R 5 is selected from methyl and methoxy.
  • Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl;
  • D is C-R 3 ;
  • E is selected from N and C-R 4 ;
  • X is -NH-
  • R 1* is methyl
  • R 2 is selected from chloro and fluoro
  • R 3 is selected from H, morpholin-4-yl, and -NH 2 ;
  • R 4 is -CN
  • R 5 is selected from methyl and methoxymethyl.
  • the compound of Formula (I) is a compound of Formula (Ia):
  • the present invention provides a compound selected from:
  • 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, myelodysplasia 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.
  • 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) 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).
  • Alphascreen Amplified Luminescent Proximity Assay
  • 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-specific antibodies coated Acceptor Beads using the En Vision Multilabel Plate Reader after an overnight incubation at room temperature.
  • Te ween 20 is a registered trademark of ICI Americas, Inc.
  • typical compounds of the Formula (I) are generally believed to possess JAK inhibitory activity at IC50 concentrations (concentrations to achieve 50% inhibition) or doses at a level below 10 ⁇ M when tested in an assay based in the assay (method 1) described above.
  • Activity of purified C-terminal His6-tagged human JAK2 kinase may be determined in- vitro using an Amplified Luminescent Proximity Homogeneous Assay (ALPHA) (Perkin Elmer, MA), which measures phosphorylation of a biotinylated Tyk (Tyrl 04/1055) substrate (Cell Signaling Technology, MA, Cat #2200B).
  • APHA Amplified Luminescent Proximity Homogeneous Assay
  • ATP Enzyme/Substrate/adenosine triphosphate
  • Reactions may be initiated with 5 ⁇ l of Metal mix consisting of 24mM MgCl 2 in 1.2x buffer and incubated at 25 0 C for 90 minutes and reactions may be stopped by addition of 5 ⁇ l of Detection mix consisting of 2OmM HEPES, 102mM ethylenediamine tetraacetic acid, 1.65mg/ml BSA, 136mM NaCl, 40 ⁇ g/ml Streptavidin donor beads (Perkin Elmer, MA, Catalog #6760002), and 40 ⁇ g/ml phosphotyrosine-specific antibody coated acceptor beads (Perkin Elmer, MA, Catalog #6760620). Plates may be incubated at 25 0 C for 18 hours in the dark. Phosphorylated substrate may be detected by an En Vision plate reader (Perkin Elmer, MA) 680nm excitation, 520-620nm emission. Data may be graphed and IC 50 S calculated using Excel Fit (Microsoft).
  • typical compounds of the Formula (I) are generally believed to possess JAK inhibitory activity at IC50 concentrations (concentrations to achieve 50% inhibition) or doses at a level below 10 ⁇ M when tested in an assay based in the assay (method 2) described above.
  • Janus kinase 2 (JAK2) activity may be determined by measuring the kinase's ability to phosphorylate a tyrosine residue within a peptide substrate using a mobility shift assay on a Caliper LC3000 reader (Caliper, Hopkinton, MA), which measures fluorescence of the phosphorylated and unphosphorylated substrate and calculates a ratiometric value to determine percent turnover.
  • an in-house purified enzyme may be used.
  • the enzyme may be N-terminal GST-tagged, recombinant, human JAK2 (amino acids 831-1132, PLAZA database pAZB0359) expressed in insect cells.
  • a FAM labeled SRCtide substrate adenosine triphosphate (ATP), and MgCl 2
  • ATP adenosine triphosphate
  • MgCl 2 MgCl 2
  • the kinase reaction may be stopped by the addition of 36 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the reaction may be performed in 384 well microtitre plates and the reaction products may be detected using the Caliper LC3000 Reader.
  • typical compounds of the Formula (I) are generally believed to possess JAK inhibitory activity at IC50 concentrations (concentrations to achieve 50% inhibition) or doses at a level below 10 ⁇ M when tested in an assay based in the assay (method 3) described above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament 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
  • 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
  • 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), 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 for use in the production of an anti-pro liferative 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.
  • 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
  • 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, polyvinyl-pyrrolidone, 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 hexito
  • 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.
  • preservatives such as ethyl or propyl p_-hydroxybenzoate
  • anti-oxidants such as ascorbic acid
  • coloring agents such as ascorbic acid
  • flavoring agents such as ascorbic acid
  • 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.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumor agents:
  • antiproliferative/antineoplastic drugs 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, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as tax
  • 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 5 ⁇ -reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
  • agents which inhibit cancer cell invasion for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function;
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl 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
  • 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 (PBK) 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;
  • PBK phosphotidylinositol 3-kinase
  • 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 [AvastinTM], 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 ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • 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 trans fection 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 drugs 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 1311-metaiodobenzylguanidine (131I-MIBG), anti-G(D2) monoclonal antibody therapy with or without granulocyte- macrophage colony-stimulating factor (GM-CSF) following chemotherapy.
  • dexamethasone proteasome inhibitors (including bortezomib), isotretinoin (13-cis retinoic acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitors CEP-701 and CEP-2563
  • 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 a process selected from:
  • Formula (D) 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 is a leaving group as described hereinabove.
  • protecting groups may be used as necessary.
  • Leaving groups suitable for use in Process A and Process B include halo groups such as chloro.
  • 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 O 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 t-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.
  • Process B Compounds of Formula (C) and compounds of Formula (D) may be reacted together under the conditions described for the reaction of the compound of Formula (A) with the compound of Formula (B) in Process A.
  • compounds of Formula (E) (which are compounds of Formula (B) having the indicated stereochemistry, and in which X is -NH-, and R 4 is an alkyl group such as methyl) may be prepared via chiral synthesis according to Scheme 1.
  • Scheme 1
  • Reaction of a compound of Formula (F) with an organometallic reagent R 4 -M (wherein R 4 is an alkyl group such as methyl, and M is a metal species such as -MgCl, -MgBr or -Li), followed by quenching, may be used to obtain a compound of Formula (G).
  • Reaction of a compound of Formula (G) with amine donor R 7 -NH 2 (in which R 7 is a group such as isopropyl or methylbenzyl) in the presence of an omega transaminase may be used to obtain a compound of Formula (E).
  • Suitable amine donors may include alanine in the presence of pyruvatedecarboxylase, benzylamine, S-methylbenzylamine and isopropylamine.
  • Suitable omega transaminases include those from Vibrio fluvalis, thermostable transaminase CNB05-01, Biocatalytics 101,102, 103, 110, 111, 114,115.
  • the biocatalysts maybe free enzymes or suitable whole cell preparations.
  • the omega transaminase and R 7 -NH2 may advantageously be mixed in solution with an aqueous buffer such as aqueous potassium phosphate or aqueous HEPES buffer, followed by addition of pyridoxyl phosphate.
  • an immiscible organic solvent such as toluene, BuOAc or diisooctylphthalate
  • the stereoselectivity of the amine can be switched from S to R by using an R selective transaminase such as Biocatalytics 117.
  • 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;
  • 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 0 C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates;
  • 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;
  • NMR data 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-d ⁇ unless otherwise stated;
  • 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;
  • 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;
  • SFC super critical fluid chromatography
  • ASFC Analytical SFC
  • Preparative SFC APS- 1000 AutoPrep Preparative SFC
  • 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
  • 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
  • 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 dimethylacetamide.
  • 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.
  • N-[(15)-l-(5-Fluoropyrimidin-2-yl)ethyl]acetamide (Intermediate 8, 0.20 g, 1.09 mmol), DMAP (0.027 g, 0.22 mmol) and BoC 2 O (0.60 g, 2.73 mmol) in THF (10 ml) was stirred at 50 0 C for 40 hours. After cooling to room temperature, lithium hydroxide monohydrate (0.094 g, 2.24 mmol) and water (10 ml) was added. The reaction mixture was stirred at room temperature for 9 hours. Ether (30 ml) was added, organic layer was separated, washed with brine (20 ml) and dried over sodium sulfate.
  • the catalyst was filtered via Celite and the filtrate of l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (0.4 M in ethyl acetate) (180 mL, 72.00 mmol) was treated with (7 ⁇ -Mandelic acid (5.81 g, 38.16 mmol). Precipitation was observed almost instantaneously and the resulting mixture was allowed to stir o/n. The title product was collected via filtration (8.5 g, 69.4 %).
  • reaction mixture was stirred at 5O 0 C for 3 hours. Solid NaCl and EtOAc was added to quench the reaction, stirred for 1 hour at room temperature, and was then filtered through Celite® and rinsed with EtOAc. The organic layer was washed with 5 ml
  • l-(3,5-Difluoropyridin-2-yl)ethanamine hydrochloride may be obtained by stirring l-(3,5- difluoropyridin-2-yl)ethanamine (Intermediate 17) for 1 hour in MeOH in the presence of HCl (4N in dioxane) and subsequently evaporating the volatiles under reduced pressure.
  • the hydrochloride salt may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvents provides the hydrochloride salt of the title compound as a tan solid. While it is believed that the product thus obtained exists in the form of a dihydrochloride salt, it is possible that it exists in the form of the monohydrochloride salt.
  • the first eluting compound had a retention time of 4.49 minutes, >98% ee.
  • the second eluting compound had a retention time of 7.16 minutes, >98% ee.
  • the first eluting compound had a retention time of 8.83 minutes, >98% ee.
  • the second eluting compound had a retention time of 11.12 minutes, >98% ee.
  • the S enantiomer of Example 3 may be prepared according to the procedure described below for Example 3(a).
  • Example 2 providing the title compound as a pale yellow solid (132.9 mg).
  • the compound had a retention time of 2.57 minutes, >98% ee.
  • the first eluting compound had a retention time of 0.76 minutes, >98% ee.
  • 1 H NMR 300 MHz, MeOD
  • the second eluting compound had a retention time of 1.40 minutes, >98% ee.
  • the first eluting compound had a retention time of 5.10 minutes, >98% ee.
  • the second eluting compound had a retention time of 5.67 minutes, >98% ee.
  • the first eluting compound had a retention time of 0.88 minutes, 94.8% ee.
  • the second eluting compound had a retention time of 1.15 minutes, >98% ee.
  • the first eluting compound had a retention time of 4.93 minutes, 97.7% ee.
  • the second eluting compound had a retention time of 6.38 minutes, >98% ee.
  • the first eluting compound had a retention time of 5.73 minutes.
  • the second eluting compound had a retention time of 6.21 minutes, >98% ee.
  • the title product may also be obtained using 6-chloro- ⁇ / 2 -[(li?)-l-(3,5-difluoropyridin-2-yl)-2- methoxyethyl]- ⁇ / 4 -(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4-diamine (Example 22) as the starting material instead of chloro- ⁇ / 2 -[(15)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]- ⁇ / 4 -(l- methyl-lH-imidazol-4-yl)pyrimidine-2,4-diamine (Example 23).
  • the first eluting compound had a retention time of 1.84 minutes, >98% ee.
  • the second eluting compound had a retention time of 2.22 minutes, >98% ee.
  • 1 H NMR 300 MHz, MeOD
  • LCMS 447 [M+H] + .
  • the first eluting compound had a retention time of 10.5 minutes, ee was not determined.
  • the second eluting compound had a retention time of 16.2 minutes, >98% ee.
  • the second eluting compound had a retention time of 5.75 minutes, >98% ee.
  • the first eluting compound had a retention time of 4.96 minutes, >98% ee.
  • This material was purified utilizing ISCO (2-5% MeO ⁇ /DCM, 5 min, 5% MeO ⁇ /DCM isocratic, 5 min, 5-10% MeO ⁇ /DCM, 5 min, 10% MeO ⁇ /DCM isocratic, 5 min). Concentration of the fractions in vacuo provided the title compound, a mixture of enantiomers, as a yellow solid (160 mg).
  • the first eluting compound had a retention time of 10.11 minutes, >98% ee.
  • the second eluting compound had a retention time of 11.89 minutes, >98% ee.
  • the first eluting compound had a retention time of 9.07 minutes, >98% ee.
  • the second eluting compound had a retention time of 11.25 minutes, >98% ee.

Abstract

The present inv ention relates to compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted on carbon with one or more R6, and wherein if said 5- or 6- membcred heteroaryl contains an -NH- moiety, that -NH- moiety is optionally substituted with R6; D is selected from N and C-R3; E is selected from N and C-R4, wherein at least one of D and E is carbon; X is selected from -NH-, -O-, and -S-; and to their pharmaceutical compositions, methods of use, and methods for their preparation. These compounds provide a treatment for myeloproliferative disorders and cancer.

Description

2-(IMIDAZOLYLAMINO)-PYRIDINE DERIVATIVES AND THEIR USE AS JAK KINASE INHIBITORS
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
Formula (I)
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
Formula (I) and pharmaceutically acceptable salts thereof, wherein
Ring A is 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted on carbon with one or more R6, and wherein if said 5- or 6-membered heteroaryl contains an -NH- moiety, that -NH- moiety is optionally substituted with R6*;
D is selected from N and C-R3;
E is selected from N and C-R4, wherein at least one of D and E is carbon; X is selected from -NH-, -O-, and -S-;
R1* is selected from H, -CN, C1-6alkyl, carbocyclyl, heterocyclyl, -ORla, -N(Rla)2, -C(O)H, -C(O)Rlb, -C(O)2Rla, -C(O)N(Rla)2, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R10, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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 on carbon with one or more R10, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R10*; Rlb in each occurrence is selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R10, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R10*;
R2 is selected from H, halo, -CN, C^alkyl, C2_6alkenyl, C2_6alkynyl, 3- to 6 membered carbocyclyl, 4- to 6-membered heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -N(R2a)(OR2a), -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a), -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 on carbon with one or more R20, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R20*; R2a in each occurrence is independently selected from H, C^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R20*; R2b in each occurrence is 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 on carbon with one or more R20, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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, -N(R3a)(OR3a), -O-N(R3a)2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -C(O)N(R3a)(OR3a), -OC(O)N(R3a)2, -N(R3a)C(O)2R3, -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 d_6alkyl, C2.6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R30, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R30*;
R3a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R30*; R3b in each occurrence is 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 on carbon with one or more R30, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R30*;
R4 is selected from H, halo, -CN, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)(OR4a), -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -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 d_6alkyl, C2.6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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 on carbon with one or more R40, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R40*; R4b in each occurrence is selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R40*;
R5 is selected from H, 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, -N(R5a)(OR5a), -O-N(R5a)2, -C(O)H, -C(O)R5b, -C(O)2R5a, -C(O)N(R5a)2, -C(O)N(R5a)(OR5a) -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 are optionally substituted on carbon with one or more R50, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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 on carbon with one or more R50, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R50*; R5b in each occurrence is selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R50, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R50*;
R6 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2-6alkenyl, C2.6alkynyl, carbocyclyl, heterocyclyl, -OR6a, -SR6a, -N(R6a)2, -N(R6a)C(O)R6b, -N(R6a)N(R6a)2, -NO2, -N(R6a)(OR6a), -O-N(R6a)2, -C(O)H, -C(O)R6b, -C(O)2R6a, -C(O)N(R6a)2, -C(O)N(R6a)(OR6a) -OC(O)N(R6a)2, -N(R6a)C(O)2R6a, -N(R6a)C(O)N(R6a)2, -OC(O)R6b, -S(O)R6b, -S(O)2R6b, -S(O)2N(R6a)2, -N(R6a)S(O)2R6b, -C(R6a)=N(R6a), and -C(R5a)=N(OR5a), wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R60*; R6* in each occurrence is independently selected from -CN, C^alkyl, carbocyclyl, heterocyclyl, -OR6a, -N(R6a)2, -C(O)H, -C(O)R6b, -C(O)2R6a, -C(O)N(R6a)2, -S(O)R6b, -S(O)2R6b, -S(O)2N(R6a)2, -C(R6a)=N(R6a), and -C(R6a)=N(OR6a), wherein said d_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R60*;
R6a 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 on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R60*; R6b in each occurrence is selected from Ci-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R60*;
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, -N(R10a)(OR10a), -O-N(R10a)2, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -C(O)N(R10a)(OR10a), -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);
R10* in each occurrence is independently selected from d_6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -C(R1Oa)=N(R1Oa), and -C(R10a)=N(OR10a);
R1Oa in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; R1Ob in each occurrence is independently selected from
Figure imgf000010_0001
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, -N(R20a)N(R20a)2, -NO2, -N(R20a)(OR20a), -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -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 :((RR220( a)=N(OR20a);
R20* in each occurrence is independently selected from C^aUcyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a);
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, carbocyclyl, and heterocyclyl;
R30 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2-6alkenyl, C2.6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b, -N(R30a)N(R30a)2, -NO2, -N(R30a)(OR30a), -O-N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -C(O)N(R30a)(OR30a), -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(R30a)=N(R30a), and -C(R30a)=N(OR30a);
R30* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl, -OR30a, -N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a);
R30a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl;
R30b in each occurrence is independently selected from d_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl;
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, -N(R40a)N(R40a)2, -NO2, -N(R40a)(OR40a), -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -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);
R40* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl,
-OR40a, -N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b,
-S(O)2N(R40a)2, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a);
R40a in each occurrence is independently selected from H,
Figure imgf000011_0001
carbocyclyl, and heterocyclyl;
R40b in each occurrence is independently selected from
Figure imgf000011_0002
C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R50 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2.6alkynyl, carbocyclyl, heterocyclyl, -OR50a, -SR5Oa, -N(R50a)2, -N(R50a)C(O)R50b,
-N(R5Oa)N(R5Oa)2, -NO2, -N(R50a)(OR50a), -O-N(R50a)2, -C(O)H, -C(O)R50b, -C(O)2R50a,
-C(O)N(R50a)2, -C(O)N(R50a)(OR50a), -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);
R50* in each occurrence is independently selected from -CN, Ci-βalkyl, carbocyclyl, heterocyclyl,
-OR50a, -N(R50a)2, -C(O)H, -C(O)R50b, -C(O)2R50a, -C(O)N(R50a)2, -S(O)R50b, -S(O)2R50b,
-S(O)2N(R50a)2, -C(R5Oa)=N(R5Oa), and -C(R50a)=N(OR50a);
R50a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R50b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R60 in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C2_6alkenyl,
C2.6alkynyl, carbocyclyl, heterocyclyl, -OR60a, -SR60a, -N(R60a)2, -N(R60a)C(O)R60b,
-N(R60a)N(R60a)2, -NO2, -N(R60a)(OR60a), -O-N(R60a)2, -C(O)H, -C(O)R60b, -C(O)2R60a,
-C(O)N(R60a)2, -C(O)N(R60a)(OR60a), -OC(O)N(R60a)2, -N(R60a)C(O)2R60a, -N(R60a)C(O)N(R60a)2,
-OC(O)R60b, -S(O)R60b, -S(O)2R60b, -S(O)2N(R60a)2, -N(R60a)S(O)2R60b, -C(R60a)=N(R60a), and
-C(R60a)=N(OR60a);
R60* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl,
-OR60a, -N(R60a)2, -C(O)H, -C(O)R60b, -C(O)2R60a, -C(O)N(R60a)2, -S(O)R60b, -S(O)2R60b, -S(O)2N(R60a)2, -C(R60a)=N(R60a), and -C(R50a)=N(OR60a);
R60a in each occurrence is independently selected from H, d_6alkyl, carbocyclyl, and heterocyclyl; and
R60b 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 t-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.
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.
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, morpholinyl, 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, thiomorpholinyl, thiophenyl, pyridine-Λ/-oxidyl and quinoline-iV-oxidyl.
4- to 6- Membered Heterocyclyl - In one aspect, "heterocyclyl" may be "4- to 6-membered heterocyclyl." The term "4- to 6-membered heterocyclyl" refers to a saturated, partially saturated, or unsaturated, 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 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 heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxoimidazolidinyl, 3-oxo-l- piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydro furanyl, oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydro furanyl, tetrahydropyranyl, thiazolyl, 1,3,4- thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, 4H-l,2,4-triazolyl, and pyridine-Λ/-oxidy 1.
5- or 6-Membered Ηeterocyclyl - In one aspect, "heterocyclyl" and "4- to 6-membered heterocyclyl" may be "5- or 6-membered heterocyclyl." 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 dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxoimidazolidinyl, 3-oxo-l- piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydro furanyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydro furanyl, tetrahydropyranyl, thiazolyl, 1,3,4- thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, 4H-l,2,4-triazolyl, and pyridine-Λ/-oxidy 1.
6-Membered Ηeterocyclyl - In one aspect, "heterocyclyl," "4- to 6-membered heterocyclyl," and "5- or 6-membered heterocyclyl" may be "6-membered heterocyclyl." 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, morpholinyl, piperazinyl, piperidinyl, 2H- pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
5- or 6-Membered Ηeteroaryl - In one aspect, "heterocyclyl," "4- to 6-membered heterocyclyl," and "5- or 6-membered heterocyclyl" may be "5- or 6-membered heteroaryl." As used herein, the term "5- or 6-membered heteroaryl" is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen. 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 heteroaryl" include furanyl, imidazolyl, isothiazolyl, isoxazole, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, pyrimidinyl, pyridinyl, pyrrolyl, 1,3,4- thiadiazolyl, thiazolyl, thiophenyl, and 4H-l,2,4-triazolyl.
6-Membered Ηeteroaryl - In one aspect, "heterocyclyl", "4- to 6-membered heterocyclyl," "5- or 6-membered heterocyclyl," "6-membered heterocyclyl," and "5- or 6-membered heteroaryl" 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. 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 Saturated Heterocyclyl - In one aspect, "heterocyclyl" and "4- to 6-membered heterocyclyl," may be "4 to 6-membered saturated heterocyclyl." The term "4- to 6-membered saturated heterocyclyl" refers to a saturated, 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 saturated 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 saturated heterocyclyl" include azetidinyl, 1,1-dioxidothiomorpholinyl, morpholinyl, oxetanyl, oxopiperazinyl, 2- oxopyrrolidinyl, oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, and thiomorpholinyl.
6-Membered Saturated Heterocyclyl - In one aspect, "heterocyclyl," "4- to 6-membered heterocyclyl," and "4 to 6-membered saturated heterocyclyl" may be "6-membered saturated heterocyclyl." The term "6-membered saturated heterocyclyl" refers to a saturated, 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 saturated 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 saturated heterocyclyl" include 1,1-dioxidothiomorpholinyl, morpholinyl, oxopiperazinyl, piperazinyl, piperidyl, 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 t-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 t-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 R1 for illustrative purposes, the following substituent definitions have the indicated meanings:
Figure imgf000019_0001
RR13 O
-N(Ria)S(O)2R1b = J— N-S-R1b
O R1a R1a
-N(R1a)N(R1a)2 1a
-N— N— R
Figure imgf000020_0001
O -C(O)2R13 1a
OR
Figure imgf000020_0002
The compounds discussed herein were named with ACD/Name (Release: 10.00; Product Version: 10.04 (Build 18136, 22 March, 2007)) 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 centers and/or geometric isomeric centers (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 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R6; and R6 is halo.
In another aspect, Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R6; and R6 is halo.
In still another aspect, Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are substituted with at least one R6; and R6 is halo.
In yet another aspect, Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R6; and R6 is fluoro.
In a further aspect, Ring A is selected from pyridin-2-yl and pyrimidin-2-yl, wherein said pyridin-2-yl and pyrimidin-2-yl are optionally substituted with one or more R6; and R6 is fluoro. In one aspect, Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl.
D and E
In one aspect, D is C-R > 3 ;
E is selected from N and C-R4;
R3 is selected from H, halo, 5- or 6-membered heterocyclyl, and -NH2; and
R4 is -CN.
In another aspect, D is C-R3;
E is selected from N and C-R4;
R3 is selected from H, 5- or 6-membered heterocyclyl, and -NH2; and
R4 is -CN.
In still another aspect, D is C-R3;
E is N; and
R3 is selected from H, 5- or 6-membered heterocyclyl, and -NH2.
In yet another aspect, D is C-R ;
E is C-R4;
R3 is selected from H, 5- or 6-membered heterocyclyl, and -NH2; and
R4 is -CN.
In a further aspect, D is C-R3; E is selected from N and C-R4;
R3 is selected from H, morpholin-4-yl, and -NH2; and
R4 is -CN.
In still a further aspect, D is C-R3; E is selected from N and C-R4; R3 is H; and R4 is -CN.
X
In one aspect, X is -NH-.
In one aspect, R1* is Ci_6alkyl.
In another aspect, R1* is methyl.
E!
In one aspect, R2 is selected from H, halo, Ci_6alkyl, and -OR2a; and R2a is Ci_6alkyl.
In another aspect, R2 is selected from H, fluoro, chloro, methyl, and methoxy.
In still another aspect, R2 is halo.
In yet another aspect, R2 is selected from fluoro and chloro.
In one aspect, R5 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more -OR5a; and R5a is Ci_6alkyl.
In another aspect, R5 is selected from methyl and methoxy.
In still another aspect, R5 is selected from methyl and methoxymethyl.
Ring A, D, E, X, R1', and R5
In one aspect, Ring A is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R6;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R1* is Ci_6alkyl;
R2 is selected from H, halo, C1-6alkyl, and -OR2a;
R2a is Ci_6alkyl;
R3 is selected from H, halo, 5- or 6-membered heterocyclyl, and -NH2;
R4 is -CN;
R5 is Ci_6alkyl, wherein said C^alkyl is optionally substituted with one or more -OR5a;
R5a is Ci_6alkyl; and
R6 is halo.
In another aspect, Ring A is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R6;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R1* is Ci_6alkyl;
R2 is selected from H, halo, d_6alkyl, and -OR2a;
R2a is Ci_6alkyl;
R3 is selected from H, 5- or 6-membered heterocyclyl, and -NH2;
R4 is -CN;
R5 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more -OR5a;
R5a is Ci_6alkyl; and
R6 is halo.
In still another aspect, Ring A is 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R6;
D is C-R3;
E is selected from N and C-R4; X is -NH-; R1* is Ci_6alkyl; R2 is halo; R3 is H;
R4 is -CN;
R5 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more -OR5a;
R5a is Ci_6alkyl; and
R6 is halo.
In yet another aspect, Ring A is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R6;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R1* is methyl;
R2 is selected from fluoro and chloro;
R3 is H;
R4 is -CN;
R5 is selected from methyl and methoxy; and
R6 is fluoro.
In a further aspect, Ring A is selected from pyridin-2-yl and pyrimidin-2-yl, wherein said pyridin-2-yl and pyrimidin-2-yl are optionally substituted with one or more R6;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R1* is Ci_6alkyl;
R2 is selected from H, halo, d_6alkyl, and -OR2a;
R2a is Ci_6alkyl;
R3 is selected from H, halo, 6-membered heterocyclyl, and -NH2;
R4 is -CN; R5 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more -OR5a; R5a is Ci_6alkyl; and
R6 is halo.
In still a further aspect, Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R2 is selected from fluoro and chloro;
R3 is H;
R4 is -CN; and
R5 is selected from methyl and methoxy.
In yet a further aspect, Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R1* is methyl;
R2 is selected from chloro and fluoro;
R3 is selected from H, morpholin-4-yl, and -NH2;
R4 is -CN; and
R5 is selected from methyl and methoxymethyl.
In one aspect, the compound of Formula (I), is a compound of Formula (Ia):
Figure imgf000028_0001
Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein Ring A, D, E, X, R1*, R2, and R5 are as defined hereinabove.
In another aspect, the present invention provides a compound selected from:
5 -fluoro-2- { [ 1 -(5 -fluoropyrimidin-2-yl)ethyl] amino } -6-[( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- { [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] amino } -6-[( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- {[( Ii?)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] amino } -6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -chloro-Λ/2- [ 1 -(5 -fluoropyrimidin-2-yl)ethyl]-Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine;
5 -chloro-Λ/2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-y l)pyrimidine-
2,4-diamine;
5 -chloro-Λ/2- [(IR)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
5 -fluoro-2- {[ 1 -(5-fluoropyridin-2-yl)ethyl]amino} -6-[(l -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- {[(IS)- 1 -(5 -fluoropyridin-2-yl)ethyl] amino } -6-[(l -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- {[( IR)- 1 -(5 -fluoropyridin-2-yl)ethyl] amino } -6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile; 5-chloro-N2-[ 1 -(5-fluoropyridin-2-yl)ethyl]-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine;
5 -chloro-JV2- [( 1 S)- 1 -(5 -Fluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine;
5-chloro-Λ/2-[(li?)-l-(5-Fluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
2- { [ 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl]amino } -5 -fluoro-6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
2- { [( IR)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] amino } -5 -fluoro-6-[( 1 -methyl- 1 H- imidazol-4-yl)amino]nicotinonitrile;
2- { [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] amino } -5 -fluoro-6- [( 1 -methyl- IH- imidazol-4-yl)amino]nicotinonitrile;
5 -chloro-N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5 -chloro-N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
2- { [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] amino } -5 -fluoro-6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
2- { [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] amino } -5 -fluoro-6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
2- {[( IR)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] amino } -5 -fluoro-6- [( 1 -methyl- 1 H-imidazol-4- yl)amino]nicotinonitrile;
5 -chloro-Λ/2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine;
5 -chloro-Λ/2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -7V4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
5-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin- 4-ylpyrimidine-2,4-diamine;
N2 -[(IR)- 1 -(3 ,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2- [ 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
Λ/2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -5 -fluoro-Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- y lpyrimidine-2 ,4 -diamine;
N2-[(15)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
Λ/2-[l-(5-fluoropyrimidin-2-yl)ethyl]-5-methoxy-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine;
N2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl]-5 -methoxy-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
N2 -[(1R)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -5 -methoxy-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
Λ/2-[l-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine -2,4- diamine;
Λ/2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
N2 -[(1R)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -5 -methyl-Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
S-fluoro-Λ^-f 1 -(5 -fluoropyrimidin-2-yl)ethyl] -N^-(I -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine; 5-fluoro-Λ/2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
5-fluoro-Λ/2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
5 -fluoro-Λ/2-[( 1 S)- 1 -(5 -fluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
5-fluoro-N2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
Λ/2-[l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
Λ/2-[(li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4-yl)-
6-morpholin-4-ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl] -5 -fluoro-Λ/4-( 1 -methyl- lH-imidazol-4-yl)-
6-morpholin-4-ylpyrimidine-2,4-diamine;
Λ/2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-2,4,6- triamine;
N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
N2-[(15)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4-yl)-6-morpholin-4- y lpyrimidine-2 ,4 -diamine;
Λ/2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
6-chloro-Λ/2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-y l)pyrimidine-
2,4-diamine;
6-chloro-JV2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-y l)pyrimidine-
2,4-diamine;
6-chloro-N2-[( Ii?)- 1 -(3 ,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine; 6-chloro-iV2-[ 1 -(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ/4-(l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-JV2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -5 -fluoio-iV4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5-fluoro-Λ/2-[(15)-l-(5-fluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5-fluoro-Λ/2-[(li?)-l-(5-fluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5 -fluoro-Λ/2-[( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5-fluoro-Λ/2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-JV2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -5 -fluoio-iV4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-Λ/2-[l-(3,5-difluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-2,4- diamine;
6-chloro-Λ/2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine; and
6-chloro-Λ/2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-
2,4-diamine, or a pharmaceutically acceptable salt thereof.
Utility
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, myelodysplasia 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.
Assay (Method 1)
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-specific antibodies coated Acceptor Beads using the En Vision Multilabel Plate Reader after an overnight incubation at room temperature. "T ween 20" is a registered trademark of ICI Americas, Inc.
JAK2 Hu Phos AScrn CRICsn ENZ 5PT JAK2 ASl JAK2 Mean ICsn (υM) Assay
Figure imgf000034_0001
Although the pharmacological properties of the compounds of the Formula (I) may vary with structural change, typical compounds of the Formula (I) are generally 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 in the assay (method 1) described above.
Assay Method 2
Activity of purified C-terminal His6-tagged human JAK2 kinase may be determined in- vitro using an Amplified Luminescent Proximity Homogeneous Assay (ALPHA) (Perkin Elmer, MA), which measures phosphorylation of a biotinylated Tyk (Tyrl 04/1055) substrate (Cell Signaling Technology, MA, Cat #2200B). Commercially available JAK2 (amino acids 808-end, Genbank Accession number NM 004972, Upstate Biotechnology, MA, Catalog 14-640) was expressed by baculovirus in Sf21 cells and affinity purified by Ni+2/NTA agarose.
The phosphorylation of Tyk substrate in the presence and absence of the compound of interest was determined. Briefly, 5μl of Enzyme/Substrate/adenosine triphosphate (ATP) mix consisting of 1.44nM JAK2, 192nM Tyk, and 12mM ATP in 1.2x buffer may be preincubated with 2μl of compound for 20 minutes at 25 0C. Reactions may be initiated with 5μl of Metal mix consisting of 24mM MgCl2 in 1.2x buffer and incubated at 25 0C for 90 minutes and reactions may be stopped by addition of 5μl of Detection mix consisting of 2OmM HEPES, 102mM ethylenediamine tetraacetic acid, 1.65mg/ml BSA, 136mM NaCl, 40μg/ml Streptavidin donor beads (Perkin Elmer, MA, Catalog #6760002), and 40μg/ml phosphotyrosine-specific antibody coated acceptor beads (Perkin Elmer, MA, Catalog #6760620). Plates may be incubated at 25 0C for 18 hours in the dark. Phosphorylated substrate may be detected by an En Vision plate reader (Perkin Elmer, MA) 680nm excitation, 520-620nm emission. Data may be graphed and IC50S calculated using Excel Fit (Microsoft).
Although the pharmacological properties of the compounds of the Formula (I) may vary with structural change, typical compounds of the Formula (I) are generally 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 in the assay (method 2) described above.
Assay Method 3
Janus kinase 2 (JAK2) activity may be determined by measuring the kinase's ability to phosphorylate a tyrosine residue within a peptide substrate using a mobility shift assay on a Caliper LC3000 reader (Caliper, Hopkinton, MA), which measures fluorescence of the phosphorylated and unphosphorylated substrate and calculates a ratiometric value to determine percent turnover.
To measure JAK2 kinase activity, an in-house purified enzyme may be used. The enzyme may be N-terminal GST-tagged, recombinant, human JAK2 (amino acids 831-1132, PLAZA database pAZB0359) expressed in insect cells. After incubation of the kinase with a FAM labeled SRCtide substrate, adenosine triphosphate (ATP), and MgCl2 for 90 minutes at room temperature, the kinase reaction may be stopped by the addition of 36 mM ethylenediaminetetraacetic acid (EDTA). The reaction may be performed in 384 well microtitre plates and the reaction products may be detected using the Caliper LC3000 Reader.
Figure imgf000036_0001
Although the pharmacological properties of the compounds of the Formula (I) may vary with structural change, typical compounds of the Formula (I) are generally 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 in the assay (method 3) described above.
When tested in assays based on the in- vitro assays (methods 1-3) described above, the JAK inhibitory activity of the following examples were measured at the indicated IC50S (μM) shown in Table 1. A hyphen indicates that an IC50 measurement is not provided for that particular compound, and is not meant to imply that the particular compound does not possess IC50 activity.
Table 1
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
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), 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, 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), 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 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-pro liferative 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, polyvinyl-pyrrolidone, 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.
Combinations
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 drugs 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, epirubicin, 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]) , farnesyl 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
Λ/-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), 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 (PBK) 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 trans fection 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 drugs 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 1311-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, 5th 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, D, E, X, R1*, R2, and R5, unless otherwise defined, are as defined hereinabove). Where a particular solvent or reagent is shown in a Process 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 Process is 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 Process.
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 herein, to obtain necessary starting materials and products.
In one aspect, compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be prepared by a process selected from:
1) Process A - reacting a compound of Formula (A):
Figure imgf000051_0001
Formula (A) with a compound of Formula (D):
Figure imgf000051_0002
Formula (B); and
2) Process B - reacting a compound of Formula (C)
Figure imgf000051_0003
Formula (C) with a compound of Formula (D)
Figure imgf000051_0004
Formula (D) 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 is a leaving group as described hereinabove.
It is to be understood that protecting groups may be used as necessary. Leaving groups suitable for use in Process A and Process B include halo groups such as chloro.
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 O0C 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 t-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.
Process B: Compounds of Formula (C) and compounds of Formula (D) may be reacted together under the conditions described for the reaction of the compound of Formula (A) with the compound of Formula (B) in Process A.
In one aspect, compounds of Formula (E) (which are compounds of Formula (B) having the indicated stereochemistry, and in which X is -NH-, and R4 is an alkyl group such as methyl) may be prepared via chiral synthesis according to Scheme 1. Scheme 1
Figure imgf000053_0001
Formula (F) Formula (G) transaminase Formula (E)
Reaction of a compound of Formula (F) with an organometallic reagent R4 -M (wherein R4 is an alkyl group such as methyl, and M is a metal species such as -MgCl, -MgBr or -Li), followed by quenching, may be used to obtain a compound of Formula (G). Reaction of a compound of Formula (G) with amine donor R7 -NH2 (in which R7 is a group such as isopropyl or methylbenzyl) in the presence of an omega transaminase may be used to obtain a compound of Formula (E). Suitable amine donors may include alanine in the presence of pyruvatedecarboxylase, benzylamine, S-methylbenzylamine and isopropylamine. Suitable omega transaminases include those from Vibrio fluvalis, thermostable transaminase CNB05-01, Biocatalytics 101,102, 103, 110, 111, 114,115. The biocatalysts maybe free enzymes or suitable whole cell preparations. Before reaction with the compound of Formula (K), the omega transaminase and R7-NH2 may advantageously be mixed in solution with an aqueous buffer such as aqueous potassium phosphate or aqueous HEPES buffer, followed by addition of pyridoxyl phosphate. In the case of an immiscible organic solvent (such as toluene, BuOAc or diisooctylphthalate) may or may not be advantageously added. The stereoselectivity of the amine can be switched from S to R by using an R selective transaminase such as Biocatalytics 117.
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) "Gilson chromatography," unless otherwise indicated, refers to chromatography uisng a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H2OZMeCN 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, PA19380, 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 have been used:
BINAP 2,2 ' -bis(diphenylphosphino)- 1,1 ' -binapthyl
BoC2O ter/-butyloxycarbonyl anhydride
DCM dichloromethane
DIPEA N, jV-diisopropylethylamine
DMAc JV,iV-dimethylacetamide
DMF Λ/,Λ/-dimethylformamide dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
DMAP 4-dimethylaminopyridine
DMSO dimethylsulfoxide
EtOAc ethyl acetate
Et2O diethyl ether
GC gas chromatography
HPLC high-performance liquid chromatography hr hours
LDA Lithium diisopropylamide
LCMS liquid chromatography mass spectroscopy mins minutes
NMP JV-methylpyrrolidone o/n overnight
Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
/PrOH /-propanol rac. racemic
TBME tert-butylmethyl ether TEA triethylamine
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethyl silyl
Tosyl, Ts para-toluenesulfonyl
Intermediate 1
1 -(5 -Fluoropyridin-2-yl)ethanone
2-Bromo-5-fluoropyridine (13.0 g, 73.9 mmol), copper(I) iodide (2.10 g, 11.1 mmol) and dichlorobis (triphenylphosphine) palladium(II) in anhydrous acetonitrile (100 ml) was added tributyl(l-ethoxyvinyl)stannane (27.5 ml, 81.3 mmol). The reaction mixture was heated at reflux. After heating for 70 hours, 1.5 M aqueous HCl (20 ml) was added to quench the reaction and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ether (3x100 ml). The combined organic layers were dried over dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane: ether = 5:1) to give the title compound as a clear oil [11.3 g (75% pure), 82%]. 1H NMR (400 MHz, CDCl3) 8.51 (d, J= 3.2 Hz, IH), 8.11 (dd, J= 4.4 and 4.4 Hz, IH), 7.51 (ddd, J= 2.8, 3.2 and 2.8 Hz, IH), 2.71 (s, 3H).
Intermediate 2
1 -(5 -Fluoropyridin-2-yl)ethanol l-(5-Fluoropyridin-2-yl)ethanone (Intermediate 1, 11.3 g, (75% pure), 60.9 mmol) in MeOH was added sodium boronhydride (2.30 g, 60.9 mmol) potion wise at 0 0C. After adding, the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. Water (10 ml) was added and the solution was extracted with ether (2x50 ml). The combined organic layers were dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (ether) to give the title compound as a clear oil (7.5 g, 87%). 1H NMR (400 MHz) 8.46 (d, J= 3.2 Hz, IH), 7.69 (ddd, J= 3.2, 3.2 and 3.2 Hz, IH), 7.55 (m, IH), 5.44 (d, J= 4.4 Hz, IH), 4.73 (m, IH), 1.34 (d, J= 6.4 Hz, 3H).
Intermediate 3
2-( 1 - Azidoethyl)-5 -fluoropyridine l-(5-Fluoropyridin-2-yl)ethanol (Intermediate 2, 7.5 g, 53.1 mmol) and triethyl amine (9.3 ml, 66.4 mmol) in anhydrous DCM (50 ml) was added methanesulfonyl chloride (4.5 ml, 58.5 mmol) at 0 0C. After adding, the reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The solvent was removed. The residue was dissolved in anhydrous DMF (50 ml) and sodium azide (6.9 g, 106 mmol) was added. The reaction stirred at room temperature for 2 hours. Water (50 ml) was added and extracted with ether (2x75 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-ether=4:l)) to give the title compound as a clear oil (7.7 g,
1U NMR (400 MHz) 8.60 (d, J= 2.8 Hz, IH), 7.79 (ddd, J= 2.8, 2.8 and 2.8 Hz, IH), 7.54 (m, IH), 4.79 (q, J= 6.8 Hz, IH), 1.52 (d, J= 6.8 Hz, 3H).
Intermediate 4
1 -(5 -Fluoropyridin-2-yl)ethanamine
2-(l-Azidoethyl)-5 -fluoropyridine (Intermediate 3, 7.7 g, 46.3 mmol) and Pd (10 wt. %, dry basis, on activated carbon, 2.47 g, 2.32 mmol) in methanol (20 ml) was placed under H2 for 4 hours. The reaction mixture was then evacuated, flushed with N2, filtered, washed with MeOH (3 x 30 ml), and concentrated to give the title compound as pale yellow oil (6.40 g, 99%).
1H NMR (400 MHz) 8.45 (d, J= 2.8 Hz, IH), 7.67 (ddd, J= 2.8, 2.8 and 2.8 Hz, IH), 7.54 (m,
IH), 4.01 (q, J= 6.8 Hz, IH), 1.97 (b, 2H), 1.27 (d, J= 6.8 Hz, 3H).
The hydrochloride salt of l-(5-Fluoropyridin-2-yl)ethanamine was prepared as shown below for Intermediate 4(a).
Intermediate 4(a)
1 -(5-Fluoropyridin-2-yl)ethanamine hydrochloride
5-Fluoro-2-formylpyridine (5g, 40mmol) and racemic t-butyl sulfanamide (9.7g, 80mmol) were dissolved in DCM (10OmL) and CuSθ4 (12.8g, 80mmol) was added. The reaction mixture was stirred overnight at rt under nitrogen atmosphere. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite® and washed with DCM. The filtrate was evaporated in vacuo to obtain a light yellow oil, which was purified by column chromatography (Hexane/EtOAc = 80:20) to provide N-[(IE α/?<i/orZ)-(5-fluoropyridin-2-yl)methylene]-2- methylpropane-2-sulfmamide (7.2g, 82%) as a white solid. LCMS: 229 [M+H]+.
To a solution of N-[(IE α/?<i/orZ)-(5-fluoropyridin-2-yl)methylene]-2-methylpropane-2- sulfmamide in CH2Cl2 at -450C was added methylmagnesium bromide. The reaction mixture was stirred at -4O0C for 30 minutes and to the mixture was added water. The layers were separated and the organic layer was concentrated. Column chromatography on silica gel (EtOAc/Hexanes) gave N-[I -(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide.
To a solution of N-[l-(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide in MeOH was added hydrochloric acid (4 M in dioxane) at O0C and the mixture was stirred for 15 minutes and was subsequently concentrated. The mixture was triturated from hexanes, providing the title product.
Refer to Intermediate 23 for a synthesis of the i?-enantiomer of l-(5-fluoropyridin-2- yl)ethanamine in the form of a dihydrochloride salt.
Intermediate 5
1 -Methyl-4-nitro- lH-imidazole
4-Nitro-lH-imidazole (2 g, 17.69 mmol) was dissolved in acetonitrile (20 mL) and potassium carbonate (3.67 g, 26.53 mmol) and iodomethane (1.327 mL, 21.22 mmol) were added. The reaction mixture was then heated at 650C overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo leaving a reddish orange solid (3.214 g). This material was purified utilizing ISCO (0-10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a yellow solid (2.071 g). The title compound was re-crystalized out of isopropanol leaving an off-white solid (1.564 g). LCMS: 128 [M+H]+.
Intermediate 6
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 dimethylacetamide. 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 (Utilizing ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a creamy solid (1.50 g, 80%). 1H NMR (CDCl3) δ: 8.80 (s, 2H). GC-MS: 123 [M].
Intermediate 7
N-\l -(5-Fluoropyrimidin-2-yl)vinyl"|acetamide
5-Fluoropyrimidine-2-carbonitrile (Intermediate 6, 1.0 g, 8.1 mmol) in THF (10 ml) was added to a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether drop wise at 0 0C. After addition, the reaction mixture was warmed to room temperature, stirred at room temperature for 1 hour and then diluted with DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 1 hour and 40 0C for 1 hour. Saturated sodium bicarbonate solution (10 ml) was added and extracted with EtOAc (2x20 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (2.5:1 v/v hexane : EtOAc) to give the title compound as a white solid (0.38 g, 26%).
1H NMR (400 MHz) δ: 9.34 (s, IH), 8.95 (s, 2H), 6.25 (s, IH), 6.03 (s, IH), 2.11 (s, 3H). LCMS: 182 [M+H]+.
Intermediate 8
N- \( 1 S)- 1 -(5 -Fluoropyrimidin-2-yl)ethyll acetamide Λ/-[l-(5-Fluoropyrimidin-2-yl)vinyl]acetamide (Intermediate 7, 0.10 g, 0.55 mmol) in MeOH (5 ml) under N2 was added (+)-l,2-bis((2S, 55)-2,5-diethylphospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (0.096 g, 95%). 1H NMR (400 MHz) δ: 8.84 (d, 2H), 8.34 (d, IH), 5.00 (m, IH), 1.84 (s, 3H), 1.37 (d, 3H). LCMS: 184 [M+H]+. Enantiomeric excess determined by HPLC (Chiralpak IA; 95:5 CO2/MeOH), >99% ee.
Intermediate 9 tert-Butyl IY 1 S)- 1 -(5 -fluoropyrimidin-2-vDethvHcarbamate
N-[(15)-l-(5-Fluoropyrimidin-2-yl)ethyl]acetamide (Intermediate 8, 0.20 g, 1.09 mmol), DMAP (0.027 g, 0.22 mmol) and BoC2O (0.60 g, 2.73 mmol) in THF (10 ml) was stirred at 50 0C for 40 hours. After cooling to room temperature, lithium hydroxide monohydrate (0.094 g, 2.24 mmol) and water (10 ml) was added. The reaction mixture was stirred at room temperature for 9 hours. Ether (30 ml) was added, organic layer was separated, washed with brine (20 ml) and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (Hex-EtOAc=5:l) to give the title compound as a pale yellow oil (0.21 g, 80%). 1H NMR (400 MHz) δ: 8.84 (s, 2H), 7.24 (d, IH), 4.74 (m, IH), 1.35 (s, 12H). LCMS: 242 [M+H]+.
Intermediate 10
( 1 S)- 1 -(5 -Fluoropyrimidin-2-yl)ethanamine hydrochloride
To a solution of tert-butyi [(15)-l-(5-fluoropyrimidin-2-yl)ethyl]carbamate
(Intermediate 9, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed to give the title product as white solid (quantitative).
LCMS: 142 [M+H]+.
Intermediate 11 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone
3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -720C (external -8O0C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 30C during addition. The reaction mixture turned into a deep brownish, thick phase and was stirred for 30 minutes at this temperature. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2h. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -780C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification utilizing ISCO (0-25% EtOAc/hexanes), gave the title compound (3 g). LCMS: 188 [M+H]+.
Intermediate 12 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone oxime l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone (Intermediate 11) dissolved in ethanol (255 ml, 10 vol). Hydroxylamine hydrochloride (14.22 g, 204.61 mmol) was added, followed by drop-wise by triethylamine (28.5 ml, 204.61 mmol). The resulting colored mixture was heated to 50° C for 2 hours. The volatiles were evaporated under reduced pressure and the residue left was partitioned between water (255 ml) and ethyl acetate (255 ml). The separated aqueous layer was further extracted into 2 x ethyl acetate (255 ml). The combined organic extracts washed with water (255 ml), saturated brine (255 ml), dried over MgSO4, filtered and concentrated in vacuo to give 42g of a brown oil. Purification by column chromatography (25- 40% EtOAc in isohexanes) gave 32g of the title compound as yellow oily solid (~3:1 mixture of isomers).
Trituration in MTBE gave the title compound (12.3 g, 60.84 mmol, 44.6 %, single isomer) as a white solid. The liquor was evaporated under reduced pressure and the residue was re-columned using the conditions described previously, followed by trituration with EtOAc/isohexanes, giving additional title compound (7.2 g, 35.62 mmol, 26.1 %). LCMS: 203 [M+H]+. Intermediate 13
(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanamine, ^-Mandelic Acid Salt l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone oxime (Intermediate 12) was dissolved in EtOAc (0.4M) and was subsequently subjected to catalytic hydrogenation (Pd on C) in a Parr Hydrogenator (Pressure 5 bar at 4O0C) for 1 hour. The catalyst was filtered via Celite and the filtrate of l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (0.4 M in ethyl acetate) (180 mL, 72.00 mmol) was treated with (7^-Mandelic acid (5.81 g, 38.16 mmol). Precipitation was observed almost instantaneously and the resulting mixture was allowed to stir o/n. The title product was collected via filtration (8.5 g, 69.4 %).
1H NMR (400 MHz) δ ppm 8.6 (s, IH) 8.01 (m, IH) 7.41 (t, 2H) 7.36 (t, 2H) 7.19 (m, IH) 4.81 (s, IH) 4.50 (m, IH) 3.57 (d, 2H) 3.23 (s, 3H). LCMS: 188 [M-H]+.
Intermediate 14
(161-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanamine, dSVMandelic Acid Salt
The title product was prepared using a procedure similar to the one described for Intermediate
13, except that (S^-Mandelic acid was used instead of fSj-Mandelic acid.
Intermediate 15 l-(3,5-Difluoropyridin-2-yl)ethanone
A solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N2 and cooled to -780C. 3,5-difiuoropicolinonitrile (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temperature was kept below -40C. After the addition was complete, the reaction mixture was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction mixture was stirred at O0C for 30 minutes and at room temperature for 30 minutes. To this solution 150 ml of EtOAc was added to extract product. The aqueous phase was neutralized to pH9 with NaHCO3 and extracted with EtOAc (2 X 20 ml). The organic layers were combined and the volatiles were removed under reduced pressure. Purification utilizing ISCO (0-10% EtOAc- hexanes) gave the title compound as light yellow oil. LC-MS: 158 [M+H]+. Intermediate 16 l-(3,5-Difluoropyridin-2-yl)ethanone oxime
To a solution of l-(3,5-difluoropyridin-2-yl)ethanone (Intermediate 15, 12.91 g, 82.17 mmol) in ethanol (164 ml) was added hydroxylamine hydrochloride (8.56 g, 123.25 mmol) followed by
Et3N (17.18 ml, 123.25 mmol) and the resulting mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAcZH2O. The organic extracts washed with brine and dried. Orange yellow solid was obtained and purification utilizing ISCO (10%EtOAc/hexanes->25%
EtOAc/hexanes) gave the title compound (9.73 g, 68.8 %) as yellow solid.
1H NMR (300 MHz, DMSO-J6) δ ppm 2.19 (s, 3 H) 7.98 (ddd, J=10.97, 8.81, 2.26 Hz, 1 H) 8.55
(d, J=2.26 Hz, 1 H) 11.70 (s, 1 H).
LC-MS: 173 [M+H]+.
Intermediate 17 l-(3,5-Difluoropyridin-2-yl)ethanamine l-(3,5-Difluoropyridin-2-yl)ethanone oxime (Intermediate 16, 9.73 g, 56.53 mmol) was added to water (113 ml) to form a suspension. Ammonium hydroxide (22.01 ml, 565.26 mmol) was added to the above solution, followed by ammonium acetate (5.23 g, 67.83 mmol). The mixture was heated at 5O0C and subsequently zinc (14.79 g, 226.11 mmol) was added portion wise while maintain the internal temperature below 650C.
After the addition was complete, the reaction mixture was stirred at 5O0C for 3 hours. Solid NaCl and EtOAc was added to quench the reaction, stirred for 1 hour at room temperature, and was then filtered through Celite® and rinsed with EtOAc. The organic layer was washed with 5 ml
2.5% NaOH (aq.) then 10 ml NH4OH. The organic layer was then washed with brine and dried with Na2SO4. The organic layer was concentrated under reduced pressure to obtain the title compound as light yellow oil.
1H NMR (400 MHz, MeOD) δ ppm 1.62 (d, J=6.82 Hz, 3 H) 4.86 (q, J=6.82 Hz, 1 H) 7.75 (ddd,
J=10.11, 8.34, 2.27 Hz, 1 H) 8.49 (d, J=2.27 Hz, 1 H).
Intermediate 17(a) l-(3,5-Difluoropyridin-2-yl)ethanamine hydrochloride l-(3,5-Difluoropyridin-2-yl)ethanamine hydrochloride may be obtained by stirring l-(3,5- difluoropyridin-2-yl)ethanamine (Intermediate 17) for 1 hour in MeOH in the presence of HCl (4N in dioxane) and subsequently evaporating the volatiles under reduced pressure.
Intermediate 18
(iy)-l-(3,5-Difluoropyridin-2-yl)ethanamine, ^-Mandelic Acid Salt l-(3,5-Difluoropyridin-2-yl)ethanamine (Intermediate 17, 0.83 g, 5.25 mmol) and (R)-2- hydroxy-2-phenylacetic acid (R-mandelic acid, 0.399 g, 2.62 mmol) in ethyl acetate (10 mL) was heated to 50 0C. Solid formed after heating for a few minutes. Continued to stir the reaction mixture for 1 hour at 50 0C. After 1 hour, the reaction mixture was cooled to ambient temperature. The solid was collected via gravity filtration (no vacuum) washing with ethyl acetate until orange color disappeared. The solid (265 mg) was identified as the title compound (e.e >98%).
Conditions for e.e. determination
Column: Daicel Crownpak CR+ 0.4 x 15 cm
Mobile Phase: 98:2:0.1 (v/v/v) H2O:MeOH:Trifluoroacetic Acid
Flow Rate: 1 mL/min
Detection: 254 nm
Intermediate 19
5 -Fluoropyridine-2-carbonitrile
A mixture of 2-bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), dppf (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) were heated at 95 0C for 3 hours. After cooling to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1 : 1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ: 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH).
Intermediate 20
N- r 1 -(5 -fluoropyridin-2-vDvinvH acetamide
A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous
THF and cooled to 0 0C. 5-Fluoropyridine-2-carbonitrile (Intermediate 19, 53.6 g, 425.82 mmol) in THF (170 ml) was added drop-wise. The reaction mixture was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM
(100 ml) was added drop-wise at 0 0C. After the addition, the reaction mixture was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g,
35%).
1H NMR (400 MHz) δ: 9.37 (s, IH), 8.57 (d, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08
(s, 3H).
LC-MS: 181 [M+H]+.
Intermediate 21
N- \( 1 S)- 1 -(5 -Fluoropyridin-2-yl)ethy 1] acetamide
To a solution of N-[l-(5-fluoropyridin-2-yl)vinyl]acetamide (Intermediate 20, 11.0 g, 61.1 mmol) in MeOH (120 ml) under N2 was added (+)-l,2-bis((25,5<S)-2,5- diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g,
0.611 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction mixture was stirred at room temperature and maintained at a pressure between 120-150 psi for 7 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (9.8 g, 88%).
1H NMR (400 MHz) δ: 8.49 (d, J= 2.4 Hz, IH), 8.32 (d, J= 7.6 Hz, IH), 7.66 (m, IH), 7.39 (dd,
J= 4.4 and 8.8 Hz, IH), 4.95 (m, IH), 1.85 (s, 3H), 1.34 (d, J= 7.2 Hz, 3H).
LC-MS: 183 [M+H]+.
Enantiomeric excess determined by SFC (Chiralpak IA; 70:30 CO2/MeOH), 95.3% ee. Intermediate 22 tert-Butyi |Y 1 S)- 1 -(5 -fluoropyridin-2-yπethyllcarbamate
A solution of Λ/-[(15)-l-(5-fluoropyridin-2-yl)ethyl]acetamide (Intermediate 21, 11.0 g, 60.37 mmol), DMAP (1.48 g, 12.07 mmol) and di-tert-butyl-dicarbonate (26.35 g, 120.7 mmol) in THF (100 ml) was stirred at 50 0C for 20 hours. After cooling to room temperature, lithium hydroxide monohydrate (5.19 g, 123.8 mmol) and water (100 ml) were added. The reaction mixture was stirred at room temperature for 5 hours and diluted with ether (200 ml). The organic layer was separated, washed with brine (100 ml), and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 5:1) to give the title compound as a pale yellow oil (13.6 g, 94%).
1H NMR (400 MHz) δ: 8.46 (d, IH), 7.69 (m, IH), 7.35-7.41 (m, 2H), 4.67 (m, IH), 1.37 (s, 9H), 1.32 (d, 3H). LC-MS: 241 [M+H]+.
Intermediate 23
( 1 S)- 1 -(5 -Fluoropyridin-2-yl)ethanamine dihydrochloride
To a solution of tert-butyl [(I S)- 1 -(5 -fluoropyridin-2-yl)ethyl] carbamate (Intermediate 22, 12.8 g, 53.3 mmol) in DCM (100 ml) was added HCl/dioxane solution (107 ml, 4 N, 428 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed and 50 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (6 x 400 ml), dried over sodium sulfate and concentrated to give the title compound (7.30 g,
98%) as pale yellow oil.
1H NMR (400 MHz) δ: 8.44 (d, IH), 7.66 (m, IH), 7.53 (m, IH), 4.01 (q, IH), 1.94 (b, 2H), 1.26
(d, 3H).
LC-MS: 141 [M+H]+.
The hydrochloride salt may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvents provides the hydrochloride salt of the title compound as a tan solid. While it is believed that the product thus obtained exists in the form of a dihydrochloride salt, it is possible that it exists in the form of the monohydrochloride salt.
Intermediate 24
2, 5-Dichloro-Λ/-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (7.868 mL) and Pd/C (10 wt%, Degussa®, 105 mg, 0.10 mmol) was added. The reaction mixture was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite® and 2,4,5-trichloropyrimidine (0.361 mL, 3.15 mmol) and TEA (1.097 mL, 7.87 mmol) were added. The reaction mixture was stirred overnight at rt. The reaction mixture was filtered providing the title compound as a pale yellow solid (538 mg). LCMS: 245 [M+Η]+.
Intermediate 25
2,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)aminolnicotinonitrile l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (7.868 mL) and Pd/C (10 wt%, Degussa®, 105 mg, 0.10 mmol) was added. The reaction mixture was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and the filtrate was cooled to O0C. 2,5,6-trifluoronicotinonitrile (497 mg, 3.15 mmol) and TEA (1.097 mL, 7.87 mmol) were added and the reaction mixture was allowed to warm to rt slowly overnight. The reaction mixture was filtered providing the title compound as a yellow solid (566 mg). LCMS: 236 [M+Η]+.
Intermediate 26
2, 6-Dichloro-Λ/-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lΗ-imidazole (Intermediate 5, 1.0 g, 7.87 mmol) was dissolved in ethanol (12.82 ml) and Pd/C (10 wt%, Degussa®, 0.209 g, 0.20 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. TLC analysis indicated that the reaction was completed and the reaction mixture was filtered through Celite® and cooled to 00C. TEA (2.193 ml, 15.74 mmol) and 2,4,6-trichloropyrimidine (0.722 ml, 6.29 mmol) were added and the reaction was allowed to slowly warm to rt overnight. LCMS confirmed formation of the desired product. The reaction mixture was then filtered leaving a tan solid (1.526 g) which was confirmed by LCMS to be the title compound with 99% purity. The material was used in a subsequent step without any further purification. LCMS: 245 [M+H]+.
Intermediate 27
2,6-Dichloro-5-fluoro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (6.771 mL) and Pd/C (10 wt%, Degussa®, 105 mg, 0.10 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. TLC indicated that the reaction was completed, and the reaction mixture was filtered through Celite®. The filtrate was cooled to 00C and TEA (1.097 mL, 7.87 mmol) and 2,4,6-trichloro-5-fluoropyrimidine (obtained via the procedure described in PCT Pub. No. WO2008/132502, 792 mg, 3.93 mmol) were added. The reaction was allowed to warm to room temperature slowly overnight. The reaction mixture was filtered providing the title compound as a yellow solid (820 mg) with 95% purity. LCMS: 263 [M+Η]+.
Intermediate 28
2-Chloro-5-methoxy-N-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 400 mg, 3.15 mmol) was dissolved in ethanol (4.063 mL) and Pd/C (10 wt%, Degussa®, 84 mg, 0.08 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite® and TEA (0.877 mL, 6.29 mmol) and 2,4-dichloro-5-methoxypyrimidine (563 mg, 3.15 mmol) were added. The reaction was subsequently heated to reflux overnight. The volatiles were concentrated in vacuo leaving a rust solid (1.140 g). This material was purified utilizing ISCO (0-10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a yellow solid (603 mg). LCMS: 240 [M+Η]+.
Intermediate 29
2-Chloro-5-methyl-N-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 400 mg, 3.15 mmol) was dissolved in ethanol (4.063 mL) and Pd/C (10 wt%, Degussa®, 84 mg, 0.08 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite® and TEA (0.877 mL, 6.29 mmol) and 2,4-dichloro-5-methylpyrimidine (0.369 mL, 3.15 mmol) were added. The reaction was heated to reflux overnight. The reaction was subsequently heated to reflux overnight. The volatiles were concentrated in vacuo leaving a rust solid (1.207 g). This material was purified utilizing ISCO (0-10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a yellow solid (542 mg). LCMS: 224 [M+Η]+.
Intermediate 30
2-Chloro-5-fluoro-Λ/-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 400 mg, 3.15 mmol) was dissolved in ethanol (4.063 mL) and Pd/C (10 wt%, Degussa®, 84 mg, 0.08 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite® and TEA (0.877 mL, 6.29 mmol) and 2,4-dichloro-5-fluoropyrimidine (525 mg, 3.15 mmol) were added. The reaction was stirred at rt overnight. The reaction mixture was filtered providing the title compound as a white solid (495 mg). LCMS: 228 [M+Η]+.
Intermediate 31
A/VDiphenylmethyleneVA/2- IY 1 S)- 1 -(5 -fluoropyrimidin-2-vOethvH -N6 -(I -methyl- lH-imidazol-4- yl)pyrimidine-2,4,6-triamine
A solution of 6-chloro-Λ/2-[(15)- 1 -(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine (Example 21, 1.5 g, 4.30 mmol), Pd2dba3 (0.276 g, 0.30 mmol), BINAP (0.402 g, 0.65 mmol), and CS2CO3 (6.31 g, 19.35 mmol) was heated to 110 0C in DMA (20.07 ml) overnight. The reaction mixture was diluted with DCM and washed with brine. Concentration of organic layer under reduced pressure provided a residue, which was purified utilizing ISCO (EtOAc then 5 to 15% MeOΗ/DCM) to yield the title compound. LCMS: 493 [M+Η]+. Example 1
5 -Fluoro-2- { [ 1 -(5 -fluoropyrimidin-2-yl)ethvH amino I -6- IY 1 -methyl- lH-imidazol-4- yl)amino"|nicotinonitrile, Trifluoroacetic Acid Salt
Figure imgf000070_0001
2,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)amino]nicotinonitrile (Intermediate 25, 100 mg, 0.43 mmol), (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 10, 94 mg, 0.53 mmol), and DIPEA (0.297 mL, 1.70 mmol) were stirred in butan-1-ol (2 mL) and the reaction mixture was microwaved at 1600C for 21600s. The reaction mixture was concentrated in vacuo leaving an orange solid (265 mg). This material was purified utilizing ISCO (0-12% MeOΗ/DCM). Concentration of the fractions in vacuo gave a yellow solid (158 mg). This material was purified utilizing Gilson chromatography [15-40% MeCNZH2O (0.1% TFA), 35 min, XTerra Prep, 100 mg/mL, 1.5 mL inj, 254 nm]. Concentration of the fractions in vacuo provided the title product as a mixture of enantiomers, in the form of a pale yellow solid (120.7 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.72 (s, 2 H) 7.26 - 7.51 (m, 3 H) 5.41 (q, 1 H) 3.80 (s, 3 H) 1.63 (d, 3 H). LCMS: 357 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC (AD-H column).
Column dimensions: 21 x 250 mm, 5 μ
Mobile phase: 15% MeOH/0.4% dimethylethylamine
Flow rate (ml/min): 60 mL/min Pressure: 100 bar
Oven Temperature: 4O0C Detection (nm): 254 nm
Post purification purity check
Sample purity was checked with an AD-H column.
Column dimensions: 4.6 x 250 mm, 10 μ
Mobile phase : 15 % MeOH/dimethylethylamine
Flow: 2.5 mL/min
Pressure: 120 bar
Oven Temperature: 350C
Detection: 254 nm
Example l(a), First Eluting Compound
5 -Fluoro-2- { [ 1 -(5 -fluoropyrimidin-2-vOethyli amino I -6- IY 1 -methyl- lH-imidazol-4- yl)amino"|nicotinonitrile, Enantiomer (A)
The first eluting compound had a retention time of 4.49 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.72 (s, 2 H) 7.26 - 7.51 (m, 3 H) 5.41 (q, 1 H) 3.80 (s, 3 H)
1.63 (d, 3 H).
LCMS: 357 [M+H]+.
Example Kb), Second Eluting Compound
5 -Fluoro-2- { [ 1 -(5 -fluoropyrimidin-2-yl)ethyll amino I -6- [( 1 -methyl- lH-imidazol-4- yl)amino"|nicotinonitrile, Enantiomer (B)
The second eluting compound had a retention time of 7.16 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.72 (s, 2 H) 7.26 - 7.51 (m, 3 H) 5.41 (q, 1 H) 3.80 (s, 3 H)
1.63 (d, 3 H).
LCMS: 357 [M+H]+.
Example 2
S-Chloro-Λ^-f 1 -(5-fiuoropyrimidin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine
Figure imgf000072_0001
In a microwave vessel, 2,5-dichloro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 24, 100 mg, 0.41 mmol) and (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 10, 91 mg, 0.51 mmol) suspended in butan-1-ol (1 mL) was added DIPEA (0.286 mL, 1.64 mmol). The reaction mixture was subjected to microwave irradiation at 1600C for 21600s. The reaction mixture was concentrated in vacuo leaving a brown oil (338 mg). This material was purified utilizing ISCO (2-10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a mixture of enantiomers, in the form of a yellow solid (100.6 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 7.83 (s, 1 H) 7.40 (s, 2 H) 5.25 (q, 1 H) 3.78 (s, 3 H) 1.58 (d, 3 H). LCMS: 349 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC (AD-H column).
Column dimensions: 21 x 250 mm, 5μ
Mobile phase: 15% MeOH/0.4% dimethylethylamine
Flow rate (ml/min): 60 mL/min
Pressure: 100 bar
Oven Temperature: 4O0C
Detection (nm): 254 nm Post purification purity check
Sample purity was checked with a AD-H column.
Column dimensions: 4.6 x 250 mm
Mobile phase : 15 % MeOH/dimethylethylamine
Flow: 2.5 mL/min
Pressure: 120 bar
Oven Temperature: 350C
Detection: 254 nm
Example 2(a), First Eluting Compound
S-Chloro-A^-T 1 -(5-fluoropyrimidin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (A)
The first eluting compound had a retention time of 8.83 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 7.83 (s, 1 H) 7.40 (s, 2 H) 5.25 (q, 1 H) 3.78 (s,
3 H) 1.58 (d, 3 H).
LCMS: 349 [M+H]+.
Example 2(b), Second Eluting Compound
S-Chloro-Λ^-f 1 -(5-fluoropyrimidin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (B)
The second eluting compound had a retention time of 11.12 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 7.83 (s, 1 H) 7.40 (s, 2 H) 5.25 (q, 1 H) 3.78 (s,
3 H) 1.58 (d, 3 H).
LCMS: 349 [M+H]+.
Example 3
5 -Fluoro-2- { [ 1 -(5 -fluoropyridin-2-yl)ethyllamino I -6- [( 1 -methyl- lH-imidazol-4- vDaminolnicotinonitrile, Trifluoroacetic Acid Salt
Figure imgf000074_0001
2,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)amino]nicotinonitrile (Intermediate 25, 100 mg, 0.43 mmol) and l-(5-fluoropyridin-2-yl)ethanamine (Intermediate 4, 94 mg, 0.53 mmol) and DIPEA (0.297 mL, 1.70 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 2, providing the title product a mixture of enantiomers, in the form of a pale yellow solid (91.9 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.56 (s, 1 H) 8.43 (d, 1 H) 7.45 - 7.69 (m, 3 H) 7.25 (d, 1 H) 5.21 (q, 1 H) 3.94 (s, 3 H) 1.60 (d, 3 H). LCMS: 356 [M+H]+.
5 -Fluoro-2- { [ 1 -(5 -fluoropyridin-2-yl)ethyl]amino } -6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile, trifluoroacetic acid salt (Example 3) may also be prepared using l-(5- fluoropyridin-2-yl)ethanamine hydrochloride (Intermediate 4(a)) as the starting material.
The S enantiomer of Example 3 may be prepared according to the procedure described below for Example 3(a).
Example 3(a)
5 -Fluoro-2- {[(161- 1 -(5-fluoropyridin-2-yl)ethyl]amino| -6- [(I -methyl- lH-imidazol-4- vDaminolnicotinonitrile, Trifluoroacetic Acid Salt
Figure imgf000075_0001
2,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)amino]nicotinonitrile (Intermediate 25, 100 mg,
0.43 mmol) and (lS)-l-(5-Fluoropyridin-2-yl)ethanamine dihydrochloride (Intermediate 23, 113 mg, 0.53 mmol) were reacted using a procedure similar to the one described for the synthesis of
Example 2, providing the title compound as a pale yellow solid (132.9 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.64 (s, 1 H) 8.42 (d, 1 H) 7.50 - 7.66 (m, 3 H) 7.27 (d, 1 H)
5.21 (q,l H) 3.95 (s, 3 H) 1.60 (d, 3 H).
LCMS: 356 [M+H]+.
Purity (e.e. determination) check
Sample purity was checked with Chiral SFC (OJ-H column).
Column dimensions: 4.6 x 250 mm
Mobile phase: 15% MeOH
Flow: 2.5 mL/min
Pressure: 120 bar
Oven Temperature: 350C
Detection: 220 nm
The compound had a retention time of 2.57 minutes, >98% ee.
Example 4
5-Chloro-N2-[ 1 -(5-fluoropyridin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine
Figure imgf000076_0001
2, 5-Dichloro-iV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 24, 100 mg, 0.41 mmol) and l-(5-fluoropyridin-2-yl)ethanamine (Intermediate 4, 90 mg, 0.51 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 2, providing the title compound as a yellow solid (65.2 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.44 (d, 1 H) 7.85 (s, 1 H) 7.42 - 7.66 (m, 2 H) 7.37 (s, 1 H) 5.09 (q, 1 H) 3.73 (s, 3 H) 1.55 (d, 3 H). LCMS: 348 [M+H]+.
5-Chloro-Λ/2-(l-(5-fluoropyridin-2-yl)ethyl)-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-2,4- diamine may also be prepared using l-(5-fluoropyridin-2-yl)ethanamine hydrochloride (Intermediate 4(a)) as the starting material.
Example 4 (Alternative Preparation)
5-Chloro-N2-[ 1 -(5-fluoropyridin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine
Figure imgf000076_0002
2, 5-Dichloro-iV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 24, 100 mg, 0.41 mmol) and (lS)-l-(5-Fluoropyridin-2-yl)ethanamine dihydrochloride (Intermediate 23, 109 mg, 0.51 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 2, providing the title compound, a mixture of enantiomers, as a yellow solid (77.7 mg). 1H NMR (300 MHz, MeOD) δ ppm 8.44 (d, 1 H) 7.85 (s, 1 H) 7.42 - 7.66 (m, 2 H) 7.37 (s, 1 H) 5.09 (q, 1 H) 3.73 (s, 3 H) 1.55 (d, 3 H). LCMS: 348 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC (AD-H column).
Column dimensions: 21 x 250 mm, 5μ
Mobile phase: 20% MeOH
Flow rate (ml/min): 60 mL/min
Pressure: 100 bar
Oven Temperature: 4O0C
Detection (nm): 254 nm
Post purification purity check
Sample purity was checked with a AD-H column.
Column dimensions: 4.6 x 250 mm
Mobile phase: 15% MeOH/0.4%dimethylethylamine
Flow: 2.8 mL/min
Pressure: 120 bar
Oven Temperature: 350C
Detection: 220 nm
Example 4(a), First Eluting Compound
5-Chloro-N2-[ 1 -(5-fluoropyridin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (A)
The first eluting compound had a retention time of 0.76 minutes, >98% ee. 1H NMR (300 MHz, MeOD) δ ppm 8.44 (d, 1 H) 7.85 (s, 1 H) 7.42 - 7.66 (m, 2 H) 7.37 (s, 1 H) 5.09 (q, 1 H) 3.73 (s, 3 H) 1.55 (d, 3 H). LCMS: 348 [M+H]+.
Example 4(b), Second Eluting Compound
5-Chloro-N2-[ 1 -(5-fluoropyridin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (B)
The second eluting compound had a retention time of 1.40 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.44 (d, 1 H) 7.85 (s, 1 H) 7.42 - 7.66 (m, 2 H) 7.37 (s, 1 H)
5.09 (q, 1 H) 3.73 (s, 3 H) 1.55 (d, 3 H).
LCMS: 348 [M+H]+.
Example 5
2- {[l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyllamino|-5-fluoro-6-[(l -methyl- lH-imidazol-4- vDaminolnicotinonitrile, Trifluoroacetic Acid Salt
Figure imgf000078_0001
2,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)amino]nicotinonitrile (Intermediate 25, 100 mg, 0.43 mmol) and (li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine, (7^-mandelic acid salt (Intermediate 13, 181 mg, 0.53 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 2, providing the title product as a mixture of enantiomers, in the form of a pale yellow solid (83.9 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.77 (s, 1 H) 8.38 (d, 1 H) 7.51 - 7.74 (m, 2 H) 7.46 (d,l H) 5.60 (t,l H) 3.91 - 4.09 (m, 3 H) 3.69 - 3.89 (m, 2 H) 3.35 (s, 3 H). LCMS: 404 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral HPLC, Chiralpak
AD column.
Column dimensions: 2 x 25 cm, lOμ
Mobile phase: 50:50:0.1 Hexane:Isopropanol:diethylamine
Flow rate (ml/min): 20 mL/min
Detection (nm): 220 nm
Post purification purity check
Sample purity was checked with a AD-H column.
Column dimensions: 4.6 x 250 mm, 1O u
Mobile phase: 50:50:0.1 Hexane:Isopropanol:diethylamine
Flow: 1.0 mL/min
Detection: 220 nm
Example 5(a), First Eluting Compound
2-{ri-(3,5-Difluoropyridin-2-yl)-2-methoxyethyllamino|-5-fluoro-6-r(l-methyl-lH-imidazol-4- yl)amino"|nicotinonitrile, Enantiomer (A)
The first eluting compound had a retention time of 5.10 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.77 (s, 1 H) 8.38 (d, 1 H) 7.51 - 7.74 (m, 2 H) 7.46 (d,l H)
5.60 (t,l H) 3.91 - 4.09 (m, 3 H) 3.69 - 3.89 (m, 2 H) 3.35 (s, 3 H).
LCMS: 404 [M+H]+.
Example 5(b), Second Eluting Compound
2- {[l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyllamino|-5-fluoro-6-[(l -methyl- lH-imidazol-4- vDaminolnicotinonitrile, Enantiomer (B)
The second eluting compound had a retention time of 5.67 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.77 (s, 1 H) 8.38 (d, 1 H) 7.51 - 7.74 (m, 2 H) 7.46 (d,l H)
5.60 (t,l H) 3.91 - 4.09 (m, 3 H) 3.69 - 3.89 (m, 2 H) 3.35 (s, 3 H). LCMS: 404 [M+H]+.
Example 6
5-Chloro-N2-r 1 -(3.5-difluoropyridin-2-ylV2-methoxyethyll-A/4-('l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine
Figure imgf000080_0001
2, 5-Dichloro-JV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 24, 100 mg, 0.41 mmol) and (li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine, (7^-mandelic acid salt (Intermediate 13, 174 mg, 0.51 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 2Λ providing the title compound as a mixture of enantiomers, in the form of a salmon-colored solid (65.5 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1 H) 7.86 (s, 1 H) 7.50 - 7.64 (m, 1 H) 7.42 (s, 2 H) 5.56 - 5.70 (m, 1 H) 3.65 - 3.89 (m, 5 H) 3.33 (s, 3 H). LCMS: 396 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC ( AD-H column).
Column dimensions: 21 x 250 mm, 5μ
Mobile phase: 15% MeOH/0.4% dimethylethylamine
Flow rate (ml/min): 60 mL/min
Pressure: 100 bar
Oven Temperature: 4O0C Detection (nm): 254 nm
Post purification purity check
Sample purity was checked with an AD-H column.
Column dimensions: 4.6 x 250 mm
Mobile phase: 15% MeOH/0.4%dimethylethylamine
Flow: 5 mL/min
Pressure: 120 bar
Oven Temperature: 350C
Detection: 220 nm
Example 6(a), First Eluting Compound
5-Chloro-N2-r 1 -(3.5-difluoropyridin-2-vπ-2-methoxyethyl1-Λ/4-(l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine, Enantiomer (A)
The first eluting compound had a retention time of 0.88 minutes, 94.8% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1 H) 7.86 (s, 1 H) 7.50 - 7.64 (m, 1 H) 7.42 (s, 2 H)
5.56 - 5.70 (m, 1 H) 3.65 - 3.89 (m, 5 H) 3.33 (s, 3 H).
LCMS: 396 [M+H]+.
Example 6(b), Second Eluting Compound
5-Chloro-N2-r 1 -(3.5-difluoropyridin-2-vπ-2-methoxyethyl1-Λ/4-(l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine, Enantiomer (B)
The second eluting compound had a retention time of 1.15 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1 H) 7.86 (s, 1 H) 7.50 - 7.64 (m, 1 H) 7.42 (s, 2 H)
5.56 - 5.70 (m, 1 H) 3.65 - 3.89 (m, 5 H) 3.33 (s, 3 H).
LCMS: 396 [M+H]+.
Example 7
2- { [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyll amino I -5 -fluoro-6- [( 1 -methyl- lH-imidazol-4- vDaminolnicotinonitrile, Trifluoroacetic Acid Salt
Figure imgf000082_0001
2,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)amino]nicotinonitrile (Intermediate 25, 100 mg, 0.43 mmol) and (15)-l-(3,5-difluoropyridin-2-yl)ethanamine, (7^-mandelic acid salt (Intermediate 18, 165 mg, 0.53 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 2, providing the title product as a mixture of enantiomers, in the form of a yellow solid (143.2 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.77 (s, 1 H) 8.32 (d, 1 H) 7.49 - 7.71 (m, 2 H) 7.45 (d, 1 H) 5.45 (q, 1 H) 3.99 (s, 3 H) 1.55 (d, 3 H). LCMS: 374 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral HPLC (Chiralpak
AD column).
Column dimensions: 20 x 250 mm, lOμ
Mobile phase: 50:50:0.1 Hexane:Isopropanol:diethylamine
Flow rate (ml/min): 20 mL/min
Detection (nm): 220 nm
Post purification purity check
Sample purity was checked with a AD-H column.
Column dimensions: 4.6 x 250 mm, 1O u
Mobile phase: 50:50:0.1 Hexane:Isopropanol:diethylamine
Flow: 1.0 mL/min
Detection: 220 nm Example 7(a), First Eluting Compound
2- { [ 1 -(3 ,5 -Difluoropyridin-2-yl)ethyll amino I -5 -fluoro-6- |Y 1 -methyl- lH-imidazol-4- yl)amino"|nicotinonitrile, Enantiomer (A)
The first eluting compound had a retention time of 4.93 minutes, 97.7% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.77 (s, 1 H) 8.32 (d, 1 H) 7.49 - 7.71 (m, 2 H) 7.45 (d, 1 H)
5.45 (q, 1 H) 3.99 (s, 3 H) 1.55 (d, 3 H).
LCMS: 374 [M+H]+.
Example 7(b), Second Eluting Compound
2- { [ 1 -(3 ,5 -Difluoropyridin-2-yl)ethyll amino I -5 -fluoro-6- |Y 1 -methyl- lH-imidazol-4- vDaminolnicotinonitrile, Enantiomer (B)
The second eluting compound had a retention time of 6.38 minutes, >98% ee.
1H NMR (300 MHz, MeOD) d ppm 8.77 (s, 1 H) 8.32 (d, 1 H) 7.49 - 7.71 (m, 2 H) 7.45 (d, 1 H)
5.45 (q, 1 H) 3.99 (s, 3 H) 1.55 (d, 3 H).
LCMS: 374 [M+H]+.
Example 8
5-Chloro-Λ/2-[l-(3,5-difluoropyridin-2-yl)ethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-2,4- diamine
Figure imgf000083_0001
2, 5-Dichloro-iV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 24, 100 mg, 0.41 mmol) and (15)-l-(3,5-difluoropyridin-2-yl)ethanamine, (7^-mandelic acid salt (Intermediate 18, 127 mg, 0.41 mmol) 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, in the form of a pink solid (67.8 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.32 (d,l H) 7.84 (s, 1 H) 7.56 (ddd,l H) 7.42 (s, 2 H) 5.45
(q, I H) 3.76 (s, 3 H) 1.53 (d, 3 H).
LCMS: 366 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral HPLC (Chiralpak
AD column).
Column dimensions: 20 x 250 mm, lOμ
Mobile phase: 50:50:0.1 Hexane:Isopropanol:diethylamine
Flow rate (ml/min): 20 mL/min
Detection (nm): 254 nm
Post purification purity check
Sample purity was checked with AD-H column.
Column dimensions: 4.6 x 250 mm, 1O u
Mobile phase: 50:50:0.1 Hexane:Isopropanol:diethylamine
Flow: 1.0 mL/min
Detection: 254 nm
Example 8(a), First Eluting Compound
5-Chloro-Λ/2-ri-(3.5-difluoropyridin-2-vπethyl1-Λ/4-(l-methyl-lH-imidazol-4-vπpyrimidine-2.4- diamine, Enantiomer (A)
The first eluting compound had a retention time of 5.73 minutes.
Example 8(b), Second Eluting Compound
5-Chloro-Λ/2-ri-(3,5-difluoropyridin-2-yl)ethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (B)
The second eluting compound had a retention time of 6.21 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.32 (d,l H) 7.84 (s, 1 H) 7.56 (ddd,l H) 7.42 (s, 2 H) 5.45 (q, I H) 3.76 (s, 3 H) 1.53 (d, 3 H). LCMS: 366 [M+H]+.
Example 9
N2-\\ -(3,5-Difluoropyridin-2-yl)-2-methoxyethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin- 4-ylpyrimidine-2,4-diamine, Trifluoroacetic Acid Salt
Figure imgf000085_0001
6-Chloro-Λ/2-[(15)- 1 -(3, 5 -difluoropyridin-2-yl)-2-methoxy ethyl] -N4 -(I -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine (Example 23, 58 mg, 0.15 mmol) was dissolved in ethanol (0.3 niL) and morpholine (0.447 niL, 5.13 mmol) was added. The resulting mixture was stirred at 800C overnight. The reaction mixture was concentrated in vacuo leaving an orange semi-solid (92 mg). This material was purified utilizing Gilson chromatography (Atlantis Prep T3, 20-27% MeCN/Η2O(0.1% TFA), 7 minute elution time, concentration of 190 mg/mL in MeOH, 350 μl inj., collection at 240 nm). Evaporation of the collected fractions gave the title product (45 mg) as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.37 (d, 1 H) 7.73 (br. s., 1 H) 7.53 - 7.68 (m, 1 H) 6.93 (br. s., 1 H) 5.59 (t, 1 H) 3.47 - 3.90 (m, 14 H) 3.36 (s, 3 H). LCMS: 447 [M+H]+.
The title product may also be obtained using 6-chloro-Λ/2-[(li?)-l-(3,5-difluoropyridin-2-yl)-2- methoxyethyl]-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-2,4-diamine (Example 22) as the starting material instead of chloro-Λ/2-[(15)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ/4-(l- methyl-lH-imidazol-4-yl)pyrimidine-2,4-diamine (Example 23). Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC, (Chiralpak AD-
H column).
Column dimensions: 21 x 250 mm, 5 μm
Modifier: 30% Isopropanol with 0.4% Dimethylethylamine
Flow rate (ml/min): 60
Outlet Pressure (bar): 100
Detection (nm): 254
Post purification purity check
Sample purity was checked by SFC with a AD-H column.
Column dimensions: 4.6 x 100 mm
Modifier: 30% Isopropanol with 0.4% Dimethylethylamine
Flow: 5 mL/min
Outlet Pressure : 120 bar
Detection: 254 nm
Example 9(a), First Eluting Compound
Λ/2-[l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-
4-ylpyrimidine-2,4-diamine, Enantiomer (A)
The first eluting compound had a retention time of 1.84 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.35 (d, 1 H) 7.54 (ddd, 1 H) 7.35 (d, I H) 7.17 (d, 1 H) 5.66
(t, 1 H) 5.36 (s, 1 H) 3.59 - 3.87 (m, 9 H) 3.37 - 3.46 (m, 4 H) 3.33 (s, 3 H).
LCMS: 447 [M+H]+.
Example 9(b), Second Eluting Compound
N2-\\ -(3,5-Difluoropyridin-2-yl)-2-methoxyethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-
4-ylpyrimidine-2,4-diamine, Enantiomer (B)
The second eluting compound had a retention time of 2.22 minutes, >98% ee. 1H NMR (300 MHz, MeOD) δ ppm 8.35 (d, 1 H) 7.54 (ddd, 1 H) 7.35 (d, 1 H) 7.17 (d, 1 H) 5.66 (t, 1 H) 5.36 (s, 1 H) 3.59 - 3.87 (m, 9 H) 3.37 - 3.46 (m, 4 H) 3.33 (s, 3 H). LCMS: 447 [M+H]+.
Example 10
Λ/2-[l-(5-Fluoropyrimidin-2-yl)ethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine
Figure imgf000087_0001
6-Chloro-Λ/2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine- 2,4-diamine (Example 21, 323 mg, 0.93 mmol) and morpholine (807 mg, 9.26 mmol) in n-BuOΗ (2 ml) was heated at 900C overnight. The volatiles were removed under reduced pressure to give a residue which was purified utilizing ISCO (5%MeOΗ/0.5%NΗ4OΗ in DCM) to afford the title compound (200 mg) as a mixture of enantiomers. LCMS: 400 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC, 4mg 10 (a) and
128 mg 10(b).
Column type/particle size: Chiralpak AD/ lOμ
Column dimensions (mm): 20 X 250
Mobile phase: 100% 1 :1 ethanol methanol, 0.1% diethylamine
Flow rate (ml/min): 20ml/min
Post purification purity check: Sample purity was checked by.Chiral HPLC (Agilent 1100) using Diode Array
Column type/particle size: Chiralpak AD/ lOμ
Column dimensions (mm): 4.6 X 250
Mobile phase: 100% 1 :1 ethanol methanol, 0.1% diethylamine
Flow rate: 1 ml/min
Detection: 240 nm
Example 10(a), First Eluting Compound
Λ/2-[l-(5-Fluoropyrimidin-2-yl)ethyll-Λ/4-(l -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine, Enantiomer (A)
The first eluting compound had a retention time of 10.5 minutes, ee was not determined. LCMS: 400 [M+Η]+.
Example 10(b), Second Eluting Compound
Λ/2-ri-(5-Fluoropyrimidin-2-yl)ethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine, Enantiomer (B)
The second eluting compound had a retention time of 16.2 minutes, >98% ee.
1H NMR (400 MHz, MeOD) δ ppm 8.67 (s, 2 H) 7.33 (s, 1 H) 7.17 (d, 1 H) 5.49 (s, 1 H) 5.31 (s,
1 H) 3.71 (s, 3 H) 3.59 - 3.68 (m, 4 H) 3.33 - 3.40 (m, 4 H) 1.53 (d, 3 H).
LCMS: 400 [M+H]+.
Example 11
Λ/2-ri-(3.5-Difluoropyridin-2-vπethyl1-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4-vπ-6-morpholin-4- ylpyrimidine-2,4-diamine
Figure imgf000088_0001
6-Chloro-Λ/2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl]-5 -fluoro-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine, trifluoroacetic acid salt (Example 24, 69 mg, 0.14 mmol) was slurried in ethanol (2 mL) and morpholine (0.423 rnL, 4.85 mmol) was added. The reaction mixture was heated at 1000C overnight. The reaction mixture was concentrated in vacuo leaving a brown oil (129 mg). This material was purified utilizing ISCO (0-10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a mixture of enantiomers, in the form of a yellow solid (48 mg).
1U NMR (300 MHz, MeOD) δ ppm 8.30 (d, 1 H) 8.04 (s, 0.24H) 7.44 - 7.62 (m, 1 H) 7.22 - 7.41 (m, 2 H) 5.35 (q, 1 H) 3.38 - 3.88 (m, 16 H) 1.48 (d, 3 H). LCMS: 435 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC, (Chiralpak AD-
H column).
Column dimensions: 21 x 250 mm, 5 μm
Modifier: 20 % Isopropanol with 0.4 % dimethylethylamine
Flow rate (ml/min): 60
Outlet Pressure (bar): 100
Detection (nm): 254
Post purification purity check
Sample purity was checked by SFC with a AD-H column.
Column dimensions: 4.6 x 100 mm
Modifier: 25% Solvent 4
Flow: 3 mL/min
Outlet Pressure : 120 bar
Detection: 254 nm
Example Ufa), First Eluting Compound
Λ/2-ri-(3.5-Difluoropyridin-2-vπethyl1-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4-vπ-6-morpholin-4- ylpyrimidine-2,4-diamine, Enantiomer (A) The first eluting compound had a retention time of 4.42 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.30 (d, 1 H) 7.53 (ddd, 1 H) 7.21 - 7.42 (m, 2 H) 5.22 - 5.51
(m, 1 H) 3.60 - 3.84 (m, 7 H) 3.40 - 3.62 (m, 4 H) 1.47 (d, 3 H).
LCMS: 435 [M+H]+.
Example 1Kb), Second Eluting Compound
Λ/2-ri-(3.5-Difluoropyridin-2-vπethyl1-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4-vπ-6-morpholin-4- ylpyrimidine-2,4-diamine, Enantiomer (B)
The second eluting compound had a retention time of 5.75 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.30 (d, 1 H) 7.42 - 7.67 (m, 1 H) 7.22 - 7.43 (m, 2 H) 5.35
(q, 1 H) 3.61 - 3.82 (m, 7 H) 3.44 - 3.61 (m, 4 H) 1.47 (d, 3 H).
LC-MS: 435 [M+H]+.
Example 12
/^-[^(S-Fluoropyrimidin^-yπethyll-S-methoxy-Λ^-d -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine
Figure imgf000090_0001
2-Chloro-5-methoxy-N-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 28, 200 mg, 0.83 mmol) and (15)-l-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 10, 185 mg, 1.04 mmol) were suspended in butan-1-ol (2 mL) and DIPEA (0.583 mL, 3.34 mmol) was added. The reaction was heated in a microwave at 160° for 21600s. The reaction mixture was concentrated in vacuo leaving a brown semi-solid (595 mg). This material was purified utilizing ISCO (2-5% MeOΗ/DCM, 5 min, 5% MeOΗ/DCM isocratic, 10 min, 5-10% MeOΗ/DCM, 5 min, 10% MeOΗ/DCM isocratic, 10 min). Concentration of the fractions in vacuo provided the title compound, a mixture of enantiomers, as a yellow solid (45 mg). 1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.50 (s, 1 H) 7.45 (d, 1 H) 7.37 (d,l H) 5.25 (q,l H) 3.80 (d, 6 H) 1.57 (d, 3 H). LCMS: 345 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral HPLC (Chiralpak
AD column).
Column dimensions: 5x50 cm, 20μ
Mobile phase : 1 : 1 EtOH/MeOH, 0.1% diethylamine
Flow rate (ml/min): 120 mL/min
Detection (nm): 254 nm
Post purification purity check
Sample purity was checked with an AD-H column.
Column dimensions: 4.6 x 250 mm, 1O u
Mobile phase : 1 : 1 EtOH/MeOH, 0.1% diethylamine
Flow: 1.0 mL/min
Detection: 254 nm
Example 12(a), First Eluting Compound
Λ^-fl-fS-Fluoropyrimidin^-yπethyll-S-methoxy-Λ^-d -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (A)
The first eluting compound had a retention time of 4.96 minutes, >98% ee.
1Η NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.50 (s, 1 H) 7.45 (d, 1 H) 7.37 (d,l H) 5.25
(q,l H) 3.80 (d, 6 H) 1.57 (d, 3 H).
LCMS: 345 [M+H]+.
Example 1Kb), Second Eluting Compound
N2-\\ -(S-Fluoropyrimidin^-vOethyli-S-methoxy-A^-π -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (B) The second eluting compound had a retention time of 5.79 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.50 (s, 1 H) 7.45 (d, 1 H) 7.37 (d, 1 H) 5.25
(q,l H) 3.80 (d, 6 H) 1.57 (d, 3 H).
LCMS: 345 [M+H]+.
Example 13
N2- \ 1 -(5 -Fluoropyrimidin-2-yl)ethyll -5 -methyl-A^-f 1 -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine
Figure imgf000092_0001
2-Chloro-5-methyl-N-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 29, 200 mg, 0.89 mmol) and (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 10, 199 mg, 1.12 mmol) were suspended in butan-1-ol (2 mL) and DIPEA (0.625 mL, 3.58 mmol) was added. The reaction was heated in a microwave at 160° for 21600s. The reaction mixture was concentrated in vacuo leaving a brown oil (708 mg). This material was purified utilizing ISCO (2-5% MeOΗ/DCM, 5 min, 5% MeOΗ/DCM isocratic, 5 min, 5-10% MeOΗ/DCM, 5 min, 10% MeOΗ/DCM isocratic, 5 min). Concentration of the fractions in vacuo provided the title compound, a mixture of enantiomers, as a yellow solid (160 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.61 (s, 1 H) 7.42 (s, 1 H) 7.37 (d, 1 H) 5.29 (q, 1 H) 3.78 (s, 3 H) 1.96 - 2.10 (m, 3 H) 1.57 (d, 3 H). LCMS: 329 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC, (Chiralpak AD-
H column). Column dimensions: 21 x 250 mm, 5 μm
Modifier: 15% Methanol with 0.4% Dimethylethylamine
Flow rate (ml/min): 60
Outlet Pressure (bar): 100
Detection (nm): 254
Post purification purity check
Sample purity was checked by SFC with a AD-H column.
Column dimensions: 4.6 x 250 mm
Modifier: 15% Methanol with 0.4% Dimethylethylamine
Flow: 2.5 mL/min
Outlet Pressure: 120 bar
Detection: 254 nm
Example 13(a), First Eluting Compound
N2- \ 1 -(5 -Fluoropyrimidin-2-yl)ethyll -5 -methyl-A^-f 1 -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (A)
The first eluting compound had a retention time of 10.11 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.61 (s, 1 H) 7.42 (s, 1 H) 7.37 (d, 1 H) 5.29 (q,
1 H) 3.78 (s, 3 H) 1.96 - 2.10 (m, 3 H) 1.57 (d, 3 H).
LC-MS: 329 [M+H]+.
Example 13(b), Second Eluting Compound
N2- \ 1 -(5 -Fluoropyrimidin-2-vDethvH -5 -methyl-A^-f 1 -methyl- lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (B)
The second eluting compound had a retention time of 11.89 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.61 (s, 1 H) 7.42 (s, 1 H) 7.37 (d, 1 H) 5.29 (q,
1 H) 3.78 (s, 3 H) 1.96 - 2.10 (m, 3 H) 1.57 (d, 3 H).
LC-MS: 329 [M+H]+.
Example 14 S-Fluoro-Λ^-fl-fS-fluoropyrimidin-l-yπethyll-Λ^-fl-methyl-lH-imidazol^-yπpyrimidine-lΛ- diamine
Figure imgf000094_0001
2-Chloro-5-fluoro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 30, 200 mg, 0.88 mmol) and (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 10, 195 mg, 1.10 mmol) were suspended in butan-1-ol (2 mL) and DIPEA (0.614 mL, 3.51 mmol) was added. The reaction was heated in a microwave at 160° for 21600s. The reaction mixture was concentrated in vacuo leaving a brown solid (526 mg). This material was purified utilizing ISCO (5 min 2-5% MeOΗ/DCM ramp up, then 5% MeOΗ/DCM, isocratic). Concentration of the fractions in vacuo provided the title compound, a mixture of enantiomers, as peach solid (125 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.72 (d, 1 H) 7.43 (s, 1 H) 7.38 (s, 1 H) 5.23 (q,l H) 3.78 (s, 3 H) 1.57 (d, 3 H). LCMS: 333 [M+H]+.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC, (Chiralpak AD-
H column).
Column dimensions: 21 x 250 mm, 5 μm
Modifier: 15% Methanol with 0.4% Dimethylethylamine
Flow rate (ml/min): 60
Outlet Pressure (bar): 100
Detection (nm): 254
Post purification purity check Sample purity was checked by SFC with a AD-H column.
Column dimensions: 4.6 x 250 mm
Modifier: 15% Methanol with 0.4% Dimethylethylamine
Flow: 2.5 mL/min
Outlet Pressure: 120 bar
Detection: 254 nm
Example 14(a), First Eluting Compound
5-FIuOrO-A^-[I -(5-fluoropyrimidin-2-yl)ethyll-Λ/4-(l-methyl-lH-imidazol-4-yl)pyrimidine-2,4- diamine, Enantiomer (A)
The first eluting compound had a retention time of 9.07 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.72 (d, 1 H) 7.43 (s, 1 H) 7.38 (s, 1 H) 5.23
(q,l H) 3.78 (s, 3 H) 1.57 (d, 3 H).
LCMS: 333 [M+H]+.
Example 14(b), Second Eluting Compound
Figure imgf000095_0001
diamine, Enantiomer (B)
The second eluting compound had a retention time of 11.25 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 7.72 (d, 1 H) 7.43 (s, 1 H) 7.38 (s, 1 H) 5.23
(q,l H) 3.78 (s, 3 H) 1.57 (d, 3 H).
LCMS: 333 [M+H]+.
Example 15
5-Fluoro-A/2-[(iy)-l-(5-fluoropyridin-2-vπethyl1-A/4-(l-methyl-lH-imidazol-4-vπ-6-morpholin- 4-ylpyrimidine-2,4-diamine
Figure imgf000096_0001
6-Chloro-5-fluoro-N2-[(15)- 1 -(5 -fluoropyridin-2-yl)ethyl] -A^-(I -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine (Example 25, 52mg, 0.14 mmol) was suspended in morpholine (1239 mg, 14.22 mmol) and the resulting mixture was heated at 1000C for 5 hours. Evaporation of the volatiles under reduced pressure afforded a residue which was purified utilizing ISCO (100%DCM^80%DCM/20% MeOH containing NH4OH) to give the title compound (29.0 mg, 49.0 %). 1H NMR (400 MHz, MeOD) δ ppm 8.29 (s, IH), 7.82 (s, IH), 7.46 (m, IH), 7.38 (m,lH), 7.03 (br, IH), 4.85 (m, IH), 3.70 (s, 3H), 3.54 (m, 4H), 3.42 (m, 4H), 1.40 (d, 3H). LCMS: 417 [M+H]+.
Example 16
5-Fluoro-Λ/2-r(iy)-l-(5-fluoropyrimidin-2-vπethyl1-Λ/4-(l-methyl-lH-imidazol-4-vπ-6- morpholin-4-ylpyrimidine-2,4-diamine
Figure imgf000096_0002
6-Chloro-5-fluoro-Λ/2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine (Example 26, 114mg, 0.31 mmol) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 16, providing the title compound (14 mg). 1H NMR (400 MHz, MeOD) δ ppm 8.59 (s, 2H), 7.81 (s, IH), 7.12 (s, IH), 5.0 (m, IH), 3.72 (s, 3H), 3.55 (m, 4H), 3.44 (m, 4H), 1.42 (d, 3H). LCMS: 418 [M+H]+.
Example 17
Λ^-ri-fS.S-Difluoropyridin^-vπ^-methoxyethyli-S-fluoro-Λ^-d-methyl-lH-imidazol^-vπ-β- morpholin-4-ylpyrimidine-2,4-diamine
Figure imgf000097_0001
6-Chloro-Λ/2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl]-5 -fluoro-Λ/4^ 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine (Example 27, 120mg, 0.31 mmol) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 16, providing the title compound (94 mg, 69.2 %) as a mixture of enantiomers.
Column and solvent conditions
The R and S enantiomers of the title compound were separated using Chiral SFC, (Chiralpak AD-
Η column).
Column type/particle size (μ): Chiralpak AD/ 10
Column dimensions (mm): 20 X 250
Mobile phase: 80 % Ηexane, 20 % ethanol:methanol (1 : 1), 0.1 % diethylamine Flow rate (ml/min): 20ml/min
Post purification purity check
The sample purity was checked using Chiral ΗPLC (Agilent 1100) using Diode Array
Column type/particle size (μ): Chiralpak AD/ 10 Column dimensions (mm): 4.6 X 250
Mobile phase: 80 % Hexane, 20 % ethanol:methanol (1 : 1), 0.1 % diethylamine
Flow rate (ml/min): 1
Detection: 300 nm
Example 17(a), First Eluting Compound
Λ^-ri-O.S-Difluoropyridin^-vπ^-methoxyethyli-S-fluoro-Λ^-d-methyl-lH-imidazol^-vπ-β- morpholin-4-ylpyrimidine-2,4-diamine, Enantiomer (A) The first eluting compound was not characterized
Example 17(b), Second Eluting Compound
Λ^-ri-O.S-Difluoropyridin^-vπ^-methoxyethyli-S-fluoro-Λ^-d-methyl-lH-imidazol^-vπ-β- morpholin-4-ylpyrimidine-2,4-diamine, Enantiomer (B)
The second eluting compound had a retention time of 13.6 minutes, >95% ee.
1H NMR (400 MHz, MeOD) δ ppm 8.21 (d, IH), 7.42 (t, IH), 7.22 (s, IH), 7.20 (s, IH), 5.45
(m, IH), 3.66 (m, IH), 3.60 (m, 3H), 3.58 (s, 3H), , 3.55 (s, 3H), 3.42 (m, 4H), 3.26 (s, 2H).
LCMS: 465 [M+H]+.
Example 18
6-Chloro-Λ/2-ri-(3.5-difluoropyridin-2-vπethyl1-Λ/4-(l-methyl-lH-imidazol-4-vπpyrimidine-2.4- diamine, Trifluoroacetic Acid Salt
Figure imgf000098_0001
To a mixture of 2,6-dichloro-iV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 26, 2.449 g, 10.03 mmol) and l-(3,5-difluoropyridin-2-yl)ethanamine hydrochloride (Intermediate 17(a), 2.318 g, 10.03 mmol) in n-BuOH (24.00 ml) was added TEA (5.59 ml, 40.13 mmol). The reaction mixture was heated at 1200C overnight. LC-MS indicated 75% formation of the desired product as well as ~5% 2-chloro-N4-(l-(3,5-difluoropyridin-2-yl)ethyl)- N6-(l -methyl- lH-imidazol-4-yl)pyrimidine-4,6-diamine. The reaction mixture was filtered leaving an off- white solid (3.066 g). Purification utilizing Gilson chromatography (Waters Xbridge RPl 8, 25% -» 40% MeCN/0.1%TFA H2O) gave the title compound as a mixture of enantiomers in the form of a white solid (1.759 g). LC-MS: 366 [M+H]+.
Example 19
Λ/2-r(iy)-l-(5-Fluoropyrimidin-2-vπethyl1-Λ/4-(l-methyl-l/f-imidazol-4-vπpyrimidine-2.4.6- triamine
Figure imgf000099_0001
^-(Diphenylmethylene)-^2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -N6 -(I -methyl- l/f-imidazol-4- yl)pyrimidine-2,4,6-triamine (Intermediate 31, 2122 mg, 4.3 mmol) in THF (13 mL) was treated with hydrogen chloride (8600 μl, 17.20 mmol, 2N aq). After stirring for 2 hours, the reaction mixture was diluted with water. The aqueous layer was washed with EtOAc and subsequently was neutralized to pH= 10 using NaOH (IN) and extracted with MeOH/DCM (10%, 3x). The combined organic layers were dried in vacuum to provide a residue, which was purified utilizing ISCO (0 to 10% DCM/MeOH/1% ammonia hydroxide) yielding the title compound (400 mg). 1H NMR (300 MHz, DMSO-Je) δ ppm 8.74 - 8.90 (m, 2 H), 8.59 (s, 1 H), 7.25 (d, 1 H), 7.13 (br. s., 1 H), 6.27 (d, 1 H), 5.61 (s, 2 H), 5.23 (t, 1 H), 5.18 (s, 1 H), 3.61 (s, 3 H), 1.46 (d, 3 H). LCMS: 329 [M+H]+.
Example 20
Λ/2-ri-(3.5-Difluoropyridin-2-vπethyl1-Λ/4-(l-methyl-l/f-imidazol-4-vπ-6-morpholin-4- ylpyrimidine-2,4-diamine
Figure imgf000100_0001
To a solution of 6-chloro-Λ/2-[l-(3,5-difluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine, trifluoroacetic acid salt (Example 18, 1.759 g, 3.67 mmol) in ethanol (7.15 ml) was added morpholine (11.18 ml, 128.32 mmol). The reaction mixture was heated at 1000C overnight and subsequently the reaction mixture was concentrated in vacuo leaving a brown oil (3.910 g). This material was purified by ISCO (5-15% MeOΗ/DCM). Concentration of the fractions in vacuo gave the title compound as a mixture of enantiomers in the form of a tan solid (1.049 g). LC-MS: 417 [M+Η]+.
The R and S enantiomers of the title compound were separated using Chiral SFC, (Chiralpak AD-
H column).
Column dimensions: 21 x 250 mm, 5 μm
Modifier: 30% isopropanol with 0.1% Dimethylethylamine
Flow rate (ml/min): 60
Outlet Pressure (bar): 100
Detection (nm): 220
Post purification purity check
Sample purity was checked by SFC with a AD-H column.
Column dimensions: 4.6 x 100 mm
Modifier: 30% isopropanol with 0.1% Dimethylethylamine
Flow: 5.0 mL/min
Outlet Pressure : 120 bar Detection: 220 nm
Example 20(a), First Eluting Compound
Λ/2-ri-(3.5-Difluoropyridin-2-vπethyl1-Λ/4-(l-methyl-lH-imidazol-4-vπ-6-morpholin-4- ylpyrimidine-2,4-diamine, Enantiomer (A)
(246.3 mg)
The first eluting compound had a retention time of 7.98 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.30 (d, 1 H) 7.52 (ddd, 1 H) 7.35 (s, 1 H) 7.14 (d, 1 H) 5.39
- 5.60 (m, 1 H) 5.33 (s, 1 H) 3.58 - 3.81 (m, 7 H) 3.36 - 3.50 (m, 4 H) 1.49 (d, 3 H).
LC-MS: 417 [M+H]+.
Example 20(b), Second Eluting Compound
Λ/2-ri-(3.5-Difluoropyridin-2-vπethyl1-Λ/4-(l-methyl-lH-imidazol-4-vπ-6-morpholin-4- ylpyrimidine-2,4-diamine, Enantiomer (B)
(264.2 mg)
The second eluting compound had a retention time of 9.80 minutes, >98% ee.
1H NMR (300 MHz, MeOD) δ ppm 8.30 (d, 1 H) 7.44 - 7.67 (m, 1 H) 7.34 (s, 1 H) 7.15 (d, 1 H)
5.47 (q, 1 H) 5.33 (s, 1 H) 3.58 - 3.80 (m, 7 H) 3.37 - 3.50 (m, 4 H) 1.48 (d, 3 H).
LC-MS: 417 [M+H]+.
Example 21
6-Chloro-Λ/2- IY 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyll -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine- 2,4-diamine
Figure imgf000101_0001
2, 6-Dichloro-iV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 26, 244 mg, 1.00 mmol), (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 10, 213 mg,
1.20 mmol), DIPEA (0.436 ml, 2.50 mmol) in n-BuOU (2 ml) and NMP (0.5 ml) was heated at
900C for 24 hours. LCMS indicated complete conversion. The volatiles were removed under reduced pressure and the derived residue was purified utilizing ISCO to afford the title compound
(287 mg, 82%).
1H NMR (400 MHz, DMSO-J6) δ ppm 9.65 (br. s., 1 H) 8.79 - 9.01 (m, 2 H) 7.76 (br. s., 1 H)
7.32 (br. s., 1 H) 7.01 (br, IH) 6.01 (br. s., 1 H) 5.16 (br. s., 1 H) 3.56 - 3.70 (m, 3 H) 1.49 (d, 3
H).
LCMS: 349 [M+H]+.
Example 22
6-Chloro-Λ/2-r(li?)-l-(3.5-difluoropyridin-2-yl)-2-methoxyethyl1-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine
Figure imgf000102_0001
2, 6-Dichloro-iV-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 26, 244 mg, 1.00 mmol) and (li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine, (i?)-mandelic acid salt (Intermediate 13, 442 mg, 1.30 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 21, providing the title compound (150 mg) which was directly carried over to the subsequent step. It is believed that the title product undergoes partial racemization. LCMS: 396 [M+Η]+.
Example 23 6-Chloro-N2-r(lS)- 1 -(3.5-difluoropyridin-2-viy2-methoxyethyll-A/Vl -methyl- lH-imidazol-4- v0pyrimidine-2,4-diamine
Figure imgf000103_0001
2, 6-Dichloro-N-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 26, 100 mg, 0.41 mmol) and (15)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine, fSj-mandelic acid salt (Intermediate 14, 153 mg, 0.45 mmol) were slurried in butan-1-ol (1 mL) and TEA (0.228 mL, 1.64 mmol) was added. The reaction mixture was heated at 1200C overnight. The reaction mixture was concentrated in vacuo to give a brown semi-solid (367 mg). This material was purified utilizing ISCO (0-4% MeOΗ/DCM, 6 min, 4% isocratic, 5 min, 4-8%, 4 min). The cleaner fractions from the separation were combined and concentrated in vacuo providing the title compound as a yellow solid (58 mg). It is believed that the title product undergoes partial racemization. LCMS: 396 [M+Η]+.
Example 24
6-Chloro-Λ/2-ri-(3.5-difluoropyridin-2-vπethyl1-5-fluoro-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine, Triflouroacetic Acid Salt
Figure imgf000104_0001
2,6-Dichloro-5-fluoro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 27, 200 mg, 0.76 mmol) and l-(3,5-difluoropyridin-2-yl)ethanamine hydrochloride (Intermediate 17(a), 133 mg, 0.84 mmol) were slurried in butan-1-ol (2 mL) and TEA (0.213 mL, 1.53 mmol) was added. The reaction was then heated at 1200C overnight. The reaction was concentrated in vacuo leaving a brown solid (368 mg). This material was purified utilizing ISCO (2-10% MeOΗ/DCM). Concentration of the fractions in vacuo gave a yellow solid. This material was purified again utilizing ISCO (0-5% MeOΗ/DCM). Concentration of the fractions in vacuo gave a yellow solid. This material was further purified utilizing Gilson chromatography (XTerra Prep 50x250 mm, lOμm, 25-45% MeCN/water (0.1% TFA), 35 min elution, concentration of 24 mg/mL in MeOH (2.6 ml inj), collected 240 nm). Concentration of the fractions in vacuo provided the title compound as a mixture of enantiomers in the form of a white solid (69 mg). LCMS: 384 [M+Η]+.
1H NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1 H) 8.32 (d, 1 H) 7.50 - 7.63 (m, 1 H) 7.45 (s, 1 H) 5.20 - 5.49 (m, 1 H) 3.85 - 4.01 (m, 3 H) 1.51 (d, 3 H).
2-Chloro-N-[l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ/'-(l-methyl-lH-imidazol-4- yl)pyrimidine-4,6-diamine was isolated as a by-product of the reaction used to produce Example 24.
Example 25
Figure imgf000104_0002
yl)pyrimidine-2,4-diamine
2,6-Dichloro-5-fluoro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 27,
460mg, 1.76 mmol) and (15)-l-(5-fluoropyridin-2-yl)ethanamine dihydrochloride (Intermediate
23, 374 mg, 1.76 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 21, providing after purification the title compound (52 mg).
LCMS: 366, 368 [M+Η]+.
1H NMR (400 MHz, CDCl2) δ ppm 9.50 (s, IH), 8.35 (s, IH), 7.31 (d, 2H), 7.13 (s, IH), 7.07 (br,
IH), 5.75 (br, IH), 5.07 (t, IH), 3.55 (s, 3H), 1.44 (d, 3H).
2-Chloro-5 -fluoro-iV- [( 1 S)- 1 -(5 -fluoropyridin-2-yl)ethyl]-Λ^-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-4,6-diamine (30 mg) was isolated as a by-product of the reaction used to synthesize Example 25.
LCMS: 366, 368 [M+Η]+.
1H NMR (400 MHz, CDCl2) δ ppm 9.93 (s, IH), 8.34 (s, IH), 7.34 (m, IH), 7.26 (m, IH), 7.21
(s, IH), 7.17 (s, IH), 6.02 (d, IH), 5.23 (m, IH), 3.58 (s, 3H), 1.45 (d, 3H).
Example 26
6-Chloro-5-fluoro-Λ/2-r(lιy)-l-(5-fluoropyrimidin-2-vπethyl1-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine
Figure imgf000106_0001
2,6-Dichloro-5-fluoro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 27,
460mg, 1.76 mmol) and (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate
10) were reacted using a procedure similar to the one described for the synthesis of Example 21, providing after purification the title compound (114 mg).
LCMS: 367, 369 [M+Η]+.
1H NMR (400 MHz, CDC12) δ ppm 9.05 (s, IH), 8.49 (s, 2H), 7.31 (s, IH), 7.16 (s, IH), 5.85
(br, IH), 5.22 (m, IH), 3.64 (s, 3H), 1.49 (d, 3H).
2-Chloro-5 -fluoro-JV- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl]-Λ/'-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-4,6-diamine (126 mg) was isolated as a by-product of the reaction used to synthesize Example 26.
LCMS: 367, 369 [M+Η]+.
1H NMR (400 MHz, CDCl2) δ ppm 9.25 (s, IH), 8.52 (s, 2H), 7.20 (s, IH), 7.18 (s, IH), 5.96 (d,
IH), 5.34 (m, IH), 3.61 (s, 3H), 1.52 (d, 3H).
Example 27
6-Chloro-N2-r(l^-l-(3.5-difluoropyridin-2-vnethyll-5-fluoro-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine
Figure imgf000107_0001
2,6-Dichloro-5-fluoro-Λ/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine (Intermediate 27, 460mg, 1.76 mmol) and (15)-l-(3,5-difluoropyridin-2-yl)ethanamine, (7^-mandelic acid salt (Intermediate 18, 545 mg, 1.76 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 21, providing after purification the title compound (110 mg). LCMS: 384, 386 [M+Η]+.
2-Chloro-N-[(15)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fiuoro-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-4,6-diamine was isolated as a by-product of the reaction used to synthesize
Example 27 (120 mg).
1H NMR (400 MHz, CDC13) δ ppm 8.24 (s, IH), 7.95 (s, IH), 7.24 (s, IH), 7.13 (m, IH), 6.10
(d, IH), 5.54 (m, IH), 3.64 (s, 3H), 1.45 (d, 3H).
LCMS: 384, 386 [M+H]+.

Claims

ClaimsWhat is claimed is:
1. A compound of Formula (I) :
Figure imgf000108_0001
Formula (I)
or a pharmaceutically acceptable salt thereof, wherein
Ring A is 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted on carbon with one or more R6, and wherein if said 5- or 6- membered heteroaryl contains an -NH- moiety, that -NH- moiety is optionally substituted with R6*;
D is selected from N and C-R3;
E is selected from N and C-R4, wherein at least one of D and E is carbon; X is selected from -NH-, -O-, and -S-;
R1* is selected from H, -CN, d_6alkyl, carbocyclyl, heterocyclyl, -ORla, -N(Rla)2, -C(O)H, -C(O)Rlb, -C(O)2Rla, -C(O)N(Rla)2, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said d_6alkyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R10, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R10*;
Rla in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R10, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R10*;
Rlb in each occurrence is 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 on carbon with one or more R10, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R10*;
R2 is selected from H, halo, -CN, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6 membered carbocyclyl, 4- to 6-membered heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -N(R2a)(OR2a), -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a), -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 on carbon with one or more R20, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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 on carbon with one or more R20, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R20*;
R2b in each occurrence is selected from Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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, -N(R3a)(OR3a), -O-N(R3a)2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -C(O)N(R3a)(OR3a), -OC(O)N(R3a)2, -N(R3a)C(O)2R3, -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 on carbon with one or more R30, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R30*;
R3a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R30*;
R3b in each occurrence is selected from d_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 on carbon with one or more R30, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R30*;
R4 is selected from H, halo, -CN, C^alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)(OR4a), -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -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_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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 on carbon with one or more R40, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R40*;
R4b in each occurrence is 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 on carbon with one or more R40, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R40*;
R5 is selected from H, 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, -N(R5a)(OR5a), -O-N(R5a)2, -C(O)H, -C(O)R5b, -C(O)2R5a, -C(O)N(R5a)2, -C(O)N(R5a)(OR5a) -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 Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R50, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with 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 on carbon with one or more R50, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R50*;
R5b in each occurrence is 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 on carbon with one or more R50, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R50*;
R6 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2-6alkenyl, C2.6alkynyl, carbocyclyl, heterocyclyl, -OR6a, -SR6a, -N(R6a)2, -N(R6a)C(O)R6b, -N(R6a)N(R6a)2, -NO2, -N(R6a)(OR6a), -O-N(R6a)2, -C(O)H, -C(O)R6b, -C(O)2R6a, -C(O)N(R6a)2, -C(O)N(R6a)(OR6a) -OC(O)N(R6a)2, -N(R6a)C(O)2R6a, -N(R6a)C(O)N(R6a)2, -OC(O)R6b, -S(O)R6b, -S(O)2R6b, -S(O)2N(R6a)2, -N(R6a)S(O)2R6b, -C(R6a)=N(R6a), and -C(R5a)=N(OR5a), wherein said d_6alkyl, C2-6alkenyl, C2.6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R60*; R6* in each occurrence is independently selected from -CN, C^alkyl, carbocyclyl, heterocyclyl, -OR6a, -N(R6a)2, -C(O)H, -C(0)R6b, -C(O)2R6a, -C(O)N(R6a)2, -S(O)R6b,
-S(O)2R6b, -S(O)2N(R6a)2, -C(R6a)=N(R6a), and -C(R6a)=N(OR6a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R60, and wherein if said heterocyclyl contains an
-NH- moiety, that -NH- moiety is optionally substituted with R60*;
R6a 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 on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that -NH- moiety is optionally substituted with R60*;
R6b in each occurrence is 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 on carbon with one or more R60, and wherein if said heterocyclyl contains an -NH- moiety, that
-NH- moiety is optionally substituted with R60*;
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,
-N(R10a)N(R10a)2, -NO2, -N(R10a)(OR10a), -O-N(R10a)2, -C(O)H, -C(O)R10b, -C(O)2R10a,
-C(O)N(R10a)2, -C(O)N(R10a)(OR10a), -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);
R10* in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b,
-S(O)2N(R10a)2, -C(R1Oa)=N(R1Oa), and -C(R10a)=N(OR10a);
R1Oa in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl;
R1Ob in each occurrence is independently selected from d_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,
-N(R20a)N(R20a)2, -NO2, -N(R20a)(OR20a), -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -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);
R20* in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b,
-S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a);
R20a in each occurrence is independently selected from H,
Figure imgf000113_0001
carbocyclyl, and heterocyclyl;
R20b in each occurrence is independently selected from
Figure imgf000113_0002
C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R30 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2.6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b,
-N(R30a)N(R30a)2, -NO2, -N(R30a)(OR30a), -O-N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a,
-C(O)N(R30a)2, -C(O)N(R30a)(OR30a), -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(R30a)=N(R30a), and -C(R30a)=N(OR30a);
R30* in each occurrence is independently selected from -CN, Ci-βalkyl, carbocyclyl, heterocyclyl, -OR30a, -N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2,
-S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a);
R30a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R30b in each occurrence is independently selected from Ci_6alkyl, 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,
-N(R40a)N(R40a)2, -NO2, -N(R40a)(OR40a), -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a,
-C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -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);
R40* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl, -OR40a, -N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a);
R40a in each occurrence is independently selected from H, d_6alkyl, carbocyclyl, and heterocyclyl;
R40b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R50 in each occurrence is independently selected from halo, -CN, C^alkyl, C2_6alkenyl,
C2.6alkynyl, carbocyclyl, heterocyclyl, -OR50a, -SR5Oa, -N(R50a)2, -N(R50a)C(O)R50b,
-N(R5Oa)N(R5Oa)2, -NO2, -N(R50a)(OR50a), -O-N(R50a)2, -C(O)H, -C(O)R50b, -C(O)2R50a,
-C(O)N(R50a)2, -C(O)N(R50a)(OR50a), -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);
R50* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl, -OR50a, -N(R50a)2, -C(O)H, -C(O)R50b, -C(O)2R50a, -C(O)N(R50a)2,
-S(O)R50b, -S(O)2R50b, -S(O)2N(R50a)2, -C(R5Oa)=N(R5Oa), and -C(R50a)=N(OR50a);
R50a in each occurrence is independently selected from H, C^alkyl, carbocyclyl, and heterocyclyl;
R50b in each occurrence is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R60 in each occurrence is independently selected from halo, -CN, Ci_6alkyl, C2_6alkenyl,
C2.6alkynyl, carbocyclyl, heterocyclyl, -OR60a, -SR60a, -N(R60a)2, -N(R60a)C(O)R60b,
-N(R60a)N(R60a)2, -NO2, -N(R60a)(OR60a), -O-N(R60a)2, -C(O)H, -C(O)R60b, -C(O)2R60a,
-C(O)N(R60a)2, -C(O)N(R60a)(OR60a), -OC(O)N(R60a)2, -N(R60a)C(O)2R60a,
-N(R60a)C(O)N(R60a)2, -OC(O)R60b, -S(O)R60b, -S(O)2R60b, -S(O)2N(R60a)2,
-N(R60a)S(O)2R60b, -C(R60a)=N(R60a), and -C(R60a)=N(OR60a);
R60* in each occurrence is independently selected from -CN, Ci_6alkyl, carbocyclyl, heterocyclyl, -OR60a, -N(R60a)2, -C(O)H, -C(O)R60b, -C(O)2R60a, -C(O)N(R60a)2,
-S(O)R60b, -S(O)2R60b, -S(O)2N(R60a)2, -C(R60a)=N(R60a), and -C(R50a)=N(OR60a);
R60a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl;
R60b 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 6-membered heteroaryl, wherein said 6-membered heteroaryl is optionally substituted with one or more R6; and R6 is halo.
3. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in either one of claim 1 or 2, wherein
D is C-R3;
E is selected from N and C-R4;
R3 is selected from H, halo, 5- or 6-membered heterocyclyl, and -NH2; and
R4 is -CN.
4. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein X is -NH-.
5. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, wherein R1* is Ci_6alkyl.
6. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein
R2 is selected from H, halo, C1-6alkyl, and -OR2a; and R2a is Ci_6alkyl.
7. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein
R5 is Ci_6alkyl, wherein said Ci_6alkyl is optionally substituted with one or more -OR5a; and
R5a is selected from Ci_6alkyl.
8. A compound of Formula (I) :
Figure imgf000116_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and
5 -fluoropyrimidin-2-yl;
D is C-R3;
E is selected from N and C-R4;
X is -NH-;
R1* is methyl;
R2 is selected from H, fluoro, and chloro;
R3 is selected from H, chloro, morpholin-4-yl, and -NH2;
R4 is -CN; and
R5 is selected from methyl and methoxymethyl.
9. A compound selected from:
5 -fluoro-2- { [ 1 -(5 -fluoropyrimidin-2-yl)ethyl] amino } -6-[( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- { [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] amino } -6-[( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- {[( Ii?)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] amino } -6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -chloro-Λ/2- [ 1 -(5 -fluoropyrimidin-2-yl)ethyl]-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-chloro-N2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5 -chloro-JV2- [(Ii?)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-fluoro-2- {[ 1 -(5-fluoropyridin-2-yl)ethyl]amino} -6-[(l -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5-fluoro-2- {[(IS)- 1 -(5 -fluoropyridin-2-yl)ethyl] amino } -6-[(l -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5 -fluoro-2- { [( Ii?)- 1 -(5 -fluoropyridin-2-yl)ethyl] amino } -6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
5-chloro-N2-[ 1 -(5-fluoropyridin-2-yl)ethyl]-Λ/4-(l -methyl- lH-imidazol-4-yl)pyrimidine-
2,4-diamine;
5 -chloro-JV2- [( 1 S)- 1 -(5 -fluoropyridin-2-yl)ethyl]-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-chloro-N2-[(li?)-l-(5-fluoropyridin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
2- { [ 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl]amino } -5 -fluoro-6- [( 1 -methyl- IH- imidazol-4-yl)amino]nicotinonitrile;
2- { [( Ii?)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] amino } -5 -fluoro-6-[( 1 -methyl- 1 H- imidazol-4-yl)amino]nicotinonitrile;
2- { [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] amino } -5 -fluoro-6- [( 1 -methyl- IH- imidazol-4-yl)amino]nicotinonitrile;
5 -chloro-JV2- [ 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ^-(l-methyl-lH- imidazol-4-yl)pyrimidine-2,4-diamine;
5 -chloro-N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] -Λ^-( 1 -methyl- IH- imidazol-4-yl)pyrimidine-2,4-diamine;
2- { [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] amino } -5 -fluoro-6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile; 2- { [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] amino } -5 -fluoro-6- [( 1 -methyl- lH-imidazol-4- yl)amino]nicotinonitrile;
2- {[( IR)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] amino } -5 -fluoro-6- [( 1 -methyl- 1 H-imidazol-4- yl)amino]nicotinonitrile;
5 -chloro-N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5 -chloro-N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ^-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
Λ/2-[l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2-[( IR)- 1 -(3 ,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ^-( 1 -methyl- lH-imidazol-4-yl)-
6-morpholin-4-ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-
6-morpholin-4-ylpyrimidine-2,4-diamine;
N2- [ 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-
4-ylpyrimidine-2,4-diamine;
Λ/2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)-6-morpholin-
4-ylpyrimidine-2,4-diamine;
N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -5 -fluoro-Λ/4^ 1 -methyl- lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2-[(15)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
Λ/2-[l-(5-fluoropyrimidin-2-yl)ethyl]-5-methoxy-Λ/4-(l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl]-5 -methoxy-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
N2 -[(IR)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -5 -methoxy-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
N2- [ 1 -(5 -fluoropyrimidin-2-yl)ethyl]-5 -methyl-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl]-5 -methy l-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
N2 -[(IR)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -5 -methyl-Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-fluoro-N2-[ 1 -(5 -fluoropyrimidin-2-yl)ethyl] -N4 -(I -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-fluoro-N2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5-fluoro-Λ/2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
5 -fluoro-N2-[( 1 S)- 1 -(5 -fluoropyridin-2-yl)ethyl] -Λ^-( 1 -methyl- lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
5-fluoro-Λ/2-[(15)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxyethyl]-5 -fluoro-Λ/4-( 1 -methyl- lH-imidazol-4- yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;
N2-[(li?)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-5-fluoro-Λ^-(l-methyl-lH- imidazol-4-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)-2-methoxy ethyl] -5 -fluoro-Λ/4^ 1 -methyl- IH- imidazol-4-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;
N2 -[(\ S)-I -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)pyrimidine-
2,4,6-triamine;
N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine;
N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4-yl)-6-morpholin-
4-ylpyrimidine-2,4-diamine; N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;
6-chloro-JV2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-JV2- [( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-N2-[( Ii?)- 1 -(3 ,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ^-( 1 -methyl- IH- imidazol-4-yl)pyrimidine-2,4-diamine;
6-chloro-N2-[(15)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-Λ^-(l-methyl-lH- imidazol-4-yl)pyrimidine-2,4-diamine;
6-chloro-N2-[ 1 -(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ/4-(l -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-N2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -5 -fluoro-Λ/4-( 1 -methyl- lH-imidazol-
4-yl)pyrimidine-2,4-diamine;
6-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ/4-(l-methyl-lH-imidazol-
4-yl)pyrimidine-2,4-diamine;
6-chloro-5-fluoro-Λ/2-[(15)-l-(5-fluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5-fluoro-Λ/2-[(li?)-l-(5-fluoropyridin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5 -fluoro-Λ/2-[( 1 S)- 1 -(5 -fluoropyrimidin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine;
6-chloro-5-fluoro-Λ/2-[(li?)-l-(5-fluoropyrimidin-2-yl)ethyl]-Λ/4-(l-methyl-lH-imidazol-
4-yl)pyrimidine-2,4-diamine;
6-chloro-N2-[(15)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-
4-yl)pyrimidine-2,4-diamine;
6-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-5-fluoro-Λ^-(l-methyl-lH-imidazol-
4-yl)pyrimidine-2,4-diamine;
6-chloro-N2- [ 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine; 6-chloro-JV2- [( 1 S)- 1 -(3 ,5 -difluoropyridin-2-yl)ethyl] -Λ/4-( 1 -methyl- lH-imidazol-4- yl)pyrimidine-2,4-diamine; and
6-chloro-N2-[(li?)-l-(3,5-difluoropyridin-2-yl)ethyl]-Λ^-(l-methyl-lH-imidazol-4- yl)pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.
10. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, for use as a medicament.
11. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for the treatment of cancer.
12. 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 9.
13. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, for use in the treatment of cancer in a warm-blooded animal such as man.
14. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
15. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, wherein said process is selected from:
Process A - reacting a compound of Formula (A):
Figure imgf000122_0001
Formula (A) with a compound of Formula (D):
Figure imgf000122_0002
Formula (B); and
Process B - reacting a compound of Formula (C)
Figure imgf000122_0003
Formula (C) with a compound of Formula (D)
Figure imgf000122_0004
Formula (D) 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 is a leaving group.
PCT/GB2009/051032 2008-08-19 2009-08-18 2-(imidaz0lylamin0)-pyridine derivatives and their use as jak kinase inhibitors WO2010020810A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118388A1 (en) 2013-02-04 2014-08-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for assaying jak2 activity in red blood cells and uses thereof
JP2014521673A (en) * 2011-08-01 2014-08-28 アルミラル・ソシエダッド・アノニマ Pyridin-2 (1H) -one derivatives as JAK inhibitors
WO2018167283A1 (en) 2017-03-17 2018-09-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the diagnosis and treatment of pancreatic ductal adenocarcinoma associated neural remodeling
WO2018189335A1 (en) 2017-04-13 2018-10-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the diagnosis and treatment of pancreatic ductal adenocarcinoma
EP3359154A4 (en) * 2015-10-08 2019-05-15 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
WO2020092015A1 (en) 2018-11-02 2020-05-07 University Of Rochester Therapeutic mitigation of epithelial infection
CN112094227A (en) * 2020-05-29 2020-12-18 凯美克(上海)医药科技有限公司 Synthesis method of 1- (5-chloro-3-fluoropyridin-2-yl) ethylamine
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme
US10975056B2 (en) 2016-06-13 2021-04-13 Glaxosmithkline Intellectual Property Development Limited Substituted pyridines as inhibitors of DNMT1

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082392A1 (en) * 2005-02-04 2006-08-10 Astrazeneca Ab Pyrazolylaminopyridine derivatives useful as kinase inhibitors
WO2007031745A1 (en) * 2005-09-16 2007-03-22 Astrazeneca Ab Pyrimidine derivatives for the inhibition of igf-ir tyrosine kinase activity
WO2007049041A1 (en) * 2005-10-28 2007-05-03 Astrazeneca Ab 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
WO2008117050A1 (en) * 2007-03-27 2008-10-02 Astrazeneca Ab Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082392A1 (en) * 2005-02-04 2006-08-10 Astrazeneca Ab Pyrazolylaminopyridine derivatives useful as kinase inhibitors
WO2007031745A1 (en) * 2005-09-16 2007-03-22 Astrazeneca Ab Pyrimidine derivatives for the inhibition of igf-ir tyrosine kinase activity
WO2007049041A1 (en) * 2005-10-28 2007-05-03 Astrazeneca Ab 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
WO2008117050A1 (en) * 2007-03-27 2008-10-02 Astrazeneca Ab Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014521673A (en) * 2011-08-01 2014-08-28 アルミラル・ソシエダッド・アノニマ Pyridin-2 (1H) -one derivatives as JAK inhibitors
WO2014118388A1 (en) 2013-02-04 2014-08-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for assaying jak2 activity in red blood cells and uses thereof
EP3359154A4 (en) * 2015-10-08 2019-05-15 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
US10450300B2 (en) 2015-10-08 2019-10-22 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
US10975056B2 (en) 2016-06-13 2021-04-13 Glaxosmithkline Intellectual Property Development Limited Substituted pyridines as inhibitors of DNMT1
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme
WO2018167283A1 (en) 2017-03-17 2018-09-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the diagnosis and treatment of pancreatic ductal adenocarcinoma associated neural remodeling
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WO2020092015A1 (en) 2018-11-02 2020-05-07 University Of Rochester Therapeutic mitigation of epithelial infection
CN112094227A (en) * 2020-05-29 2020-12-18 凯美克(上海)医药科技有限公司 Synthesis method of 1- (5-chloro-3-fluoropyridin-2-yl) ethylamine
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