WO2009027736A2 - Composés chimiques 000-1 - Google Patents

Composés chimiques 000-1 Download PDF

Info

Publication number
WO2009027736A2
WO2009027736A2 PCT/GB2008/050739 GB2008050739W WO2009027736A2 WO 2009027736 A2 WO2009027736 A2 WO 2009027736A2 GB 2008050739 W GB2008050739 W GB 2008050739W WO 2009027736 A2 WO2009027736 A2 WO 2009027736A2
Authority
WO
WIPO (PCT)
Prior art keywords
heterocyclyl
carbocyclyl
alkyl
occurrence
optionally
Prior art date
Application number
PCT/GB2008/050739
Other languages
English (en)
Other versions
WO2009027736A3 (fr
Inventor
Stephanos Ioannidis
Michelle Lamb
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2009027736A2 publication Critical patent/WO2009027736A2/fr
Publication of WO2009027736A3 publication Critical patent/WO2009027736A3/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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 genes which 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- J AK2, Bcr-JAK2 and PCM1-JAK2 translocations resulting in the fusion of the JAK2 kinase domain with an oligomerization domain, TEL- J AK2, Bcr-JAK2 and PCM1-JAK2
  • TEL- J AK2, Bcr-JAK2 and PCM1-JAK2 have been implicated in the pathogenesis of various hematologic malignancies (SD Turner and Alesander DR, Leukemia,
  • V617F valine-to- phenylalanine
  • the present invention provides compounds of Formula (I):
  • Typical 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, 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 autoimmune, inflammatory,
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma,
  • the present invention relates to compounds of Formula (I):
  • Ring A is selected from aromatic carbocyclyl and aromatic heterocyclyl, wherein said aromatic carbocyclyl and aromatic heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said aromatic heterocyclyl is optionally substituted with R 2 *;
  • R 1 is selected from H, halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )0R la , -0N(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R la , -C(0)
  • R lb in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2 in each occurrence is independently selected from H, halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • Ci ⁇ alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 3 is selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl,
  • R 3a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 3b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 4 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, 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
  • R 4c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 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 1Ob in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 a , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R a ;
  • R 1Oc in each occurrence is independently selected from C h alky!, 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 a , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R a* ;
  • R 20 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 -6alkynyl, 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 20b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 b , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R b* ;
  • R 20c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R b , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R b* ;
  • R 30 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 3Oa , -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 30 ⁇ 2 , -C(O)N(R 30a )(OR 30a ), -OC(O)N(R 30a ) 2 , -N(R 30a )C(O) 2 R 30a
  • R 30b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R c* ;
  • R 30c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R c ;
  • R 40 in each occurrence is independently selected from halo, -CN, C 1-6 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 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 d , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R a , R b , R c , and R d in each occurrence are independently selected from halo, -CN, C 1-6 alkyl,
  • R a *, R b *, R c *, and R d *in each occurrence are independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(0)R n , -C(O) 2 R 0 , -C(0)N(R m ) 2 , -S(O)R n , -S(O) 2 R n ,
  • R m in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R n in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R° in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl; and n is selected from 1, 2, 3, and 4.
  • C x _ y as used in terms such as C x _ y alkyl and the like indicates the numerical range of carbon atoms that are present in the group; for example, C ⁇ alkyl includes Qalkyl (methyl), C 2 alkyl (ethyl), Csalkyl (propyl and isopropyl) and C 4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-buty ⁇ ).
  • 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 - 6 alkenyl includes groups such as C 2 - 6 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 - 6 alkynyl includes groups such as C 2 - 6 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.
  • 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 examples include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, and phenyl, and tetralinyl.
  • 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 examples include 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, oxo- 1,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thi
  • Aromatic carbocyclyl refers to an aromatic mono or bicyclic carbon ring that contains 6 to 10 ring atoms.
  • Illustrative examples of “aromatic carbocyclyl” include indanyl, naphthyl, 1-oxoindanyl, and phenyl.
  • aromatic heterocyclyl is intended to refer to an aromatic mono or bicyclic ring containing 5 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
  • aromatic heterocyclyl include, but are not limited to, benzofuranyl, cinnolinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isoxazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridazinyl pyrimidinyl, pyridinyl, pyrrolyl, quinolinyl, quinoxalinyl, thiazolyl, and thiophenyl.
  • 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, C 1-6 alkyl; 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 acyl groups; 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 acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • the deprotection conditions for the above amino protecting groups necessarily vary with the choice of protecting group.
  • 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.
  • an acyl group such as a ⁇ -butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persul
  • 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).
  • 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.
  • R 2 in each occurrence is independently selected from H, halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -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(O) 2 R 2a
  • R 2a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 20 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl,
  • R 20* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 20a in each occurrence is independently selected from H, C h alky!, carbocyclyl, and heterocyclyl
  • RR 2200bb iinn eeaacchh occurrence is independently selected from C h alky!, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and R 20c in each occurrence is independently selected from C h alky!, carbocyclyl, and heterocyclyl.
  • Ring A is selected from aromatic carbocyclyl and aromatic heterocyclyl, wherein said aromatic carbocyclyl and aromatic heterocyclyl are optionally substituted on carbon with one or more R 2 ;
  • R 2 in each occurrence is independently selected from halo and -OR 2a ;
  • R 2a is Ci_ 6 alkyl.
  • Ring A is selected from phenyl and aromatic heterocyclyl, wherein said phenyl and aromatic heterocyclyl are optionally substituted on carbon with one or more R 2 ; R 2 in each occurrence is independently selected from halo and -OR 2a ; and R 2a is Ci-ealkyl.
  • Ring A is selected from indolyl, phenyl, pyrazolyl, and pyridinyl, wherein said indolyl, phenyl, pyrazolyl, and pyridinyl are optionally substituted on carbon with one or more R 2 ; and R 2 in each occurrence is independently selected from fluoro and methoxy.
  • Ring A is selected from lH-indol-5-yl, phenyl, lH-pyrazol-4-yl, pyridin-3-yl, and pyridin-4-yl, wherein said lH-indol-5-yl, phenyl, lH-pyrazol-4-yl, pyridin-3-yl, and pyridin-4-yl are optionally substituted on carbon with one or more R ; and R 2 in each occurrence is selected from fluoro and methoxy.
  • Ring A is selected from 3-fluorophenyl, 4-fluorophenyl, lH-indol-5-yl, 3-methoxyphenyl, 4-methoxyphenyl, lH-pyrazol-4-yl, pyridin-3-yl, and pyridin-4-yl.
  • R 1 is selected from ⁇ , halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )0R la , -0N(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R la , -C(O)N(R la ) 2 , -C(O)N(R la )(OR la ), -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(0)N(
  • C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more
  • R la in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R lb in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl,
  • R 10* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 1Oa in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from C h alky!, carbocyclyl, and heterocyclyl.
  • R 1 is -OR la ;
  • R ,1 l a a is Q-ealkyl.
  • R 1 is methoxy.
  • R 3 is selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -N(R 3a )-OR 3a ,
  • C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more
  • R 3a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 3b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 30 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 30* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 30a in each occurrence is independently selected from H, C h alky!, carbocyclyl, and heterocyclyl;
  • RR 3300bb iinn eeaacchh c occurrence is independently selected from C h alky!, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl; and R 30c in each occurrence is independently selected from C h alky!, carbocyclyl, and heterocyclyl.
  • R 3 is C h alky!.
  • R is methyl
  • n is selected from 0, 1, and 2.
  • R 4 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 4b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 4c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 40 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 40* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl; and n is selected from 1, 2, and 3.
  • R 4 is halo; and n is selected from 1, 2, and 3.
  • R 4 is halo; and n is 1.
  • R 4 is halo and in a position para to the C(R 4 )(NH) group; and n is 1.
  • R 4 is fluoro; and n is selected from 1, 2, and 3.
  • R 4 is fluoro; and n is 1.
  • R 4 is fluoro and in a position para to the C(R 4 )(NH) group; and n is 1.
  • Ring A is selected from aromatic carbocyclyl and aromatic heterocyclyl, wherein said aromatic carbocyclyl and aromatic heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said aromatic heterocyclyl is optionally substituted with R 2 *;
  • R 1 is selected from H, halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )0R la , -0N(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R la , -C(0)N(R la ) 2 , -C(0)N(R la )(0R la ), -0C(0)N(R la ) 2 , -N(R la )C(0) 2 R la , -N(R la )C(0) 2 R la , -N(R la )C(0) 2
  • R la in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R lb in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2 in each occurrence is independently selected from H, halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • Ci ⁇ alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 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 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 3 is selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl,
  • R 3a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 3b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 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 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 4 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, 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
  • R 4c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 10* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 1Oa in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 20* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • 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 C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 30* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 30a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 30c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 40* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • RR 4400aa iinn eeaacchh c occurrence is independently selected from H, C h alky!, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl; and n is selected from 1, 2, and 3.
  • Ring A is selected from aromatic carbocyclyl and aromatic heterocyclyl, wherein said aromatic carbocyclyl and aromatic heterocyclyl are optionally substituted on carbon with one or more R 2 ;
  • R 1 is -OR la ;
  • R la is Ci_ 6 alkyl
  • R 2 in each occurrence is independently selected from halo and -OR 2a ;
  • R 2a is Ci-ealkyl
  • R 3 is Ci-ealkyl
  • R 4 is halo; and n is 1.
  • Ring A is selected from phenyl and aromatic heterocyclyl, wherein said phenyl and aromatic heterocyclyl are optionally substituted on carbon with one or more R 2 ;
  • R 1 is -OR la ;
  • R la is Ci-ealkyl
  • R 2 in each occurrence is independently selected from halo and -OR 2a ;
  • R 2a is Ci-ealkyl
  • R 3 is Ci-ealkyl
  • R 4 is halo; and n is 1.
  • Ring A is selected from indolyl, phenyl, pyrazolyl, and pyridinyl, wherein said indolyl, phenyl, pyrazolyl, and pyridinyl are optionally substituted on carbon with one or more R 2 ;
  • R 1 is methoxy; R 2 in each occurrence is independently selected from fluoro and methoxy; R 3 is methyl; R 4 is fluoro; and n is 1.
  • Ring A is selected from 3-fluorophenyl, 4-fluorophenyl, lH-indol-5-yl,
  • R 1 is methoxy
  • R 3 is methyl
  • R 4 is fluoro; and n is 1.
  • the compound of Formula (I) is a compound of Formula (Ia):
  • Ring A, R 1 , R 3 , R 4 , and n are as defined hereinabove.
  • the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • the claims are not intended to be limited to the exemplified structures.
  • Typical compounds of Formula (I) are believed to have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinase are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • 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).
  • Amplified Luminescent Proximity Assay Alphascreen
  • 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).
  • 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.
  • Teween 20 is a registered trademark of ICI Americas, Inc.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and hematologic tumors), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof 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), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti-proliferative effect, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.
  • 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
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • 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).
  • the 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
  • 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 p-hydroxybenzoate; and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, 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.
  • 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.
  • 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 (PI3K) and for example inhibitors of mitogen activated protein kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (AbI) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (GleevecTM); and any agents that modify STAT signalling;
  • PI3K phosphotidylinositol 3-kinas
  • 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 ocv ⁇ 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 ocv ⁇ 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 transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory 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
  • 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 pharmaceutic ally- 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.
  • Leaving groups suitable for such a reaction include halo groups, such as chloro; tosylate; triflate; and phosphate.
  • Compounds of Formula (A) and compounds of Formula (B) may be reacted together under typical Suzuki Coupling conditions.
  • solvents suitable for such a reaction include dioxane and tetrahydrofuran.
  • the reaction may be performed in dry solvent, or with the addition of some water.
  • the reaction may advantageously proceed 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.
  • Examples of palladium catalysts suitable for such a reaction include tris(dibenzylideneacetone)dipalladium, and dichloro[l,l'-ferrocenylbis(diphenyl-phosphine)]palladium(II).
  • the reaction may be performed at a temperature in a range from 0 0 C to reflux, and heating the reaction may be particularly advantageous.
  • Process B - Compounds of Formula (C) and compounds of Formula (D) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • the reaction may advantageously occur in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction may be advantageously performed at a temperature in a range from 0 0 C to reflux. Heating the reaction may be particularly advantageous.
  • compounds of Formula (C) and compounds of Formula (D) may be reacted together under standard Buchwald conditions (for example see /. Am. Chem. Soc, 118, 7215; /. Am. Chem. Soc, 119, 8451; /. Org. Chem., 62, 1568 and 6066), with a suitable base.
  • suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ⁇ -butoxide.
  • Such a reaction may advantageously occur in the presence of a palladium catalyst such as palladium acetate.
  • solvents suitable for such a reaction include toluene, benzene, dioxane, and xylene.
  • the -NH- moiety of the compound of Formula (D) may advantageously be protected with a suitable protecting group, examples of which include protecting groups such as tert-butoxycarbonyl.
  • Process C - Compounds of Formula (E) and compounds of Formula (F) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (C) with compounds of Formula (D).
  • 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;
  • TLC liquid chromatography/mass spectroscopy
  • 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 DMS Od 6 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 manufacturers instruction 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 manufacturers instruction obtained from Biotage Inc, 1725 Discovery Drive Charlotteville, Virginia 22911, USA.
  • Glassson chromatography refers to chromatography using a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H 2 OMeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturers instruction obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A.
  • SFC super critical fluid chromatography
  • ASFC Analytical SFC
  • ASSC Analytical SFC System with Diode Array Detector
  • Preparative SFC APS- 1000 AutoPrep Preparative SFC
  • Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psi) and temperatures to 80 0 C.
  • reaction stirred at room temperature and maintained inside pressure between 120-150 psi for
  • the hydrochloride salt may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvents gave the hydrochloride salt of the title compound as a tan solid.
  • a microwave reaction vessel was charged with 6-chloro- ⁇ f 2 -[(lS)-l-(5-fluoropyridin-2-yl)ethyl]- ⁇ -(5-methoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (Intermediate 8, 100 mg, 0.275 mmol), pyridin-4-ylboronic acid (42 mg, 0.275 mmol), sodium carbonate (88 mg, 0.826 mmol) and dichloro[l,r-ferrocenylbis(diphenyl-phosphine)]palladium(II) (20 mg, 0.028 mmol).
  • a microwave reaction vessel was charged with 6-chloro- ⁇ f 2 -[(lS)-l-(5-fluoropyridin-2-yl)ethyl]- ⁇ / 4 -(5-methoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (Intermediate 8, 100 mg, 0.275 mmol), (3-methoxyphenyl)boronic acid (42 mg, 0.275 mmol), sodium carbonate (88 mg, 0.826 mmol), and dichloro[l,l'-ferrocenylbis(diphenyl-phosphine)]palladium(II) (20 mg, 0.028 mmol).
  • the title compound was prepared using a procedure similar to the one described for the synthesis of Example 2, using pyridin-3-ylboronic acid and 6-chloro- N 2 -[(1S)-1-(5-fluoropyridin-2- yl)ethyl]-N 4 -(5-methoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (Intermediate 8) as starting materials.
  • the title compound was prepared using a procedure similar to the one described for the synthesis of Example 2, using (3-fluorophenyl)boronic acid and 6-chloro-N 2 -[(1S)-1-(5-fluoropyridin-2- yl)ethyl]-N 4 -(5-methoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (Intermediate 8) as starting materials.
  • the title compound was prepared using a procedure similar to the one described for the synthesis of Example 2, using lH-indol-5-ylboronic acid and 6-chloro-N 2 -[(1S)-1-(5-fluoropyridin-2- yl)ethyl]-N 4 -(5-methoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (Intermediate 8) as starting materials.

Abstract

La présente invention concerne des composés de formule (I) et leurs sels, des compositions pharmaceutiques de ceux-ci ainsi que leurs procédés d'utilisation et de préparation. Ces composés permettent de traiter des troubles myéloprolifératifs et le cancer.
PCT/GB2008/050739 2007-08-27 2008-08-27 Composés chimiques 000-1 WO2009027736A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US96828207P 2007-08-27 2007-08-27
US60/968,282 2007-08-27

Publications (2)

Publication Number Publication Date
WO2009027736A2 true WO2009027736A2 (fr) 2009-03-05
WO2009027736A3 WO2009027736A3 (fr) 2009-04-23

Family

ID=40303514

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050739 WO2009027736A2 (fr) 2007-08-27 2008-08-27 Composés chimiques 000-1

Country Status (1)

Country Link
WO (1) WO2009027736A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013004332A1 (fr) * 2011-07-07 2013-01-10 Merck Patent Gmbh Azahétérocycles substitués pour le traitement du cancer
US8501936B2 (en) 2009-06-05 2013-08-06 Cephalon, Inc. Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
JP2014521673A (ja) * 2011-08-01 2014-08-28 アルミラル・ソシエダッド・アノニマ Ｊａｋ阻害剤としてのピリジン−２（１ｈ）−オン誘導体
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
JP2015503571A (ja) * 2012-01-06 2015-02-02 アジオス ファーマシューティカルズ， インコーポレイテッド 治療活性化合物およびその使用方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040214814A1 (en) * 2000-12-21 2004-10-28 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
WO2006074057A2 (fr) * 2004-12-30 2006-07-13 Exelixis, Inc. Modulateurs de kinase et procedes d'utilisation
WO2006115452A1 (fr) * 2005-04-27 2006-11-02 Astrazeneca Ab Utilisation des derives de la pyrazolyl-pyrimidine dans le traitement de la douleur
WO2006123113A2 (fr) * 2005-05-16 2006-11-23 Astrazeneca Ab Composes chimiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040214814A1 (en) * 2000-12-21 2004-10-28 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
WO2006074057A2 (fr) * 2004-12-30 2006-07-13 Exelixis, Inc. Modulateurs de kinase et procedes d'utilisation
WO2006115452A1 (fr) * 2005-04-27 2006-11-02 Astrazeneca Ab Utilisation des derives de la pyrazolyl-pyrimidine dans le traitement de la douleur
WO2006123113A2 (fr) * 2005-05-16 2006-11-23 Astrazeneca Ab Composes chimiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG TAO ET AL: "Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases." JOURNAL OF MEDICINAL CHEMISTRY 14 AUG 2008, vol. 51, no. 15, 14 August 2008 (2008-08-14), pages 4672-4684, XP002514102 ISSN: 1520-4804 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501936B2 (en) 2009-06-05 2013-08-06 Cephalon, Inc. Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
US8633173B2 (en) 2009-06-05 2014-01-21 Cephalon, Inc Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
US9156797B2 (en) 2010-10-06 2015-10-13 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9199962B2 (en) 2011-07-07 2015-12-01 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
WO2013004332A1 (fr) * 2011-07-07 2013-01-10 Merck Patent Gmbh Azahétérocycles substitués pour le traitement du cancer
AU2012280725B2 (en) * 2011-07-07 2017-02-02 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
JP2014520767A (ja) * 2011-07-07 2014-08-25 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング がんの処置のための置換されたアザ複素環
JP2014521673A (ja) * 2011-08-01 2014-08-28 アルミラル・ソシエダッド・アノニマ Ｊａｋ阻害剤としてのピリジン−２（１ｈ）−オン誘導体
JP2017075193A (ja) * 2012-01-06 2017-04-20 アジオス ファーマシューティカルズ， インコーポレイテッド 治療活性化合物およびその使用方法
JP2015503571A (ja) * 2012-01-06 2015-02-02 アジオス ファーマシューティカルズ， インコーポレイテッド 治療活性化合物およびその使用方法

Also Published As

Publication number Publication date
WO2009027736A3 (fr) 2009-04-23

Similar Documents

Publication Publication Date Title
AU2008247159B2 (en) 9-(pyrazol- 3 -yl) -9H- purine-2 -amine and 3-(pyrazol-3-yl) -3H-imidazo [4,5-B]pyridin-5-amine derivatives and their use for the treatment of cancer
EP1945631B1 (fr) Derives 4-(3-aminopyrazole)pyrimidine et leur utilisation en tant qu' inhibiteurs de tyrosine kinases dans le cadre d un traitement anticancereux
WO2008129255A1 (fr) Dérivés de 5-aminopyrazol-3-yl-3h-imidazo[4,5-b]pyridine et leur utilisation pour le traitement du cancer
AU2009259026B2 (en) Tricyclic 2,4-diamin0-L,3,5-triazine derivatives useful for the treatment of cancer and myeloproliferative disorders
WO2008132502A1 (fr) Pyrimidines substitués par pyrazolyle-amino et leur utilisation dans le traitement du cancer
WO2008117050A1 (fr) Pyrazines pyrazolyl-amino substituées et utilisation de ces composés pour le traitement du cancer
WO2009013545A2 (fr) Composés chimiques
WO2009016410A2 (fr) Composés chimiques 831
US20110201628A1 (en) Heterocyclic jak kinase inhibitors
EP2152702B1 (fr) Dérivés d'amino-thiazolyl-pyrimidine et leur utilisation pour le traitement du cancer
WO2010020810A1 (fr) Dérivés de 2-(imidazolylamino)-pyridine et leur utilisation en tant qu'inhibiteurs de la jak kinase
EP2601186A2 (fr) 4-(1h-indol-3-yl)-pyrimidines en tant qu'inhibiteurs d'alk
WO2009027736A2 (fr) Composés chimiques 000-1
WO2009007753A2 (fr) Composés chimiques 916-1
WO2009095712A2 (fr) Composés chimiques

Legal Events

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

Ref document number: 08788710

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08788710

Country of ref document: EP

Kind code of ref document: A2