WO2011075613A1 - Dérivés d'azaindole, leur préparation et leur application thérapeutique - Google Patents

Dérivés d'azaindole, leur préparation et leur application thérapeutique Download PDF

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WO2011075613A1
WO2011075613A1 PCT/US2010/060910 US2010060910W WO2011075613A1 WO 2011075613 A1 WO2011075613 A1 WO 2011075613A1 US 2010060910 W US2010060910 W US 2010060910W WO 2011075613 A1 WO2011075613 A1 WO 2011075613A1
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phenyl
methyl
pyrrolo
piperazin
chloro
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PCT/US2010/060910
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English (en)
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Christopher Arendt
Claude Barberis
Mikhail Levit
Tahir Nadeem Majid
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Sanofi
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • N-substituted azaindole derivatives and methods of preparation and use thereof.
  • Pim kinases encompassing Pim-1 , Pim-2, and Pim-3, form a distinct family of serine/threonine kinases, and have a functional role in cell growth, differentiation and apoptosis.
  • One of the mechanisms by which Pim kinases may enhance survival of cancer cells and promote the progression of cancer is through modulation of the activity of BAD, a key regulator of apoptosis.
  • the Pim kinases are highly homologous to each other and demonstrate similar oncogenic behavior.
  • Pim kinases particularly Pim-1 and Pim-2, were found to be abnormally expressed in a variety of hematological malignancies.
  • Amson et al. report the overexpression of Pim-1 in acute myeloid leukemia and acute lymphoid leukemia, and that Pim-1 overexpression appears to result from inappropriate activation in diverse leukemias ⁇ Proc. Natl. Acad. Sci., Vol. 86., 8857-8861 (1989)).
  • Studies have shown Pim-1 overexpression in primary and metastatic CNS lymphoma, an aggressive form of non-Hodgkin lymphoma (Rubenstein et al., Blood, Vol. 107, No. 9, 3716-3723 (2006)).
  • Pim-2 overexpression in B-cell chronic lymphocytic leukemia also found Pim-2 overexpression in B-cell chronic lymphocytic leukemia, and suggest that Pim-2 upregulation may be associated with more aggressive disease progression (Leukemia, 20, 1774-1782 (2006)).
  • Abnormal expression of Pim-1 and Pim-2 have been linked to multiple myeloma (Claudio et al., Blood, v. 100, No.6, 2175-2186 (2002)).
  • Pim-1 Hypermutations of Pim-1 have been identified in diffuse large cell lymphomas (Pasqualucci et al., Nature, Vol. 412, 2001 , pp. 341 -346 (2001 )) and nodular- lymphocyte-predominant and classic Hodgkin lymphoma (Liso et al., Blood, Vol. 108, No. 3, 1013-1020 (2006)).
  • An acquired mutation in Pim-1 was also recently described in an AML patient. (Akagi et al., Haematologica, 94(9) 1301 -1306 (2009). Pogacic et al.
  • Pim-1 upregulation in patients with prostate carcinoma and in high grade prostatic intraepithelial neoplasia (precancerous lesions) (The Prostate, (60) 367-371 (2004)), while Dai et al. suggest that overexpression of Pim-2 in prostate cancer is associated with more aggressive clinical features (The Prostate, 65:276-286 (2005)).
  • Xie et al. found the 44kDa Pim-1 (Pim-1 L) significantly upregulated in human prostate tumor specimens, and indicate that Pim-1 L has an anti-apoptotic effect on human prostate cancer cells in response to chemotherapeutic drugs ⁇ Oncogene, 25, 70-78 (2006)). Pim-1 is also involved in hypoxia-induced chemoresistance of sold malignancies (Chen et al., Oncogene, 1 -12 (2009)).
  • Pim-2 is linked to perineural invasion (PNI), wherein cancer cells wrap around nerves, often found in certain cancers such as prostate, pancreatic, bile duct and head and neck cancers (Ayala et al., Cancer Research, 64, 6082 - 6090 (2004)).
  • PNI perineural invasion
  • Pim-3 is aberrantly expressed in human and mouse hepatocarcinomas and human pancreatic cancer tissues (Cancer Res. 66 (13), July 1 , 2006, 6741 -6747 (2006)).
  • Aberrant Pim-3 expression was also observed in gastric adenoma and metastasis sites of gastric carcinoma (Zheng et al., J Cancer Res Clin Oncol, 134:481 -488 (2008)).
  • inhibitors of Pim kinases are useful for the therapeutic treatment of diseases caused by abnormalities of the regulation of cell proliferation, such as cancer, including leukemias, lymphomas, myelomas, and various solid tumors, including head and neck cancers, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, and oral cancer, for example, and for the treatment of hypoxia chemoresistance. Because cancer remains a disease for which the existing treatments are insufficient, there is a clear need to identify novel inhibitors of Pim kinases that are effective for the treatment of cancer.
  • cancer including leukemias, lymphomas, myelomas, and various solid tumors, including head and neck cancers, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, and oral cancer, for example, and for the treatment of hypoxia chemoresistance. Because cancer remains a disease for which the existing treatments are insufficient, there is a clear need to identify novel inhibitors of Pim kinases that are effective for the treatment
  • Ri is a radical selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxycarbonylalkyl, aryl, heteroaryl, alkylsulfonyl, sulfonamide, carboxamide, carboxamidealkyl, urea, and -NHR a ;
  • R 2 is a radical selected from the group consisting of a substituted aryl and a substituted heteroaryl, wherein said aryl and heteroaryl substituents are one or more radicals independently selected from the group consisting of alkoxy, hydroxyalkyl, - NR b R c , -alk-NR b R c , -cycloalkylene-NR b R c , -alkoxy-NR b R c , -alkylene-cycloalkylene- NRbRc, -alklyene-NR b -alkylene-NRcRd, a substituted or unsubstituted heterocyclic radical, and a substituted or unsubstituted heterocyclylalkyi radical; wherein said heterocyclic radical and heterocyclylalkyi radical substituents are independently selected from the group consisting of alkyl, cycloalkyl, amino, monoalkylamino, dialkylamino, alkyl
  • R 3 is a radical selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted bicyclic heteroaryl group; when said phenyl, heteroaryl, and bicyclic heteroaryl groups represented by R 3 are substituted, the substituents are one or more radicals independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, cycloalkylalkoxy, halogen, haloalkyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, carbamate, sulfonamide, sulfonamide-alkyl, -(CH 2 ) m -NR b R c , -alk
  • R is a radical selected from the group consisting of hydrogen, halogen, haloalkyl, NR b Rc, cyano, and alkynyl;
  • R5 is a radical selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, and cyano;
  • R6 is a radical selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl and cyano;
  • R 7 is a radical selected from the group consisting of hydrogen and alkyl
  • R a is a radical selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and cycloalkylcarbonyl;
  • Rb, Rc, and Rd are radicals independently selected from the group consisting of hydrogen and alkyl
  • n is selected from 0, 1 , and 2;
  • compositions comprising a pharmaceutically effective amount of one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
  • the compounds of Formula (I) above, their isomers and pharmaceutically acceptable salts exhibit selective inhibitory activity against one or more Pim kinase and are useful in the treatment of cancers associated with Pim kinases.
  • alkyl means a straight or branched aliphatic hydrocarbon group having 1 to about 12 carbon atoms in the chain. In one aspect, an alkyl has 1 to about 6 carbon atoms in the chain.
  • Lower alkyl means an alkyl group having 1 to about 4 carbon atoms in a linear alkyl chain that may be straight or branched. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • alk denotes an alkyl group, unless divalency is indicated, in which case the “alk” denotes the corresponding alkylene group(s).
  • alkyl(ci-c6) denotes an alkyl group having one to six carbon atoms.
  • alkyl(ci-c4) denotes an alkyl group having one to four carbon atoms.
  • Exemplary alkyl includes methyl, ethyl, / ' -propyl, i-butyl, and the like.
  • alkenyl means a straight or branched-chain aliphatic hydrocarbon group having 2 to about 12 carbon atoms in a chain which contains at least one carbon- carbon double bond. Such alkenyl moieties may exist in the E or Z configurations; the compounds provided herein include both configurations.
  • an alkenyl moiety has 2 to about 10 carbon atoms in the chain. In another aspect, an alkenyl moiety has 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl” means 2 to about 4 carbon atoms in the chain that may be straight or branched.
  • Exemplary alkenyl includes ethenyl, propenyl, n- butenyl, / ' -butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and the like.
  • alkoxy means an alkyl-O- group wherein the alkyl group is as herein described.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, / ' -propoxy, n-butoxy, f-butoxy, heptoxy, and the like.
  • alkynyl means a straight or branched-chain aliphatic hydrocarbon group having 2 to about 12 carbon atoms in the chain containing at least one carbon- carbon triple bond. In one aspect, an alkynyl has 2 to about 10 carbon atoms in the chain. In another aspect, an alkynyl has 2 to about 6 carbon atoms in the chain. "Lower alkynyl” means an alkynyl having 2 to about 4 carbon atoms in a linear alkynyl chain that may be straight or branched. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • Exemplary alkynyl includes ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
  • alkylene means a straight or branched bivalent hydrocarbon chain having from 1 to about 12 carbon atoms. In one aspect, an alkylene has 1 to about 10 carbon atoms in the chain. In another aspect, an alkylene has 1 to about 6 carbon atoms in the chain. A “lower alkylene” is an alkylene having from 1 to about 4 carbon atoms. Exemplary alkenylene includes methylene, ethylene, propylene, and butylene.
  • alkoxyalkyi means an alkyl-O-alkylene- wherein the alkyl and the alkylene are as herein described. Exemplary alkoxyalkyi groups include methoxymethylene and ethoxymethylene.
  • exemplary alkylcarbonyl moieties include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, and pentylcarbonyl.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, f-butyloxycarbonyl, and the like.
  • alkoxycarbonylalkyl means an alkoxycarbonyl-alkylene- group, wherein the alkoxycarbonyl and alkylene are as previously described.
  • alkylsulfinyl means an alkyl-SO- group in which the alkyl group is as previously described.
  • an alkylsulfinyl is an alkyl (C i-c6 ) -sulfinyl.
  • Exemplary alkylsulfinyl groups include CH 3 -SO-.
  • alkylsulfonyl means an alkyl-SCV group in which the alkyl group is as previously described.
  • an alkylsulfonyl is an alkyl (C i -c6 ) -sulfonyl.
  • Exemplary alkylsulfonyl include CH3-SO2- and CH3CH2-SO2-.
  • alkylthio means an alkyl-S- group in which the alkyl group is as previously described. Exemplary alkylthio includes CH 3 -S-.
  • aminoalkyl means a NH 2 -alkylene- wherein the alkylene is as herein described.
  • aminocycloalkyl means a NH 2 -cycloalkylene- wherein the cycloalkylene is as herein described.
  • aminocycloalkylalkyl means a Nh -cycloalkylene-alkylene- wherein the cycloalkylene and alkylene are as herein described.
  • aroyl means an aryl-CO- group wherein the aryl group is as herein described.
  • exemplary aroyl includes benzoyl, 1 -and 2-naphthoyl, and the like.
  • aryl whether used alone or with other terms, such as “aryl group”, “aryl radical”, “aryl ring”, and the like, means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms. In one aspect, aryl includes about 6 to about 10 carbon atoms. Exemplary aryl include phenyl and naphthyl.
  • arylalkyl means aryl-alkylene- in which the aryl and alkylene moieties are as previously described.
  • an arylalkyl is a aryl-alkyl (C i-c6)- moiety.
  • exemplary arylalkyl includes benzyl, 2-phenethyl and 1 - or 2-naphthalenemethyl.
  • arylalkoxy means arylalkyl-O- in which the arylalkyl group is as previously described. Exemplary arylalkoxy includes benzyloxy and 1 - or 2-naphthalenemethoxy.
  • arylalkylthio means arylalkyl-S- in which the arylalkyl group is as previously described.
  • exemplary arylalkylthio includes benzylthio.
  • aryloxy means an aryl-O- in which the aryl group is as previously described. Exemplary aryloxy includes phenoxy and 1 - or 2-naphthoxy.
  • arylsulfinyl means aryl-SO- in which the aryl group is as previously described. Exemplary arylsulfinyl includes phenylsulfinyl and 1 - or 2-naphthylsulfinyl.
  • arylsulfonyl means aryl-S02- in which the aryl group is as previously described.
  • exemplary arylsulfonyl includes phenylsulfonyl and 1 - or 2- naphthylsulfonyl.
  • arylthio means aryl-S- in which the aryl group is as previously described.
  • exemplary arylthio includes phenylthio and 1 - or 2-naphthylthio.
  • benzyl means phenyl-CH 2 -.
  • bicyclic heteroaryl mean a stable nine or ten member bicyclic heteroaromatic ring system which consists of carbon atoms and at least one hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Included within the scope of the definition of bicyclic heteroaryl are bicyclic ring systems wherein only one of the rings is aromatic. Examples include benzo(b)thienyl, benzofuranyl, 2,3- dihydrobenzofuran, benzo[1 ,3]dioxolyl, quinolinyl, isoquinolinyl and quinazolinyl.
  • cancer in a patient refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.
  • Cancer cells may be in the form of a tumor; may exist alone within a patient; may circulate in the blood stream as independent cells, such as leukemic cells; or be in the form of cancer cells with stem-cell like properties, such as leukemic stem cells.
  • a substituted carbamate, as used herein, refers to a carbamate wherein either R' or R" or both are further substituted with the indicated substituents.
  • a substituted carboxamide refers to a carboxamide wherein either R' or R" or both are further substituted with the indicated substituents.
  • carboxam ideal kyl means a carboxamide-alkyl- group in which the carboxamide and alkyl are as defined herein.
  • cycloalkyi means a non-aromatic monocyclic saturated ring system of 3 to about 10 carbon atoms, preferably of 3 to about 6 carbon atoms. Preferred ring systems include about 5 to about 6 ring atoms. Exemplary cycloalkyi include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • cycloalkylalkyl means a cycloalkyl-alkylene- group in which the cycloalkyi and alkylene are as defined herein.
  • cycloalkylalkoxy means a cycloalkyl-alkoxy- group in which the cycloalkyi and alkoxy are as defined herein.
  • cycloalkylene means a bivalent cycloalkyi group as defined herein having 3 to about 8 carbon atoms. Preferred ring sizes of the cycloalkylene include 3 to about 6 ring atoms, and such preferred ring sizes systems are also referred to as "lower”.
  • the points of binding on the cycloalkylene group include 1 ,1 -, 1 ,2-, 1 ,3-, or 1 ,4- binding patterns, and where applicable the stereochemical relationship of the points of binding is either cis or trans.
  • Exemplary monocyclic cycloalkylene includes (1 ,1 -, 1 ,2-, or 1 ,3-)cyclohexylene and (1 ,1 - or 1 ,2-)cyclopentylene.
  • dialkylamino means (alkyl)2-N-, wherein the alkyl groups, which may be the same or different, are as herein defined.
  • Dialkylamino groups include (alkyl ( ci- C6))2-N-, wherein the alkyl groups may be the same or different.
  • Exemplary dialkylamino groups include dimethylamino, diethylamino and methylethylamino.
  • dialkylaminoalkyl means (alkyl) 2 -N-alkylene-, wherein the alkyl groups may be the same or different, and the alkyl and alkylene groups are as herein defined.
  • Dialkylaminoalkyl groups include (alkyl (C i -c6))2-N-alkylene-, wherein the alkyl groups may be the same or different.
  • dialkylaminocycloalkyl means an (alkyl) 2 -N-cycloalkylene- wherein the alkyl groups may be the same or different, and the alkyl and cycloalkylene groups are as herein described.
  • dialkylaminocycloalkylalkyl means an (alkyl) 2 -N-cycloalkylene-alkylene, wherein the alkyl groups may be the same or different, and the alkyl, cycloalkylene, and alkylene groups are as herein described.
  • halo or “halogen” mean fluoro, chloro, bromo, or iodo. In some embodiments, halogens are fluoro and chloro.
  • haloalkoxy means an alkoxy substituted by one to three halogens. In some embodiments, haloalkoxy groups are lower alkoxy groups substituted by one to three halogens. Exemplary haloalkoxy groups include -0-CF 3 , -O-CH 2 CHF 2 , and - O-CF2CF3.
  • haloalkyl means an alkyl substituted by one or more halo groups. In some embodiments, haloalkyl groups are lower alkyl substituted by one to three halogens.
  • haloalkyl groups include -CF 3 , -CH 2 CHF 2 , and -CF 2 CF 3 .
  • heteroaryl whether used alone or with other terms, such as “heteroaryl group”, “heteroaryl radical”, “heteroaryl ring”, and the like, means a 5- to 6-membered aromatic cyclic group having at least one carbon atom and at least one hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • the designation of the aza, oxa or thia as a prefix before heteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide.
  • a heteroaryl When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer where such hydroxy substituted heteroaryl is capable of such.
  • Exemplary heteroaryl includes pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1 ,2,4-thiadiazolyl, pyridazinyl, 1 ,2,4-triazinyl, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl, triazolyl, and the like.
  • heteroarylalkyl means a heteroaryl-alkylene- group in which the heteroaryl and alkylene moieties are as previously described.
  • heteroarylalkyl groups contain an alkyl (C i -c4) moiety.
  • heteroarylalkoxy means a heteroaryl-alkyl-O- group in which the heteroarylalkyl group is as previously described.
  • heteroaryloxy means a heteroaryl-O- group in which the heteroaryl group is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • heterocyclyl means a 4-, 5-, or 6-membered aromatic (heteroaryl) or non- aromatic monocyclic ring system having at least one carbon atom and at least one hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • the designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • the nitrogen atom of a heterocyclyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heterocyclyl may also be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide.
  • exemplary heterocyclyl groups include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3-dioxolanyl, 1 ,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • a "substituted heterocyclyl,” as used herein, may be a heterocyclylene as defined herein.
  • heterocyclylene refers to a heterocyclyl radical that is further substituted and acts as a linking group, wherein the heterocyclyl is substituted at any heteroatom or carbon atom which results in the creation of a stable structure.
  • exemplary monocyclic heterocyclylene includes (3,3-)tetrahydrothiophenyl and (1 ,3-) or (1 ,4- )piperidinyl.
  • heterocyclylalkyl means a heterocyclyl-alkylene- group in which the heterocyclyl and alkylene moieties are as previously described.
  • a substituted heterocyclylalkyl refers to a heterocyclyl-alkylene wherein the alkylene is further substituted with the indicated substituents or a heterocyclylene- alkylene wherein the heterocyclylene or both the heterocyclylene and alkylene are further substituted with the indicated substituents.
  • hydroxyalkyl means an HO-alkylene- group, in which the alkylene is as previously defined.
  • exemplary hydroxyalkyl include HO-CH 2 - and HO-CH 2 -CH 2 -.
  • hydroxycycloalkyl means a radical of the formula HO-cycloalkylene, wherein cycloalkylene is as herein described.
  • hydroxycycloalkylalkyl means a radical of the formula HO-cycloalkylene- alkylene-, wherein cycloalkylene and alkylene are as herein described.
  • monoalkylamino means a radical of the formula alkyl-NH-, wherein the alkyl group is as herein defined.
  • a monoalkylamino is an alkyl ( ci-c6)- amino-.
  • Exemplary monoalkylamino groups include methylamino and ethylamino.
  • monoalkylaminoalkyl means an alkyl-NH-alkylene- group, wherein the alkyl and alkylene groups are as herein defined.
  • a monoalkylamino is an alkyl(ci-c6)-anninoalkylene-.
  • monoalkylaminocycloalkyl means an alkyl-NH-cycloalkylene- wherein alkyl and cycloalkylene are as herein described.
  • monoalkylaminocycloalkylalkyl means an alkyl-NH-cycloalkylene-alkylene- wherein alkyl, cycloalkylene, and alkylene are as herein described.
  • sulfonamide refers to a radical or substituent of the formula -SO 2 N R'R" or -NR'S0 2 R", wherein R' and R" are as herein described.
  • sulfonamide-alkyl refers to a radical or substituent of the formula - alkylene-S0 2 NR'R" or -alkylene-NR'S0 2 R", wherein R', R", and alkylene are as herein described.
  • treating means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to slow the appearance of symptoms of the named disorder or condition.
  • treatment refers to the act of treating.
  • treating cancer means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, leukemic stem cells, or other cancer-causing or neoplastic cells in a patient.
  • a method of treating when applied to, for example, cancer, refers to a procedure or course of action that is designed to reduce, eliminate, or inhibit the progression of the number of cancer cells in a patient; to induce differentiation of cancer cells or sensitize cancer cells to other therapeutic agents in a patient; and/or to alleviate the symptoms of a cancer.
  • therapeutically effective amount or “effective amount” means the amount of the subject compound, composition or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • “Pharmaceutically acceptable salts,” as used herein, refers to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of Formula (I). These salts can be prepared in situ during the final isolation and purification of the compounds. Some of the compounds provided herein are basic, and such compounds are useful in the form of the free base, or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acid addition salts are a convenient form for use; and in practice, use of the salt form in essence amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions.
  • acid addition salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Pharmaceutically acceptable salts include those derived from mineral acids and organic acids. See, for example S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., (66), 1 -19 (1977).
  • base addition salts may be formed and are simply a convenient form for use; and in practice, use of the salt form in essence amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations.
  • Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base derived from alkali and alkaline earth metal salts and isolating the salt thus formed.
  • salts of compounds provided herein are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • the compounds provided herein may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of formula (I) may also exhibit geometrical isomerism. It is to be understood that the compounds provided herein include individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods. Chiral chromatography techniques represent one means for separating isomers from mixtures thereof. Some compounds may be separated by chiral recrystallization techniques as an alternative means for separating isomers from mixtures thereof. Individual isomeric compounds can also be prepared by employing, where applicable, chiral precursors.
  • Ri is a radical selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxycarbonylalkyl, aryl, heteroaryl, alkylsulfonyl, sulfonamide, carboxamide, carboxamidealkyl, urea, and -
  • R 2 is a radical selected from the group consisting of a substituted aryl and a substituted heteroaryl, wherein said aryl and heteroaryl substituents are one or more radicals independently selected from the group consisting of alkoxy, hydroxyalkyl, - NRbRc, -alk-NR b R c , -cycloalkylene-NR b R c , -alkoxy-NR b R c , -alkylene-cycloalkylene- NRbRc, -alklyene-NRb-alkylene-NRcRd, a substituted or unsubstituted heterocyclic radical, and a substituted or unsubstituted heterocyclylalkyl radical; wherein said heterocyclic radical and heterocyclylalkyl radical substituents are independently selected from the group consisting of alkyl, cycloalkyl, amino, monoalkylamino, dialkylamino, alkylcarbonyl,
  • R 3 is a radical selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted bicyclic heteroaryl group; when said phenyl, heteroaryl, and bicyclic heteroaryl groups represented by R3 are substituted, the substituents are one or more radicals independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, cycloalkylalkoxy, halogen, haloalkyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, alkyl sulfonyl, alkylsulfinyl, carbamate, sulfonamide, sulfonamide-alkyl, -(CH2) m -NR b R c , -alkoxy
  • R 4 is a radical selected from the group consisting of hydrogen, halogen, haloalkyl, NR R c , cyano, and alkynyl;
  • R 5 is a radical selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, and cyano;
  • R 6 is a radical selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl and cyano;
  • R 7 is a radical selected from the group consisting of hydrogen and alkyl
  • R a is a radical selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and cycloalkylcarbonyl;
  • Rb, Rc, and Rd are radicals independently selected from the group consisting of hydrogen and alkyl;
  • n is selected from 0, 1 , and 2; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein Ri is alkyl; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein Ri is methyl; or a pharmaceutically acceptable salt thereof.
  • R 2 is a substituted aryl or heteroaryl radical selected from the group consisting of phenyl, pyridine, benzofuran, pyrazole, oxazole, and indole; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein R 2 is a phenyl substituted with a substituted or unsubstituted heterocyclic radical; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein R 2 is a phenyl para-substituted with a substituted or
  • R 2 is a phenyl or pyridine radical, wherein said phenyl or pyridine radical is substituted with a substituted or unsubstituted piperazinyl; or a
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein R 3 is a substituted or unsubstituted radical selected from the group consisting of phenyl, pyridine, pyrimidine, dihydrobenzo[b]furan, thiophene, benzo[1 ,3]dioxolyl, and pyrazole; or a pharmaceutically acceptable salt thereof.
  • R 3 is a substituted or unsubstituted radical selected from the group consisting of phenyl and pyridine; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein R 4 is halogen; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the compounds provided herein are the compounds of Formula (I) wherein R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • Ri is alkyl
  • R 2 is a phenyl para-substituted with a substituted or unsubstituted piperidine radical
  • R 3 is a substituted or unsubstituted radical selected from the group consisting of phenyl and pyridine;
  • R is halogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • Methods for treating Eg5-mediated diseases including cellular proliferative disorders, such as cancer are also provided herein.
  • the methods for treating comprise administering to a patient a therapeutically effective amount of a compound provided herein.
  • the compounds of Formula (I) can be useful in the treatment of a variety of cancers, including, but not limited to, malignancies derived from hematopoietic cells and solid tumors.
  • the cancer to be treated is selected from breast cancer, bone cancer, lung cancer, oral cancer, cancer of the esophagus, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anal region, liver cancer, stomach cancer, cancer of the bile ducts or bile vesicle, pancreatic cancer, cancer of the urinary pathways (for example, cancer of the kidneys, ureter, or bladder), cancer of female genital organs, (for example, cancer of the uterus, cervix or ovaries), cancers of male genital organs (for example, cancer of the penis, prostate cancer, cancer of the seminal vesicles or of the testicles), cancer of the endocrine system (for example, cancer of the thyroid, pituitary or adrenal glands), skin cancer, cancer of the head and neck, tumors of the central and peripheral nervous system (for example, neuroblastomas, schwannomas, and meningiomas), hematopoietic malignancies
  • methods for treating cancer in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound provided herein, wherein the cancer is selected from the group consisting of breast cancer, bone cancer, lung cancer, oral cancer, cancer of the esophagus, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anal region, liver cancer, stomach cancer, cancer of the bile ducts or bile vesicle, pancreatic cancer, cancer of the urinary pathways, cancer of female genital organs, cancer of male genital organs, prostate cancer, cancer of the endocrine system, skin cancer, cancer of the head and neck, tumors of the central and peripheral nervous system, leukemia, acute lymphocytic leukemia, acute myeloid (myelogenous) leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, chloroma, prolymphocytic leukemia, T-cell leukemia, T-
  • hematopoietic malignancy including, but not limited to, leukemia, such as acute lymphocytic leukemia, acute myeloid (myelogenous) leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, chloromas, prolymphocytic leukemia, and T-cell leukemia; and lymphoma, such as non-Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, NK cell lymphoma, Hodgkin lymphoma, and Burkitt's lymphoma; and myeloma.
  • leukemia such as acute lymphocytic leukemia, acute myeloid (myelogenous) leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, chloromas, prolymphocytic leukemia, and T-cell leukemia
  • lymphoma
  • kits for using the compounds provided herein for the preparation of a medicinal product intended for treating cancers are provided herein.
  • medicaments characterized in that the medicaments comprise a compound provided herein.
  • the compounds provided herein are useful in modulating Pim kinase function. Therefore, these compounds are useful for treating diseases and conditions mediated by Pim kinase function or that would benefit from modulation of Pim kinase function. Accordingly, provided herein are methods of treating or preventing a Pirn kinase- mediated disease or condition in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound provided herein. The therapeutic amount varies according to the specific disease and is discernable to the skilled artisan without undue experimentation.
  • the Pirn kinase-mediated disease or condition is a cellular proliferative disorder.
  • Cellular proliferative disorders include cancer, tumor, smooth muscle cell proliferation, hyperplasia, angiogenesis, synovitis, restenosis, cardiac hyperplasia, immune disorder, and inflammation.
  • the contact is occurs in vivo.
  • the inhibition occurs in the body tissues or fluid of a mammal.
  • the inhibition occurs in a biological sample. Inhibition of Pirn kinase activity in a biological sample is useful for various purposes, including, but not limited to, storage of biological specimens, study of gene regulatory pathways, characterization of signal transduction cascades, and identification of potential downstream drugable targets.
  • the compounds provided herein are useful for treating cancer in patients, including humans. When administered to a patient, the compounds can be used alone, or as a pharmaceutical composition. Also provided herein are pharmaceutical compositions comprising at least one of the compounds provided herein in admixture with a pharmaceutically acceptable carrier.
  • the compounds provided herein may be administered in pharmaceutically acceptable dosage forms to humans and other animals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, colonic, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • “Pharmaceutically acceptable dosage forms” refers to dosage forms of the compounds provided herein, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.
  • Pharmaceutically acceptable carriers include one or more component selected from the group comprising pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, emulsion stabilizing agents, suspending agents, isotonic agents, sweetening agents, flavoring agents, perfuming agents, coloring agents, antibacterial agents, antifungal agents, other therapeutic agents, lubricating agents, adsorption delaying or promoting agents, and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • pharmaceutically acceptable carriers include one or more component selected from the group comprising pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, emulsion stabilizing agents, suspending agents, isotonic agents, sweetening agents, flavoring agents, perfuming agents,
  • Exemplary suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.
  • Exemplary antibacterial and antifungal agents for the prevention of the action of microorganisms include parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • Exemplary isotonic agents include sugars, sodium chloride, and the like.
  • Exemplary adsorption delaying agents to prolong absorption include aluminum monostearate and gelatin.
  • Exemplary adsorption promoting agents to enhance absorption include dimethyl sulfoxide and related analogs.
  • Exemplary diluents, solvents, vehicles, solubilizing agents, emulsifiers and emulsion stabilizers include water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1 ,3-butylene glycol, glycerol, polyethylene glycols, dimethylformamide, TWEENTM 60, SPANTM 60, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate, fatty acid esters of sorbitan, vegetable oils (such as cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil) and injectable organic esters such as ethyl oleate, and the like, or suitable mixtures of these substances.
  • Exemplary excipients include lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.
  • Exemplary disintegrating agents include starch, alginic acids and certain complex silicates.
  • Exemplary lubricants include magnesium stearate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols.
  • the choice of pharmaceutically acceptable carrier is generally determined in accordance with the chemical properties of the active compound such as solubility, the mode of administration and the provisions to be observed in pharmaceutical practice.
  • compositions of provided herein suitable for oral administration may be presented as discrete units such as a solid dosage form, such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, or as a powder or granules; as a liquid dosage form such as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Solid dosage form means the dosage form of the compound provided herein is in solid form, for example capsules, tablets, pills, powders, dragees or granules.
  • the compound provided herein is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and Na 2 C0 3 , (e) solution retarders, as for example paraffin, (f) ab
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tables may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used.
  • a mixture of the powdered compounds moistened with an inert liquid diluent may be molded in a suitable machine to make molded tablets.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Solid compositions may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
  • the compounds can be microencapsulated in, or attached to, slow release or targeted delivery systems such a biocompatible, biodegradable polymer matrices (e.g., poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
  • the compounds may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Liquid dosage form means the dose of the active compound to be administered to the patient is in liquid form, for, example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as solvents, solubilizing agents and emulsifiers. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Pharmaceutical compositions suitable for topical administration mean formulations that are in a form suitable to be administered topically to a patient.
  • the formulation may be presented as a topical ointment, salves, powders, sprays and inhalants, gels (water or alcohol based), creams, as is generally known in the art, or incorporated into a matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
  • the active ingredients When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • Formulations suitable for topical administration in the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, typically sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • lozenges comprising the active ingredient in a flavored base, typically sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia
  • mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the oily phase of the emulsion pharmaceutical composition may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. In one embodiment, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxy groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • suitable oils or fats for a composition is based on achieving the desired properties.
  • a cream is a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used. These may be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • compositions suitable for rectal or vaginal administrations means formulations that are in a form suitable to be administered rectally or vaginally to a patient and containing at least one compound provided herein.
  • Suppositories are a form for such formulations that can be prepared by mixing the compounds provided herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Pharmaceutical composition administered by injection may be by transmuscular, intravenous, intraperitoneal, and/or subcutaneous injection.
  • compositions provided herein are formulated in liquid solutions, for example, in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • the compositions may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the formulations are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents and thickening agents and antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic, and have a suitably adjusted pH, with the blood of the intended recipient.
  • compositions provided herein suitable for nasal or inhalational administration means compositions that are in a form suitable to be administered nasally or by inhalation to a patient.
  • the composition may contain a carrier, in a powder form, having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.).
  • Suitable compositions wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Compositions suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Metered dose inhalers are useful for administering compositions provided herein for an inhalational therapy.
  • Actual dosage levels of active ingredient(s) in the compositions provided herein may be varied so as to obtain an amount of active ingredient(s) that is (are) effective to obtain a desired therapeutic response for a given composition and method of administration for a patient.
  • a selected dosage level for any given patient therefore depends upon a variety of factors including the desired therapeutic effect, on the route of administration, on the desired duration of treatment, the etiology and severity of the disease, the patient's condition, weight, sex, diet and age, the type and potency of each active ingredient, rates of absorption, metabolism and/or excretion and other factors.
  • Total daily dose of the compounds provided herein administered to a patient in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily.
  • the dose is 0.01 to 10 mg/kg/day.
  • the doses are generally from about 0.01 to about 100, or 0.01 to about 10, mg/kg body weight per day by inhalation, from about 0.01 to about 100, or 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.01 to about 50, or 0.01 to 10, mg/kg body weight per day by intravenous administration.
  • the percentage of active ingredient in a composition may be varied, though it should constitute a proportion such that a suitable dosage shall be obtained.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose.
  • Several unit dosage forms may be administered at about the same time.
  • a dosage may be administered as frequently as necessary in order to obtain the desired therapeutic effect.
  • Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate.
  • it may be desireable to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological status of a given patient. For example, for some patients, it may be desireable to prescribe not more than one or two doses per day.
  • the formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier that constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if desired, shaping the product.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze- dried (lyophilized) condition.
  • a sterile liquid carrier for example water for injections, can be added to the ampoule prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • an additional agent e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.
  • the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the compound provided herein.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition.
  • the compounds provided herein can be synthesized by any of the procedures known to one skilled in the art. For example, several of the starting materials used in the preparation of the compounds provided herein are known or are themselves commercially available. The compounds provided herein and several of the precursor compounds may also be prepared by methods used to prepare similar compounds as reported in the literature and as further described herein. For instance, see R. C. Larock, "Comprehensive Organic Transformations,” VCH publishers, 1989.
  • suitable amine protecting groups include without any limitation sulfonyl (e.g., tosyl), acyl (e.g., benzyloxycarbonyl or t- butoxycarbonyl) and arylalkyl (e.g., benzyl), which may be removed subsequently by hydrolysis or hydrogenation as appropriate.
  • sulfonyl e.g., tosyl
  • acyl e.g., benzyloxycarbonyl or t- butoxycarbonyl
  • arylalkyl e.g., benzyl
  • a solid phase resin bound benzyl group such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a 2,6-dimethoxy-4-[2- (polystyrylmethoxy)ethoxy] benzyl, which may be removed by acid catalyzed hydrolysis,
  • an azaindole of Formula (II) is protected with a methoxymethyl group.
  • a solvent such as acetone, DMF, or acetonitrile (e.g., anhydrous grade) is added to a mixture of an azaindole (e.g., 1 .0 eq.), a freshly powdered inorganic base (for example, KOH or NaOH) (e.g., 1 .2 eq.) and a phase transfer catalyst, such as, for example, tetrabutylammonium iodide, bromide, or tetrabutylammonium hydrogen sulphate (e.g., 3.4 mol%) under an inert (e.g., N 2 ) atmosphere.
  • an inert e.g., N 2
  • the mixture is stirred for about 5 to about 30 min, at ambient temperature.
  • the temperature can potentially be raised to about 30° C or, in some embodiments, cooled down to about 0° C, before addition of MOM-chloride (1 to 5 eq., for example about 1 .2 eq.).
  • MOM-chloride 1 to 5 eq., for example about 1 .2 eq.
  • the mixture is warmed to a temperature between room temperature and about 50° C, for about 0.5 to about 48 h.
  • the reaction mixture is then worked-up to isolate the compound of Formula (III) using general procedures known to those skilled in the art.
  • step 1 b) the compound of Formula (III) is halogenated.
  • a freshly prepared solution of base for example, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, butyllithium, isopropylmagnesium chloride, lithium chloride, or lithium diisopropylamide
  • an ethereal solvent such as Et 2 O or THF at a temperature between -100 and 0° C, for example -78° C
  • an inert atmosphere e.g, N 2
  • substituted-1 -methoxymethyl-7-azaindole e.g., 1 .0 eq.
  • This solution is aged at a temperature between -100° C and 0° C, for example -78° C, for 30 to 60 min. After this time, the reaction mixture is very slowly treated with a solution of electrophyle (1 to 5 eq., for example, 1 .2 eq.) in an ether, such as Et 2 0 or THF. After 30 min to 2 h, for example 45 min, the mixture is quenched. The reaction mixture was then worked-up to isolate the compound of Formula (IV) using general procedures known to those skilled in the art.
  • Scheme 2 illustrates the deprotection of the 7-azaindole of Formula (IV) followed by the preparation of the azaindole intermediates of Formulae (V), (VI), (VII) and (VIII).
  • Scheme 3 illustrates a Suzuki coupling to prepare the compound of Formula (la).
  • the reaction of Scheme 3 can be carried out as follows: To a mixture of a boronate or boronic acid (1 to 5 eq., for example 1 .2 eq.), an aryl halide (for example an aryl bromide, aryl chloride, or aryl iodide) (0.7 to 3 eq., for example 1 eq.) and an inorganic base (for example, KF, Na 2 C0 3 , Cs 2 C0 3 , NaHC0 3 , K 2 C0 3 , or Cs 2 C0 3 ) (2 to 10 eq., for example 2.5 eq.) in a degassed organic solvent (for example, THF, DME, DMF, 1 ,4-dioxane, DME/H 2 0 mixture, or toluene) is added a palladium catalyst (for example tris(benzylideneacetone)dipalladium (0), tetrakis(triphenylpho
  • a tri-tert-butylphosphine tetrafluoroborate can also be added.
  • the reaction mixture is heated to about 40° C to 150° C (for example, about 100° C) for about 2 to 24 h (for example, for about 18 h) or at about 100° C to 200°C (for example, about 150° C) for about 5 to 120 min, for example in a microwave, under an inert atmosphere.
  • the reaction mixture is allowed to cool to ambient temperature.
  • the reaction mixture is then worked-up to isolate the compound of Formula (la) using general procedures known to those skilled in the art.
  • Scheme 4 illustrates of a coupling between a carboxylic acid or carboxylate salt of the Formula ( ⁇ ') with an amine to generate an amide, hydroxamate, or hydrazoic acid.
  • the reaction of Scheme 4 can be carried out as follows: To a mixture of carboxylic acid or carboxylate salt (either K+, Na+, or Li+) (1 to 2.5 eq., for example 1 to 1 .5 eq.) and an amine (1 to 2.5 eq., for examplel to 1 .5 eq.) in an organic solvent (for example THF, EtOAc, Et20, DMF, or DCM) is added a coupling reagent (for example 1 ,3-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1 -Ethyl-3-(3- dimethylaminopropyl)carbodiimide o-(Benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate, tetramethylfluoroformamidininium hexafluorophosphate, or 4-(4,
  • reaction mixture is stirred at about 20 to 70° C (for example, at about 50° C) for about 5 to 120 h (for example, about 35 h) and then cooled to ambient temperature.
  • the amino function may be unmasked using the procedure generally described hereinbelow, and the resulting crude material is purified.
  • Scheme 5 illustrates an alternative alkylation at N1 to prepare compounds of Formula (lc).
  • the reaction of Scheme 5 entails mixing an azaindole and a base (for example, NaH, Lithium bis(trimethylsilyl)amide, potassium t-butoxide, potassium carbonate, or cesium carbonate in an anhydrous solvent (for example, DMF, AcN, THF, or DMPU).
  • a base for example, NaH, Lithium bis(trimethylsilyl)amide, potassium t-butoxide, potassium carbonate, or cesium carbonate
  • an anhydrous solvent for example, DMF, AcN, THF, or DMPU
  • a haloalkyl for example, bromo-, iodo-, or chloro-alkyl.
  • This mixture is heated to a temperature between room temperature and about 100° C (for example, about 50° C) for about 1 to 48 h (for example, about 17 h).
  • the reaction mixture is then worked-up to isolate the compound of Formula (lc) using general procedures known to those skilled in the art.
  • compounds provided herein can be prepared by acylation of a tertiary amine by dissolving the azaindole compound bearing the secondary amine (1 .0 eq.) in a solvent (for example, DMF, pyridine, DCM, or THF) and treating the solution with an acetyl (for example, acetylbromide, acetylfluoride, or acetylchloride). After 1 to 10 days, for example about 4.5 days, the reaction mixture is then worked- up to isolate the compound of Formula (Id) using general procedures known to those skilled in the art.
  • a solvent for example, DMF, pyridine, DCM, or THF
  • Scheme 7 illustrates a reductive amination to prepare compounds of Formula (le).
  • reaction mixture is quenched, for example with saturated aqueous sodium bicarbonate.
  • acid for example, TFA, p-toluene sulfonic acid, formic acid, or acetic acid
  • the reaction mixture is then worked-up to isolate the compound of Formula (le) using general procedures known to those skilled in the art.
  • the free base can be obtained using procedures known to skilled in the art.
  • Scheme 8 illustrates the formulation of a sulfonamide from an amine to prepare compounds of Formula (If).
  • a procedure of Scheme 8 entails stirring a mixture of the amine (for example, 1 eq.), aryl- or alkyl-sulfonyl chloride (1 to 5 eq., for example 2 eq.), and optionally a base (for example pyridine, Et 3 N, NaOH, KOH, DIEA, or polymer-bound PS-morpholine) (4 eq., for example) is stirred in an organic solvent (for example DCM, DMF, THF, or pyridine) at ambient temperature for about 1 to 24 h (for example, 5 h) with or without a phase transfer catalyst. The reaction mixture is then worked-up to isolate the compound of Formula (If) using general procedures known to those skilled in the art.
  • a base for example pyridine, Et 3 N, NaOH, KOH, DIEA, or polymer-bound PS-morpholine
  • Scheme 9 illustrates the formulation of a urea from an amine.
  • a preparation according to Scheme 9 entails stirring a mixture of the amine (1 eq., for example), an isocyanate (1 to 5 eq., for example 2 eq.), and optionally a base (for example K 2 C0 3 , pyridine, Et 3 N, DIEA, or polymer-bound PS-morpholine) in an organic solvent (for example acetonitrile, DCM, DMF, THF, or pyridine) at ambient temperature for about 1 to 24 h (for example, 5 h).
  • the reaction mixture is then worked-up to isolate the compound of Formula (Ig) using general procedures known to those skilled in the art.
  • Scheme 10 illustrates a general procedure for preparing compounds of Formula (I).
  • acid addition salts of the compounds provided herein may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compounds provided herein may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • parent compounds provided herein can be regenerated from their acid addition salts by the application or adaptation of known methods.
  • parent compounds provided herein can be regenerated from their acid addition salts by treatment with an alkali, e.g., aqueous sodium bicarbonate solution.
  • the starting materials and intermediates may be prepared by the methods described in the present application or are available commercially or are described in the literature, or else may be prepared by methods which are described therein or which are known to a person skilled in the art.
  • compounds provided herein may be prepared according to the procedures described in the foregoing examples.
  • LCMS High Pressure Liquid Chromatography - Mass Spectrometry
  • Method B WatersXBridge C18, 4.6*50, 2.5 ⁇ , H 2 0 + 0.05% TFA:acetonitrile + 0.05% TFA 95:5 (0 min) to 95:5 (0.3 min) to 5:95 (3.5 min) to 5:95 (4 min).
  • Ionization method ES+
  • Method C Waters XBridge C18 4.6*50 mm; 2.5 ⁇ , H 2 O+0.1 % TFA:acetonitrile + 0.08% TFA 97:3 (0 min) to 40:60 (3.5 min) to 2:98 (4 min) to 2:98 (5 min) to 97:3 (5.2 min) to 97:3 (6.5 min).
  • Ionization method ES+.
  • Method D SYNERGI 2U HYDRO-RP 20X4.0 MM, 0.1 % TFA in Water/Acetonitrile, 5 to 40% acetonitrile in 2 min., to 95% acetonitrile at 5 min.
  • Ionization method ESI+, MICROMASS LCT-LC MS, scan m/z 100-1200.
  • Method E Waters Acquity-SQD uPLC-MS System, 2.1 x 50mm, 1 Jmicron, BEH-C18 Acquity column, 55° C, water + 0.05 % formic acid/acetonitrile + 0.05% formic acid, 0.8 mL/min, run 1 .5 min.
  • Ionization method SQD Single Quadrupole Detector, Tunable Visible/Ultra-violet (TUV) Dual Wavelength Detector, ESI +/- (Electrospray Ionization dual positive/negative), APCI +/- (Atmospheric Pressure Chemical Ionization dual positive/negative).
  • Method P Reverse phase preparative chromatography: Gemini 10u C18 1 1 OA, 150x30 (5% to 90% acetonitrile/0.01 % aqueous TFA over 40 min at 20 mL/min).
  • Acetonitrile (30 mL, anhydrous grade) was added to a mixture of 4-chloro-7-azaindole (3.23 g, 21 .2 mmol, 1 .0 eq.), freshly powdered NaOH (1 .00 g, 25.0 mmol, 1 .2 eq.) and tetrabutylammonium hydrogen sulphate (245 mg, 0.72 mmol) under N 2 atmosphere. After aging at room temperature for 30 min, the mixture was warmed slightly to 30° C in an oil bath and treated with MOM-chloride (1 .93 mL, 25.4 mmol, 1 .2 eq.) to give a tan suspension.
  • reaction mixture was treated with a solution of iodine (5.73 g, 22.6 mmol, 1 .2 eq.) in THF (50 mL) very slowly drop-wise for 3 h and 25 min. After 45 min at -78° C, the orange solution was quenched with saturated ammonium chloride solution (10 mL) and the mixture portioned between water and EtOAc. Small amounts of NaHSO 3 were added to remove excess iodine, and the EtOAc layer was washed with brine. The combined aqueous layers were back extracted with two small portions of EtOAc.
  • Step a) Synthesis of 4-chloro-2-iodo-1 H-pyrrolo[2,3-b]pyridine An ice-cooled solution of 4-chloro-2-iodo-1 -methoxymethyl-1 H-pyrrolo[2,3-b]pyridine (20 g, 62 mmol, 1 eq.) in dry dichloromethane (300 mL) was treated with a solution of bromo-catecholborane (16.06 g, 200 mL, 80 mmol, 1 .3 eq.) to give a bright yellow solution which very quickly became a thick suspension. After 1 .5 h, the reaction mixture was evaporated.
  • Step c) Synthesis of 4-[4-(4-chloro-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]- piperazine-1 -carboxylic acid tert-butyl ester:
  • the semi-solid obtained was dried under vacuum to provide 4-[4-(4-chloro-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-piperazine-1 - carboxylic acid tert-butyl ester as a yellowish solid (4.1g, 68%).
  • the isolated solid was used in the next step without further purification.
  • 4- ⁇ 4-[4-Chloro-3-(4-hydroxymethyl-phenyl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl]- phenyl ⁇ -piperazine-1 -carboxylic acid tert-butyl ester can be prepared from 4-[4-(4- chloro-3-iodo-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-piperazine-1 -carboxylic acid tert-butyl ester generally according to the procedure described in Example 2.
  • Step f) Synthesis of 4-[4-chloro-1 -methyl-2-(4-piperazin-1 -yl-phenyl)-7-azaindole]- phenyl ⁇ -methanol
  • the resulting golden oil was partitioned between DCM and saturated NaHCOs aqueous solution, treating with NaHC0 3 until the aqueous layer was adjusted to pH ⁇ 8.
  • the aqueous layer was extracted with four further portions of DCM, and the combined DCM layers were dried (MgS0 4 ) and evaporated to give the title product as an orange solid (761 mg, 108% yield).
  • Example 105 Synthesis of 3- ⁇ 4-chloro-1 -methyl-2-[4-(4-methyl-piperazin-1 -yl)- phenyl]-7-azaindole ⁇ -N-(1 -methyl-piperidin-4-yl)-benzamide
  • Step a Synthesis of 3- ⁇ 4-chloro-1 -methyl-2-[4-(4-methyl-piperazin-1 -yl)-phenyl]-7- azaindole ⁇ -benzoic acid lithium salt
  • Step b Synthesis of 3- ⁇ 4-chloro-1 -methyl-2-[4-(4-methyl-piperazin-1 -yl)-phenyl]-7- azaindole ⁇ -N-(1 -methyl-piperidin-4-yl)-benzamide
  • reaction mixture was eluted through a pre-packed 2g SCX cartridge, washing with aqueous MeOH (1 :1 ) then with methanol.
  • the product was released from the cartridge by eluting with ammonia in MeOH (7N, about 5mL), then with THF (5mL).
  • the product-containing fraction was evaporated, and the crude material was purified by reverse phase HPLC eluting with a gradient of 10% AcN in water (0.1 % TFA) to 100% AcN over 20 min.
  • the product-containing fractions were directly passed through a pre-packed 2g SCX cartridge, washing with aqueous MeOH (1 :1 ) then methanol.
  • Example 129 Synthesis of (4- ⁇ 4-Chloro-1 -cyclobutylmethyl-2-[4-(4-methyl- piperazin-1 -yl)-phenyl]-7-azaindole ⁇ -phenyl)-methanol
  • Step b) Synthesis of (4- ⁇ 4-Chloro-1 -cyclobutylmethyl-2-[4-(4-methyl-piperazin-1 - yl)-phenyl]-7-azaindole ⁇ -phenyl)-methanol
  • reaction mixture was quenched with methanol and eluted through 2x pre-packed 2g SCX cartridges, washing with THF and MeOH.
  • the product was released from the cartridge by eluting with ammonia in MeOH (7N, about 7 mL), and then with THF (5 mL).
  • the product-containing fraction was evaporated, and the crude product was purified by reverse phase HPLC eluting with a gradient of 20% AcN in water (0.1 % TFA) to 100% AcN over 10 min.
  • the product fraction was eluted through a pre-packed 2g SCX cartridge, washing with THF and MeOH.
  • Example 138 Synthesis of 4- ⁇ 4-Chloro-1 -methyl-2-[4-(4-methyl-piperazin-1 -yl)- phenyl]-7-azaindole ⁇ -phenyl)-methanol
  • the aqueous layer was extracted with 3 small portions of DCM.
  • the combined DCM layers were evaporated, and the crude product purified by reverse phase HPLC eluting with a gradient of 20%AcN in water (0.1 % TFA) to 100% AcN over 10 min.
  • the product-containing fractions were lyophilized.
  • the product was further purified by dissolving in MeOH/THF and passing through a pre-packed 2g SCX cartridge, washing with THF and MeOH.
  • the product was released from the cartridge by eluting with ammonia in MeOH (7N, about 5 mL) then THF (5 mL). Evaporation of the product fraction gave the title compound as a white crystalline solid (42 mg, 23% yield).
  • Example 147 Synthesis of 4- ⁇ 1-Amino-4-chloro-2-[4-(4-methyl-piperazin-1 -yl)- phenyl]-7-azaindole ⁇ -N-(1 -methyl-piperidin-4-yl)-benzamide
  • the resulting solution was aged at room temperature for 25 min before being treated with a solution of O-4-nitrobenzoylhydroxylamine (0.55 M in NMP, freshly made, 1 mL, 0.55 mmol, 1 .5 eq.). After 2 h, the reaction mixture was eluted through a pre-packed 2g SCX cartridge, washing with water, THF and then methanol. The product was released from the cartridge by eluting with ammonia in MeOH (7N), and then with THF. The product-containing fraction was evaporated and the crude product purified by reverse phase HPLC eluting with a gradient of 20%AcN in water (0.1 % TFA) to 100% AcN over 10 min.
  • the resulting biphasic mixture was heated in a sealed pressure tube at 95° C for 14 h.
  • the resulting dark mixture was partitioned between EtOAc and saturated aqueous NaHCC>3.
  • the EtOAc layer was washed with brine, and the combined aqueous layers were extracted with three portions of EtOAc.
  • the combined EtOAc layers were evaporated.
  • the resulting crude residue was purified on a 20 g silica cartridge eluting with EtOAc:heptane (10% to 15% EtOAC in heptane). The clean product fractions were combined and evaporated to give the title compound as a yellow-orange solid (1 .207 g, 85% yield).
  • Step c) Synthesis of 4- ⁇ 4-[4-chloro-3-(4-ethoxycarbonyl-phenyl)-1 - methoxymethyl-7-azaindole]-phenyl ⁇ -piperazine-1 -carboxylic acid tert-butyl ester
  • a mixture of 4-[4-(4-chloro-3-iodo-1 -methoxymethyl-7-azaindole)-phenyl]-piperazine- 1 -carboxylic acid tert-butyl ester (5.68 g, 9.75 mmol, 1 .0 eq.), 4-ethoxycarbonylphenyl boronic acid (2.46 g, 12.7 mmol, 1 .3 eq.), PdCI 2 (dppf).CH 2 CI 2 (477 mg, 0.585 mmol, 6 mol%) and cesium carbonate (7.0 g, 21 .5 mmol, 2.2 eq.) was treated under N 2 with water
  • Step a) Synthesis of 4-cyano-1 -methoxymethyl-7-azaindole: Prepared using general scheme 1 -a).
  • Step b) Synthesis of 3-iodo-1 -methoxymethyl-1 H-pyrrolo[2,3-b]pyridine-4- carbonitrile
  • Step c) Synthesis of 1 -methoxymethyl-3-pyridin-3-yl-1 H-pyrrolo[2,3-b]pyridine-4- carbonitrile: prepared according to the general Suzuki procedure, as described in Example 149, step c).
  • LCMS R T (min) 0.57, M+ 264.9
  • the pharmacological properties of the compounds provided herein may be confirmed by a number of pharmacological assays.
  • the exemplified pharmacological assays which follow have been carried out with compounds provided herein as described herein.
  • the compounds provided herein are inhibitors of Pirn kinase activity.
  • TR-FRET Time Resolved-Fluorescence Resonance Energy Transfer
  • Pim kinase Recombinant N-terminal 6xHis-tagged full-length human Pim-1 , Pim-2, or Pim-3 protein, produced according to the following general procedure: N-terminal 6xHis-tagged full length human Pim-1 , Pim-2, or Pim-3 was expressed in E. coli BL21 (DE3) cells. Cells were harvested and lysed in lysis buffer containing 50 mM Tris-HCI(pH 8.0)/0.5 M NaCI/5 mM BME/PI/2% Brij35. Following homogenization using an ultrasonicator, a supernatant was obtained by centrifuging at 40,000 rpm (125,000g) at 4° C.
  • the supernatant is incubated with a Ni-NTA resin (Qiagen, Inc.) for 1 h with agitation. Following an extensive washing in a buffer containing 20 mM Tris-HCL (pH 8.0)/0.5 M NaCI/10 mM Imidazole/5 mM BME/0.01 % Brij35, the eluate was collected in a buffer containing 20 mM Tris-HCI (pH 8.0)/0.2 M NaCI/200 mM Imidazole/5 mM BME/0.01 % Brij35. Fractions were analyzed by SDS-PAGE with total protein staining. Positive fractions were indentified and pooled.
  • a Ni-NTA resin Qiagen, Inc.
  • Full length human BAD substrate Full length human BAD was cloned into the expression vector pET15 vector and was transformed into E. coli strain BL21 (DE3). Following growth at 37° C, E. coli cells were induced using 0.2 mM IPTG at 20° C overnight. E. coli were lysed by sonication in a buffer consisting of 50 mM Tris pH7.5, 200 mM NaCI, with inclusion of protease inhibitors. Following centrifugation at 40,000rpm (125000g), the filtrate was loaded onto a 5 mL HiTrap HP chromatography column.
  • His-tagged BAD was eluded with the following buffers: Buffer A: 20 mM Tris pH7.5, 0.5 M NaCI, 20 mM Imidazole; Buffer B: 20 mM Tris pH7.5, 0.5 M NaCI, 1 mM Imidazole. Further purification on positive fractions was performed by three cycles of size exclusion chromatography in a buffer of 20 mM Tris pH7.5, 100 mM NaCI, and 1 mM DTT. Positive fractions were indentified by Western blot analysis and pooled. a-His6-APC - SureLight -allophycocyanin-conjugated mouse monoclonal antibody against His6-tag (Perkin Elmer, # AD0059H, Waltham, Massachusetts, USA);
  • the assay used is based on the PerkinElmer LANCETM technology: Eu-labeled antibody binds to phospho-Serl 12 and generates TR-FRET signal by interaction with the APC-labeled His6 antibody bound to His6-tag of Bad.
  • the ratio of the fluorescence signals at 665 nm over 615 was used as a signal readout for IC-50 (calculations based on the 4-parameter logistic model).
  • the assay was set up in 384-well format; liquid manipulations were done using Beckman 3000 liquid handling workstation. Test compounds were assayed at 10 concentration points in duplicate; the highest compound concentration was typically 30 ⁇ . The concentration of ATP was 40 ⁇ , which equals to the apparent K M value.
  • Radiometric filter-binding assay To confirm their potency, compounds provided herein may be counter screened using a radiometric filter-binding assay.
  • This assay measures phosphorylation of a synthetic peptide (RSRHSSYPAGT) corresponding to amino acids 107 - 1 17 of mouse Bad, which include the phosphorylation site, Ser1 12 (Upstate #12-542), in the presence of 33 P-ATP as a second substrate.
  • the reaction is run in the same format as the TR-FRET assay described above.
  • the basic substrate peptide binds to the phosphocellulose filter, and the level of phosphorylation is quantitated by liquid scintillation counting. Again, the concentration of ATP is 40 ⁇ , which equals to the apparent K M value.
  • Compounds provided herein may also be screened for their effects on cell proliferation and viability using a variety of human-derived tumor cell lines representative of different disease indications. These cell lines include:
  • TF-1 acute myelogenous leukemia; AML M6 at diagnosis
  • KG-1 (AML; erythroleukemia progressing to AML);
  • KG-1 a (AML; immature KG-1 -derived subclone);
  • EOL-1 (AML; eosinophilic leukemia);
  • MOLM-13 (AML)
  • K-562 CML - chronic myelogenous leukemia; blast crisis
  • JURL-MK1 CML; blast crisis
  • DND-41 T-ALL - T cell acute lymphoblastic leukemia
  • T-ALL T-ALL
  • NALM-6 B-ALL - B cell ALL
  • CEM ALL; lymphosarcoma progressing to ALL
  • Jeko-1 B-NHL - B-cell non-Hodgkin's lymphoma; mantle cell lymphoma derived from large cell variant in leukemic conversion
  • WSU-DLCL2 (B-NHL; diffuse large B-cell lymphoma);
  • JVM-2 B-CLL - B-cell chronic lymphocytic leukemia
  • JVM-3 B-CLL
  • HCT-1 16 colon cancer
  • HT-29 colon cancer
  • HC-15 colon cancer
  • H460 lung cancer; non-small cell lung cancer
  • MDA-A1 breast cancer
  • MDA-MB231 (breast cancer)
  • MDA-MB231 adr breast cancer
  • PANC-1 pancreatic cancer
  • PC-3 prostate cancer
  • tumor cells are incubated in a high throughput format such as a 96-well or 384-well format for a suitable period of time, such as 48, 72, or 96 h, with a compound provided herein at three-fold serial dilutions with generally nine doses in total, with a highest dose of 10 ⁇ or 30 ⁇ .
  • Cell viability is assessed by addition of CellTiter-Blue ® (Promega, Madison, Wisconsin, USA) for 4 h, and endpoint readings are collected using a SpectraMax Genmini EM plate reader (Molecular Devices, Sunnyvale, CA, USA).
  • the CellTiter-Blue ® cell viability assay measures the ability of cells in culture to reduce resazurin to resorufin, whereby the intensity of the fluorescence signal is directly proportional to the number of live cells.
  • the EC50 represents the concentration of compound which results in a 50% reduction in cell viability/proliferative expansion.

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Abstract

L'invention porte d'une manière générale sur des composés qui inhibent les kinases Pim. L'invention porte sur des azaindoles N-substitués, ou des sels pharmaceutiquement acceptables de ceux-ci, qui sont utiles comme inhibiteurs sélectifs de kinases Pim. L'invention porte également sur des compositions pharmaceutiques comprenant ces composés, sur des procédés pour leur préparation et sur des procédés d'utilisation de celles-ci.
PCT/US2010/060910 2009-12-18 2010-12-17 Dérivés d'azaindole, leur préparation et leur application thérapeutique WO2011075613A1 (fr)

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