WO2011149827A1 - Composés et procédés - Google Patents

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WO2011149827A1
WO2011149827A1 PCT/US2011/037533 US2011037533W WO2011149827A1 WO 2011149827 A1 WO2011149827 A1 WO 2011149827A1 US 2011037533 W US2011037533 W US 2011037533W WO 2011149827 A1 WO2011149827 A1 WO 2011149827A1
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methyl
benzenesulfonamide
amino
pyrimidin
alkyl
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PCT/US2011/037533
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English (en)
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Marlys Hammond
Lara S. Kallander
Brian Griffin Lawhorn
Joanne Philp
Martha A. Sarpong
Mark Andrew Seefeld
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Glaxosmithkline Llc
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Publication of WO2011149827A1 publication Critical patent/WO2011149827A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that inhibit TNNI3K and B-Raf kinase and methods of making and using the same. Specifically, the present invention relates to anilino-deazapurines, anilino-purines, and anilino-pyrazolopyrimidines as TNNI3K and B-Raf kinase inhibitors.
  • Cardiac troponin l-interacting kinase (TNNI3K), also known as CARK (for cardiac ankyrin repeat kinase), is a protein kinase that exhibits highly selective expression for cardiac tissues and has been shown to interact with components of the sarcomere, including troponin I (Zhao, Y. et al., J. Mol. Med., 2003, 81, 297-304; Feng, Y. et al., Gen. Physiol. Biophys., 2007, 26, 104-109; Wang, H. et al., J. Cell. Mol. Med., 2008, 12, 304- 315).
  • TNNI3K a cardiac-specific kinase, promotes cardiac hypertrophy in vivo
  • Inhibition of the kinase activity of TNNI3K may disrupt these signaling pathways, and enable the mitigation and/or reversal of cardiac hypertrophy seen in patients with progressively worsening heart failure.
  • the heart In response to mechanical, neurohormonal, and genetic stimuli, the heart will undergo hypertrophy, or muscle growth and remodeling, in order to maintain sufficient cardiac output to meet tissue oxygen demands. While these structural changes are initially seen as compensatory, sustained dysregulation of hypertrophic signaling can lead to heart failure, the pathophysiological state in which the heart can no longer adequately function as a pump (Mudd, J. O. and Kass, D. A., Nature, 2008, 451, 919-928).
  • Heart failure is responsible for a reduced quality of life and premature death in a significant proportion of sufferers, and is characterized by impaired cardiac function either due to reduced pump function (systolic dysfunction) or reduced filling (diastolic
  • Congestive heart failure is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. The prevalence of heart failure is anticipated to increase with ageing populations, prompting a need for new and improved methods of treating heart failure.
  • Both receptor tyrosine kinases and serine/threonine kinases have been implicated in cellular signaling pathways that control cell function, division, growth, differentiation, and death (apoptosis) through reversible phosphorylation of the hydroxyl groups of tyrosine or serine and threonine residues, respectively, in proteins.
  • signal transduction for example, extracellular signals are transduced via membrane receptor activation, with amplification and propagation using a complex choreography of cascades of protein phosphorylation, and protein dephosphorylation events to avoid uncontrolled signaling.
  • Receptor tyrosine kinases catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation. Downstream of the several rtKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases.
  • kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2.
  • This signaling pathway also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. The ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival. Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival.
  • MAPK mitogen-activated protein kinase
  • cervical cancer (Moreno-Bueno et al., Clin. Cancer Res. (2006) 12 3865-3866), cholangiocarcinoma (Tannapfel et al., Gut (2003) 52 706-712),
  • central nervous system tumors including primary CNS tumors such as
  • glioblastomas astrocytomas and ependymomas
  • secondary CNS tumors i.e., metastases to the central nervous system of tumors originating outside of the central nervous system
  • colorectal cancer including large intestinal colon carcinoma (Yuen et al., Cancer Res. (2002) 62 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), 63 1314-1330),
  • leukemias Garnett et al., Cancer Cell (2004) supra
  • acute lymphoblastic leukemia Garnett et al., Cancer Cell (2004) supra and Gustafsson et al., Leukemia (2005) 19 310-312
  • AML acute myelogenous leukemia
  • myelodysplastic syndromes Christiansen et al., Leukemia (2005) supra
  • chronic myelogenous leukemia Mizuchi et al., Biochem. Biophys. Res. Commun.
  • Hodgkin's lymphoma (Figl et al., Arch. Dermatol. (2007) 143 495-499), non- Hodgkin's lymphoma (Lee et al., Br. J. Cancer (2003) 89 1958-1960), megakaryoblastic leukemia (Eychene et al., Oncogene (1995) 10 1 159-1 165) and multiple myeloma (Ng et al., Br. J. Haematol. (2003) 123 637-645),
  • ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203 617-619 and Davies (2002) supra), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno- Bueno et al., Clin. Cancer Res. (2006) supra),
  • pancreatic cancer (Ishimura et al., Cancer Lett. (2003) 199 169-173)
  • c-Raf Overexpression of c-Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66 3401-3408, and Zebisch ⁇ Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et la., Cell. Mol. Life Sci. (2006).
  • Raf family kinases By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J., et al., (2006) Cancer Res. 66 1 1 100-1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.
  • the invention is directed to novel anilino-deazapurines, anilino-purines, and anilino- pyrazolopyrimidines. Specifically, the invention is directed to a compound according to Formula I:
  • R 1 is (Ci-C 4 )alkyl
  • X is N or CH
  • Y is N or CR 4 ;
  • Z is N or CR 4 ;
  • R 2 is H, halogen, (d-C 8 )alkyl, (C C 8 )haloalkyl, hydroxy(C C 8 )alkyl-,
  • each R a is (C 1 -C 4 )alkyl, which is optionally substituted one to three times, independently, by halogen, hydroxyl, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino,
  • each R b is H or (d-d)alkyl
  • R a and R b taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, amino,
  • (C 1 -C 4 )alkylamino ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, oxo, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, (Ci-C 4 )alkoxy(CrC 4 )alkyl, or cyano;
  • R 3 is H
  • R 2 and R 3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl,
  • each R 4 is independently selected from H, halogen, cyano, (Ci-C 8 )alkyl,
  • aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (d-d)haloalkyl, cyano, nitro, -OR c , -N(R d )(R e ), -CON(R d )(R e ), -C0 2 R c , -CO(d-C 4 )alkyl, -S0 2 N(R d )(R e ),
  • R c is H, (Ci-C 6 )alkyl, (d-C 8 )cycloalkyl, or -(d-C 4 )alkyl(C 3 -C 8 )cycloalkyl, wherein said (d-C 6 )alkyl or (C 3 -C 8 )cycloalkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)haloalkyl, (d-d)alkoxy, amino,
  • (d-C 4 )alkylamino ((Ci-d)alkyl)((C d)alkyl)amino, -C0 2 H, -C0 2 (d-C 4 )alkyl, -CONH 2 , -CONH(Ci-d)alkyl, -CON((Ci-d)alkyl)((C d)alkyl), heterocycloalkyl, or aryl, wherein said aryl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)alkyl, (d-d)haloalkyl, (d-d)alkoxy, (d-d)haloalkoxy, hydroxy(d-d)alkyl-, amino, (C 1 -d)alkylamino, or ((C 1 -d)alkyl)((C 1 -d)alkyl)amino, -CONH 2 , -CONH(Ci
  • R d is independently selected from H, (Ci-C )alkyl, aryl, heterocycloalkyi or heterocycloalkyl-(Ci-C 2 )alkyl, wherein said (Ci-C )alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC )alkoxy, amino, (Ci-C )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, -C0 2 H, -C0 2 (C C 4 )alkyl, -CONH 2 , -CONH(Ci-C 4 )alkyl, or -CON((Ci-C )alkyl)((CrC )alkyl), and wherein any heterocycloalkyi is optionally substituted by (Ci-C )alkyl;
  • R e is (Ci-C 4 )alkyl
  • R d and R e taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (Ci-C )alkyl, (Ci-C )haloalkyl, amino,
  • R is H, (Ci-C )alkyl, cycloalkyl, 5-6-membered heterocycloalkyi, phenyl, or 5-6- membered heteroaryl, wherein said (C 1 -C 4 )alkyl, cycloalkyl, 5-6-membered
  • heterocycloalkyi, phenyl, or 5-6-membered heteroaryl is optionally substituted one to three times, independently, by (C 1 -C 4 )alkyl, hydroxyl, (CrC 4 )alkoxy, amino, (C 1 -C 4 )alkylamino, ((C C ⁇ alkylXid-C ⁇ alky amino;
  • the compounds of the invention are inhibitors of TNNI3K and can be useful for the treatment of cardiac diseases and disorders, particularly heart failure.
  • the compounds of the invention are also inhibitors of B-Raf kinase and can be useful for the treatment of susceptible neoplasms.
  • This invention is directed to pharmaceutical compositions comprising a compound of the invention or a salt, particularly a pharmaceutical salt, thereof.
  • One embodiment of this invention is directed to methods of inhibiting TNNI3K and treatment of conditions associated therewith comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a salt thereof.
  • Another embodiment of this invention is directed to a method of treating a susceptible neoplasm in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a salt thereof.
  • Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system);
  • primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas
  • secondary CNS tumors i.e., metastases to the central nervous system of tumors originating outside of the central nervous system
  • colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
  • leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelody
  • alkyl represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, pentyl, and hexyl.
  • C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “haloalkyl”, “hydroxyalkyl”, or “alkoxyalkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon double bonds. Examples include ethenyl and propenyl.
  • alkynyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon triple bonds. Examples include ethynyl and propynyl.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • (C 3 -C 8 )cycloalkyl refers to a non-aromatic cyclic
  • hydrocarbon ring having from three to eight ring carbon atoms.
  • exemplary "(C 3 -C 8 )cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkoxy means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom.
  • the term “(CrC 4 )alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(d-C 4 )alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
  • Alkylthio- means an alkyl radical containing the specified number of carbon atoms attached through a sulfur linking atom.
  • the term “(CrC 4 )alkylthio-” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through a sulfur linking atom.
  • Exemplary "(CrC 4 )alkylthio-” groups useful in the present invention include, but are not limited to, methylthio-, ethylthio-, n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and f-butylthio-.
  • Cycloalkyloxy and “cycloalkylthio” means a saturated carbocyclic ring containing
  • cycloalkyloxy moieties include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also
  • bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzo
  • heteroaryl groups present in the compounds of this invention are 5-membered and/or 6-memebred monocyclic heteroaryl groups.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms.
  • Selected 5- or 6-membered heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, hexahydro-1 H- 1 ,4-diazepinyl, azabicylo[3.2.1 ]
  • heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3- dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro-1 /-/-1 ,4-diazepinyl.
  • heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thi
  • halogen and halo represent chloro, fluoro, bromo or iodo substituents.
  • Hydrox or hydroxyl is intended to mean the radical -OH.
  • compound(s) of the invention means a compound of Formula I (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any salt or non-salt form e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof
  • any physical form thereof e.g., including non-solid forms (e.
  • the term ""optionally substituted” indicates that a group, such as alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent(s) as defined. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
  • R 1 is (C 1 -C 4 )alkyl.
  • R 1 is methyl or ethyl.
  • X is N or CH. In a specific embodiment of this invention, X is CH.
  • Y is N or CR 4 and Z is N or CR 4 .
  • Y and Z are each independently CR 4 .
  • Such compounds of the invention may be depicted according to Formula la:
  • Y is CR 4 and Z is N.
  • pounds of the invention may be depicted according to Formula lb:
  • Y is N and Z is CR 4 .
  • Such compounds of the invention may be depicted according to Formula Ic:
  • R 2 is H, halogen, (C C 8 )alkyl, (d-C 8 )haloalkyl, hydroxy(C C 8 )alkyl-, (Ci-Ce)alkylthio-, (C C 8 )haloalkylthio-, (C 3 -C 8 )cycloalkylthio-, aryl, heteroaryl, -N(R a )(R b ), or -OR c ; wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC 6 )alkyl, (Ci-C 4 )haloalkyl, hydroxyl, (Ci-C 6 )alkoxy,
  • R 2 is H, F, CI, Br, (CrC 6 )alkyl
  • (C 1 -C 4 )haloalkyl cyano, hydroxyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, hydroxy(C 1 -C 4 )alkyl-, (Ci-C 4 )alkoxy(CrC 4 )alkyl-, amino, (Ci-C 4 )alkylamino, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino.
  • R 2 is H, F, CI, methyl, phenyl, 1-methyl- pyrazol-5-yl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, n-propoxy, 3,3,3-trifluoro-n-propoxy, n-butoxy, s-butoxy, 1-methyl-3,3,3-trifluoro-n-propoxy,
  • R 3 is H.
  • R 2 and R 3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, hydroxy(Ci-C 4 )alkyl-, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, (Ci-C 4 )alkylthio-, (C C 4 )haloalkylthio-; -C0 2 R , -(C C 4 )alkyl-C0 2 R , -COR f , -CON(R d )(R e ), and -(C C 4 )alkyl-CON(R d )(R e ).
  • R 2 and R 3 taken together represent -CH 2 CH 2 -.
  • each R 4 is independently selected from H, halogen, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C C 4 )haloalkyl, (C C 4 )alkoxy,
  • aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC 6 )alkyl, (C 3 -C 6 )cycloalkyl, (CrC 4 )haloalkyl, cyano, nitro, -OR c , -N(R d )(R e ), -CON(R d )(R e ), -C0 2 R c , -CO(C C 4 )alkyl, -S0 2 N(R d )(R e ),
  • each R 4 is independently selected from H, F, CI, Br, (C C 6 )alkyl, (d-C 4 )haloalkyl, (C C 4 )alkoxy, (d-C 4 )haloalkoxy, (C C 4 )alkylthio-, cyano, -C0 2 H, -C0 2 (C C 4 )alkyl, -CONH 2 , -CONH(C C 4 )alkyl-,
  • -NHCO(Ci-C 4 )alkyl phenyl, halophenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.
  • At least one R 4 is H, F, CI, Br, methyl, isopropyl, isobutyl, cyano, carboxy, isopropyloxycarbonyl, f-butyloxycarbonyl, pyrrolidin-1 - ylcarbonyl, furan-2-yl, furan-3-yl, 5-methyl-furan-2-yl, 1-methyl-pyrazol-4-yl, 1-methyl- pyrazol-5-yl, 3,6-dihydro-2H-pyran-4-yl, phenyl, 4-fluorophenyl, 2-chlorophenyl,
  • Representative compounds of this invention include the compounds of Examples
  • the compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • polymorphism i.e. the capacity to occur in different crystalline forms. These different crystalline forms are typically known as "polymorphs.” It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • solvates of the compounds of the invention, or salts thereof, that are in crystalline form may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • the compounds of this invention are bases, wherein a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesul
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
  • hydroxybenzoates methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ -hydroxybutyrates, glycollates, tartrates, mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates and naphthalene-2-sulfonates.
  • Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base Such a
  • pharmaceutically acceptable salt may be made with a base which affords a
  • pharmaceutically acceptable cation which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ /, ⁇ /'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
  • alkali metal salts especially sodium and potassium
  • alkaline earth metal salts especially calcium and magnesium
  • aluminum salts and ammonium salts as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ /, ⁇ /'-di
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt
  • the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK a than the free acid form of the compound.
  • the compounds of Formula I may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different R 1 , R 2 , and R 3 groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula I, they are illustrative of processes that may be used to make the compounds of the invention.
  • the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar- NH-R 3 ) with an activated pyrrolopyrimidine.
  • an aryl/heteroaryl amine e.g., Ar- NH-R 3
  • Ar-NH-R 3 AgOTf, DMF, 80-100 °C, 5-20 h; b) Ar-NH-R 3 , isopropanol, ⁇ w, 100-150 °C, 10-25 min; c) Ar-NH-R 3 , AgOTf, isopropanol, ⁇ w, 100- 160 °C, 0.5-1 .25 h; d) Ar-NH-R 3 , AgOTf, isopropanol, ⁇ w, 80 °C, 16-42 h; e) Ar-NH-R 3 , isopropanol, aq. HCI, ⁇ , 150 °C, 30-60 min; f) ArNH-R 3 , 1 ,4- dioxane, AcOH, 90 °C, 24 h
  • the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar-NH-R 3 ) with an activated pyrrolopyrimidine, pyrazolopyrimidine, or imidazopyrimidine.
  • an aryl/heteroaryl amine e.g., Ar-NH-R 3
  • Ar-NH-R 3 isopropanol, 80 °C, 16-42 h; b) Ar-NH-R 3 , DMF, AgOTf, 80 °C, 16-20 h; c) Ar-NH-R 3 , 1 ,4-dioxane, AgOTf, 80-100 °C, 16-72 h; d) Ar-NH-R 3 , 1 ,4-dioxane, DIPEA, 80-100 °C, 16-72 h; e) Ar-NH-R 3 , 1 ,4- dioxane, AcOH, 80-100 °C, 20-72 h
  • the invention also includes various deuterated forms of the compounds of Formula
  • deuterated alkyl groups (/V-(deuteromethyl) amines or R a /R b or R d /R e alkyls) may be prepared by conventional techniques (see for example: methyl-c/3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).
  • Scheme 1 or Scheme 2 Employing such compounds according to Scheme 1 or Scheme 2 will allow for the compounds of Formula I in which various hydrogen atoms of the /V-methyl, phenyl or pyrimidinyl groups are replaced with a deuterium atom.
  • the present invention is directed to a method of inhibiting TNNI3K which comprises contacting the kinase with a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • This invention is also directed to a method of treatment of a TNNI3K-mediated disease or disorder comprising administering an effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof.
  • patient refers to a human or other mammal.
  • this invention is directed to a method of inhibiting TNNI3K activity, comprising contacting the kinase with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • TNNI3K activity may be inhibited in mammalian cardiac tissue by administering to a patient in need thereof, an effective amount a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention may be particularly useful for treatment of TNNI3K-mediated diseases or disorders, specifically by inhibition of TNNI3K activity, where such diseases or disorders are selected from heart failure, particularly congestive heart failure; cardiac hypertrophy; and heart failure or congestive heart failure resulting from cardiac hypertrophy.
  • diseases or disorders are selected from heart failure, particularly congestive heart failure; cardiac hypertrophy; and heart failure or congestive heart failure resulting from cardiac hypertrophy.
  • the compounds of this invention may also be useful for the treatment of heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.
  • a therapeutically "effective amount” is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate or inhibit the activity of TNNI3K such that a disease condition which is mediated by that activity is reduced, allew ' ated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC 5 o), efficacy (EC 5 o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular compound e.g., the potency (pXC 5 o), efficacy (EC 5 o), and the biological half-life of the particular compound
  • disease condition and its severity e.g., the identity of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by TNNI3K.
  • the methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • the compounds of Formula I of this invention may be useful for the treatment of heart failure, particularly congestive heart failure.
  • the compounds of Formula I of this invention may be useful for the treatment of cardiac hypertrophy, and heart failure or congestive heart failure resulting from cardiac hypertrophy, myocardial ischemia or myocardial infarction.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Treatment of TNNI3K-mediated disease conditions may be achieved using the compounds of this invention as a monotherapy, or in dual or multiple combination therapy, such as in combination with other cardiovascular agents, for example, in combination with one or more of the following agents: a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker (ARB), a calcium channel blocker, a diuretic, a renin inhibitor, a centrally acting antihypertensive, a dual ACE/NEP inhibitor, an aldosterone synthase inhibitor, and an aldosterone-receptor antagonist, which are administered in effective amounts as is known in the art.
  • a beta-blocker an ACE inhibitor
  • ARB angiotensin receptor blocker
  • beta blockers examples include timolol (such as BlocardenTM), carteolol (such as CartrolTM), carvedilol (such as CoregTM), nadolol (such as CorgardTM), propanolol (such as Innopran XLTM), betaxolol (such as KerloneTM), penbutolol (such as LevatolTM), metoprolol (such as Lopressort M and Toprol-XLTM), atenolol (such as TenorminTM), pindolol (such as ViskenTM), bisoprolol, bucindolol, esmolol, acebutolol, labetalol, nebivolol, celiprolol, sotalol, and oxprenolol.
  • timolol such as BlocardenTM
  • carteolol such as CartrolTM
  • carvedilol such as Coreg
  • ACE inhibitors examples include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril.
  • Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril.
  • angiotensin receptor blockers examples include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.
  • suitable calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. Suitable DHPs include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine,
  • Suitable non-DHPs are flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil, and their pharmaceutically acceptable salts.
  • a suitable diuretic is a thiazide derivative selected from amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.
  • a suitable renin inhibitor is aliskiren.
  • Suitable centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa.
  • suitable dual ACE/NEP inhibitors include omapatrilat, fasidotril, and fasidotrilat.
  • suitable aldosterone synthase inhibitors include anastrozole, fadrozole, and exemestane.
  • suitable aldosterone-receptor antagonists include spironolactone and eplerenone.
  • a compound of the invention may be employed alone, in combination with one or more other compounds of the invention or in combination with other therapeutic methods or agents.
  • combination with other chemotherapeutic, biologic, hormonal, antibody and supportive care agents is envisaged as well as combination with surgical therapy and radiotherapy.
  • Supportive care agents include analgesics, anti-emetics and agents used to treat heamatologic side effects such as neutropenia. Analgesics are well known in the art.
  • Anti-emetics include but are not limited to 5HT 3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like; prochlorperazine; metaclopromide; diphenhydramine; promethazine; dexamethasone; lorazepam; haloperidol; dronabinol; olanzapine; and neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopitant administered alone or in various combinations.
  • 5HT 3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like
  • prochlorperazine metaclopromide
  • diphenhydramine promethazine
  • dexamethasone dexamethasone
  • lorazepam haloperidol
  • dronabinol olanzapine
  • neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopi
  • chemotherapeutic refers to any chemical agent having a therapeutic effect on the subject to which it is administered.
  • “Chemotherapeutic” agents include but are not limited to anti-neoplastic agents.
  • anti-neoplastic agents include both cytotoxic and cytostatic agents including biological, immunological and vaccine therapies.
  • Combination therapies according to the invention thus comprise the administration of at least one compound of the invention and the use of at least one other treatment method.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and surgical therapy.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and radiotherapy.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and at least one supportive care agent (e.g., at least one anti-emetic agent).
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one other chemotherapeutic agent.
  • the invention comprises the administration of at least one compound of the invention and at least one anti-neoplastic agent.
  • the present invention provides the methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one chemotherapeutic agent.
  • the chemotherapeutic agent is an anti-neoplastic agent.
  • the invention provides a pharmaceutical composition as described above further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an antineoplastic agent.
  • the invention also provides methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one supportive care agent (e.g., anti-emetic agent).
  • the compounds of the invention and at least one additional anti-neoplastic or supportive care therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • the administration of a compound of the invention with one or more other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in one unitary
  • composition including both or all compounds or two or more separate pharmaceutical compositions each including one or more of the compounds.
  • the components of the combination may be administered separately in a sequential manner wherein one active ingredient is administered first and the other(s) second or vice versa. Such sequential administration may be close in time or remote in time.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. The appropriate dose of the compound(s) of the invention and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.
  • any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with the compounds of the invention, provided that the particular agent is clinically compatible with therapy employing a compound of the invention.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, topoisomerase I and II inhibitors, hormones and hormonal analogues; retinoids, signal transduction pathway inhibitors including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and
  • immunotherapeutic agents including monoclonals, vaccines or other biological agents.
  • Alkylating agents are non-phase specific anti-neoplastic agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Alkylating agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • alkylating agents include but are not limited to nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil; oxazaphosphor-ines; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; triazenes such as dacarbazine; and platinum
  • coordination complexes such as cisplatin, oxaliplatin and carboplatin.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. The end result of discontinuing S phase is cell death.
  • Antimetabolite neoplastic agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • antimetabolite anti-neoplastic agents include but are not limited to purine and pyrimidine analogues and anti-folate compounds, and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
  • purine and pyrimidine analogues and anti-folate compounds and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
  • Antitumor antibiotic agents are non-phase specific agents, which bind to or intercalate with DNA. Typically, such action disrupts ordinary function of the nucleic acids, leading to cell death. Antitumor antibiotics may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antitumor antibiotic agents include, but are not limited to, actinomycins such as dactinomycin; anthracyclines such as daunorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone; mitomycin C and bleomycins.
  • Antimicrotubule or antimitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Antimitotic agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antimitotic agents include, but are not limited to, diterpenoids, vinca alkaloids, polo-like kinase (PIk) inhibitors and CenpE inhibitors. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vindesine and vinorelbine. PIk inhibitors are discussed further below.
  • Topoisomerase inhibitors include inhibitors of Topoisomerase II and inhibitors of Topoisomerase I.
  • Topoisomerase II inhibitors such as epipodophyllotoxins, are antineoplastic agents derived from the mandrake plant, that typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Camptothecins including camptothecin and camptothecin derivatives, are available or under development as Topoisomerase I inhibitors.
  • Examples of camptothecins include, but are not limited to amsacrine, irinotecan, topotecan, and the various optical forms of 7- (4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy-20-camptothecin.
  • Topoisomerase inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • Antitumor hormones and hormonal analogues may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to antiestrogens, such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene; anti-androgens; such as flutamide, nilutamide, bicalutamide and cyproterone acetate;
  • adrenocorticosteroids such as prednisone and prednisolone
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane
  • progestrins such as megestrol acetate; 5a-reductase inhibitors such as finasteride and dutasteride; and gonadotropin-releasing hormones (GnRH) and analogues thereof, such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
  • progestrins such as megestrol acetate
  • 5a-reductase inhibitors such as finasteride and dutasteride
  • gonadotropin-releasing hormones (GnRH) and analogues thereof such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
  • LHRH Leutinizing Hormone-releasing Hormone
  • Retinoid(s) are compounds that bind to and activate at least one retinoic acid receptor selected from RARa, RAR3, and RARy and/or compounds that bind to and activate at least one of RARa, RAR3, and RARy and also at least one retinoic X receptor (RXR), including RXRa, RXR3, and RXRy.
  • RXR retinoic X receptor
  • Retinoids for use in the present invention typically have affinity for RAR, and particularly for RARa and/or RAR3.
  • certain synthetic retinoids, such as 9-cis-retinoic acid also have affinity for both RAR and RXR.
  • the retinoid has affinity for RARa (and RARa agonist).
  • retinoids examples include: retinoic acid; all-trans-retinoic acid (“ATRA” also known as “tretinoin”); tamibarotene (“Am80”); 9-cis-retinoic acid ((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6- trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic Acid) (also known as “9-cis-Tretinoin”) (available from Sigma); Isotretinoin ((2Z,4£,6£,8£)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid) (also known as "13-cis-retinoic acid”)
  • Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein these changes include, but are not limited to, cell proliferation or differentiation or survival.
  • Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Ras oncogenes. Signal transduction pathway inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinase inhibitors which may be combined with the compounds of the invention include those involved in the regulation of cell growth, which receptor tyrosine kinases are sometimes referred to as "growth factor receptors."
  • growth factor receptor inhibitors include but are not limited to inhibitors of: insulin growth factor receptors (IGF- 1 R, IR and IRR); epidermal growth factor family receptors (EGFR, ErbB2, and ErbB4); platelet derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), macrophage colony stimulating factor (c-fms), c-kit, c- met, fibroblast growth factor receptors (FGFRs), hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB, and TrkC), ephrin (E
  • Trastuzumab (Herceptin ® ) is an example of an anti-erbB2 antibody inhibitor of growth factor function.
  • An anti-erbB1 antibody inhibitor of growth factor function is cetuximab (ErbituxTM, C225).
  • Bevacizumab (Avastin ® ) is an example of a monoclonal antibody directed against VEGFR.
  • small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (Tykerb ® ) and erlotinib (Tarceva ® ).
  • Imatinib (Gleevec ® ) is one example of a PDGFR inhibitor.
  • VEGFR inhibitors include pazopanib (VotrientTM), ZD6474, AZD2171 , PTK787, sunitinib and sorafenib.
  • the invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with an EGFR or ErbB inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with lapatinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with trastuzumab. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with erlotinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with gefitinib.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a VEGFR inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with pazopanib.
  • Tyrosine kinases that are not transmembrane growth factor receptor kinases are termed non-receptor, or intracellular tyrosine kinases.
  • Inhibitors of non-receptor tyrosine kinases are sometimes referred to as "anti-metastatic agents" and are useful in the present invention.
  • Targets or potential targets of anti-metastatic agents include, but are not limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl and Bcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase (BTK).
  • Non-receptor kinases and agents, which inhibit non-receptor tyrosine kinase function are described in Sinha, S. and Corey, S.J., J. Hematother. Stem Cell Res. (1999) 8 465-80; and Bolen, J.B. and Brugge, J.S., Annu. Rev. of Immunol. (1997) 15 371-404.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, but not limited to, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • Src inhibitors include, but are not limited to, dasatinib and BMS-354825 (J. Med. Chem. (2004) 47 6658-6661 ).
  • Inhibitors of serine/threonine kinases may also be used in combination with the compounds of the invention in any of the compositions and methods described above.
  • Examples of serine/threonine kinase inhibitors that may also be used in combination with a compound of the present invention include, but are not limited to, polo-like kinase inhibitors (Plk family e.g., Plk1 , Plk2, and Plk3), which play critical roles in regulating processes in the cell cycle including the entry into and the exit from mitosis; MAP kinase cascade blockers, which include other Ras/Raf kinase inhibitors, mitogen or extracellular regulated kinases (MEKs), and extracellular regulated kinases (ERKs); Aurora kinase inhibitors (including inhibitors of Aurora A and Aurora B); protein kinase C (PKC) family member blockers, including inhibitors of PKC subtypes (alpha, beta, gamma,
  • PKB/Akt kinase family inhibitors and inhibitors of TGF-beta receptor kinases.
  • Examples of PIk inhibitors are described in PCT Publication No. WO04/014899 and WO07/03036.
  • Other examples of serine/threonine kinase inhibitors are known in the art.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a PIk inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with 5- ⁇ 6- [(4-methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl ⁇ -3- ⁇ (1 R)-1-[2- (trifluoromethyl)phenyl]ethoxy ⁇ thiophene-2-carboxamide.
  • Urokinase also referred to as urokinase-type Plasminogen Activator (uPA) is a serine protease. Activation of the serine protease plasmin triggers a proteolysis cascade which is involved in thrombolysis or extracellular matrix degradation. Elevated expression of urokinase and several other components of the plasminogen activation system have been correlated with tumor malignancy including several aspects of cancer biology such as cell adhesion, migration and cellular mitotic pathways as well. Inhibitors of urokinase expression may be used in combination with the compounds of the invention in the compositions and methods described above.
  • Inhibitors of Ras oncogene may also be useful in combination with the compounds of the present invention.
  • Such inhibitors include, but are not limited to, inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti- sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block Ras activation in cells containing mutant Ras, thereby acting as antiproliferative agents.
  • Inhibitors of kinases involved in the IGF-1 R signaling axis may also be useful in combination with the compounds of the present invention.
  • Such inhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and 14.3.3 signaling inhibitors. Examples of AKT inhibitors are described in PCT Publication No. WO 2007/058850, published 24 May 2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9 Nov 2006.
  • AKT inhibitor disclosed therein is 4-(2-(4-amino-1 ,2,5- oxadiazol-3-yl)-1 -ethyl-7- ⁇ [(3S)-3-piperidinylmethyl]oxy ⁇ -1 /-/-imidazo[4,5-c]pyridin-4-yl)-2- methyl-3-butyn-2-ol.
  • Cell cycle signaling inhibitors including inhibitors of cyclin dependent kinases (CDKs) are also useful in combination with the compounds of the invention in the compositions and methods described above. Examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania G. R. et al., Exp. Opin. Ther. Patents (2000) 10 215-230.
  • Receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases).
  • Other inhibitors may be used in combination with the compounds of the invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that inhibit angiogenesis; endostatin and angiostatin (non-rtK) may also prove useful in combination with the compounds of the invention.
  • VEGFR antibody is bevacizumab (Avastin ® ).
  • Inhibitors of phosphatidyl inositol-3-OH kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in combination with the present invention.
  • myoinositol signaling inhibitors such as phospholipase C blockers and myoinositol analogues.
  • siRNA, RNAi, locked nucleic acid polynucleotides, and antisense therapies may also be used in combination with the compounds of the invention.
  • antisense therapies include those directed towards the targets described above such as ISIS 2503 and gene therapy approaches such as those using thymidine kinase or cytosine deaminase.Agents used in immunotherapeutic regimens may also be useful in
  • Immunotherapeutic regimens include ex-vivo and in-vivo approaches to increasing immunogenicity of patient tumor cells such as transfection with cytokines (eg. IL-2, IL-4, GMCFS and MCFS), approaches to increase T-cell activity, approaches with transfected immune cells and approaches with anti- idiotypic antibodies.
  • cytokines eg. IL-2, IL-4, GMCFS and MCFS
  • approaches to increase T-cell activity approaches with transfected immune cells and approaches with anti- idiotypic antibodies.
  • Another potentially useful immunotherapeutic regimen is monoclonal antibodies with wild-type Fc receptors that may illicit an immune response in the host (e.g., IGF-1 R monoclonal antibodies).
  • Bcl-2 antisense oligonucleotides may also be used in combination with the compounds of the invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of Bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • mcl-1 mcl-1 . Therefore, strategies designed to downregulate the expression of Bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide.
  • the invention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by TNNI3K or B-Raf kinase.
  • the invention includes the use of compounds of the invention in the treatment of heart failure, particularly congestive heart failure; cardiac hypertrophy; heart failure or congestive heart failure resulting from cardiac hypertrophy; and heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.
  • the invention includes the use of compounds of the invention in the treatment of susceptible neoplasms.
  • Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer;
  • central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and
  • erythroleukemia hepatocellular carcinoma
  • lung cancer including small cell lung cancer and non-small cell lung cancer
  • ovarian cancer endometrial cancer
  • pancreatic cancer pituitary adenoma
  • prostate cancer renal cancer
  • sarcoma skin cancers including melanomas
  • thyroid cancers include melanomas
  • the invention includes the use of compounds of the invention in the manufacture of a medicament for use in the treatment of the above disease and disorders.
  • the compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof).
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a material, composition or vehicle involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • the compounds of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants,
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • KOf-Bu (1 .908 g, 17.00 mmol) was added to a dark orange solution of 6-bromo-4- chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine (1 .267 g, 3.4 mmol) in THF (34 mL) in a 250 mL round bottom flask. The orange suspension was then stirred at rt under nitrogen for 3.5 h. The reaction mixture was diluted with sat. aq. NaHC0 3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
  • deazapurine was prepared from 5-bromo-4-chloro-1 /-/-pyrrolo[2,3- c/]pyrimidine using the indicated alkyl halide and procedures analogous to those described in Preparation 16:
  • reaction material was purified by flash column chromatography (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ). The resulting solid was triturated with MeOH to afford the title compound (130 mg, 66.4%) as an off-white solid.
  • reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent to afford the title compound (1 .5 g, 74.8%) as an off white solid.
  • reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH 4 OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent to afford the title compound (98 mg, 31.6%) as an off white solid.
  • reaction materials were concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent.
  • the resulting solid was triturated with CH 2 CI 2 to afford the title compound (1 12 mg, 45%) as a light tan solid.
  • the organic portion was concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent.
  • the resulting solid was triturated with CH 2 CI 2 to afford 50 mg of an off-white solid.
  • the solid was further purified by reverse phase HPLC using 10-80% CH 3 CN/water (0.1 % TFA mobile phase).
  • the resulting TFA salt was neutralized with aq. NaHC0 3 , then extracted into EtOAc.
  • the organic extract was dried over Na 2 S0 4 and concentrated to afford the title compound (40 mg, 27%) as an off-white solid.
  • reaction materials were concentrated onto Celite ® and purified by flash column chromatography using 0-60% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent to afford the title compound (42 mg, 1 1 %) as an off-white solid.
  • the organic layer was concentrated onto Celite ® and purified by flash column chromatography using 30-80% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent.
  • the resulting solid was triturated with CH 2 CI 2 , followed by further purification by reverse phase HPLC using 10-50 CH 3 CN/water (0.1 % TFA in mobile phase).
  • the resulting TFA salt was basified with 1 % NH 4 OH / 9% MeOH / 90% CHCI 3 and concentrated down to dryness. The residue was triturated with water to afford the title compound (80 mg, 39%) as light pink solid.
  • a heterogeneous mixture of AgOTf (0.70 g, 2.72 mmol), 2-chloropurine (0.35 g, 2.26 mmol) and 3-amino-4-(dimethylamino)-/V-methylbenzenesulfonamide (0.62 g, 2.72 mmol) in 1 ,4-dioxane (22 mL) was stirred at 100 °C in a sealed high pressure vessel for 18 h. A dark grey precipitate formed which contained most of the product.
  • the reaction mixture was concentrated in vacuo, the solid residue dispersed into silica gel, and purified by flash column chromatography using 0-10% 10:1 :90 MeOH:NH 4 OH:EtOAc in EtOAc as eluent.
  • the desired fractions were combined and concentrated in vacuo.
  • the residue was dissolved in a small amount of CH 2 CI 2 and MeOH and a white precipitate came out of solution upon concentration. This precipitate was collected to afford the title compound (350mg, 44.5%) as an off-white solid.
  • a heterogeneous mixture of AgOTf (0.70 g, 2.72 mmol), 2-chloropurine (0.35 g, 2.26 mmol) and 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide (0.60 g, 2.77 mmol) in 1 ,4-dioxane (1 1 ml.) was stirred at 100 °C in a sealed high pressure vessel for 18 h.
  • the reaction mixture was filtered through a pad of Celite ® , washing with MeOH.
  • the filtrate was concentrated and purified by flash column chromatography, eluting with 10:1 :90 MeOH:NH 4 OH:CHCI 3 .
  • the reaction vessel was sealed and heated at 100 °C for 20 h.
  • the mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI 3 containing 0.1 % ⁇ 3 ⁇ 2 0) to afford a yellow solid which was triturated with CH 2 CI 2 to afford the title compound (133 mg, 48%) as a light yellow solid.

Abstract

L'invention porte sur des composés répondant à la formule (I), dans laquelle X, Y, Z, R1, R2 et R3 sont tels que définis par les présentes, ainsi que sur leurs procédés de fabrication et d'utilisation.
PCT/US2011/037533 2010-05-24 2011-05-23 Composés et procédés WO2011149827A1 (fr)

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WO2014044691A1 (fr) * 2012-09-20 2014-03-27 Bayer Pharma Aktiengesellschaft Pyrrolopyrimidinylaminobenzothiazolones substituées comme inhibiteurs de mknk kinase
CN104119342A (zh) * 2013-04-25 2014-10-29 苏州科捷生物医药有限公司 一种制备高纯度4-氯-5-甲基-7H-吡咯[2,3-d]嘧啶的方法
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CN109422748A (zh) * 2017-08-21 2019-03-05 南京理工大学 合成tnni3k抑制剂的方法
CN109734674A (zh) * 2019-02-26 2019-05-10 中国药科大学 苯胺类wdr5蛋白-蛋白相互作用抑制剂及其制法和用途
CN109952306A (zh) * 2016-04-19 2019-06-28 加利福尼亚大学董事会 ErbB抑制剂及其用途
JP2019535673A (ja) * 2016-10-21 2019-12-12 ニンバス ラクシュミ， インコーポレイテッド Ｔｙｋ２阻害剤およびその使用
CN112794855A (zh) * 2019-11-13 2021-05-14 中国药科大学 N-芳基嘧啶-4-胺类衍生物及其应用
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AU2012299899B2 (en) * 2011-08-23 2016-09-15 Merck Patent Gmbh Bicyclic heteroaromatic compounds
WO2013026516A1 (fr) * 2011-08-23 2013-02-28 Merck Patent Gmbh Composés hétéroaromatiques bicycliques
US9296757B2 (en) 2012-05-21 2016-03-29 Bayer Pharma Aktiengesellschaft Substituted benzothienopyrimidines
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
WO2014044691A1 (fr) * 2012-09-20 2014-03-27 Bayer Pharma Aktiengesellschaft Pyrrolopyrimidinylaminobenzothiazolones substituées comme inhibiteurs de mknk kinase
JP2015529232A (ja) * 2012-09-20 2015-10-05 バイエル・ファルマ・アクティエンゲゼルシャフト 置換ピロロピリミジニルアミノ−ベンゾチアゾロン
US9382255B2 (en) 2012-09-20 2016-07-05 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyrimidinylamino-benzothiazolones as MKNK kinase inhibitors
CN104119342A (zh) * 2013-04-25 2014-10-29 苏州科捷生物医药有限公司 一种制备高纯度4-氯-5-甲基-7H-吡咯[2,3-d]嘧啶的方法
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US11020400B2 (en) 2015-12-23 2021-06-01 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US10933065B2 (en) 2015-12-23 2021-03-02 Arqule Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US10245263B2 (en) 2015-12-23 2019-04-02 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
CN109952306A (zh) * 2016-04-19 2019-06-28 加利福尼亚大学董事会 ErbB抑制剂及其用途
EP3445768A4 (fr) * 2016-04-19 2019-12-18 The Regents of The University of California Inhibiteurs de erbb et leurs utilisations
US11020398B2 (en) 2016-08-24 2021-06-01 Arqule, Inc. Amino-pyrrolopyrimidinone compounds and methods of use thereof
JP2019535673A (ja) * 2016-10-21 2019-12-12 ニンバス ラクシュミ， インコーポレイテッド Ｔｙｋ２阻害剤およびその使用
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US11396508B2 (en) 2016-10-21 2022-07-26 Nimbus Lakshmi, Inc. TYK2 inhibitors and uses thereof
CN109422748A (zh) * 2017-08-21 2019-03-05 南京理工大学 合成tnni3k抑制剂的方法
US11479545B2 (en) 2018-04-23 2022-10-25 China Pharmaceutical University Compositions and methods for inhibiting phenyl triazole MLL1-WDR5 protein-protein interaction
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
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