WO2012045195A1 - Pyrrolopyrimidines à titre d'inhibiteurs de fak et d'alk pour le traitement des cancers et autres maladies - Google Patents

Pyrrolopyrimidines à titre d'inhibiteurs de fak et d'alk pour le traitement des cancers et autres maladies Download PDF

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WO2012045195A1
WO2012045195A1 PCT/CN2010/001578 CN2010001578W WO2012045195A1 WO 2012045195 A1 WO2012045195 A1 WO 2012045195A1 CN 2010001578 W CN2010001578 W CN 2010001578W WO 2012045195 A1 WO2012045195 A1 WO 2012045195A1
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Prior art keywords
amino
methyl
pyrrolo
pyrimidin
methylsulfonyl
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PCT/CN2010/001578
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English (en)
Inventor
Jennifer Van Camp
Xiangdong Xu
Augustine Toby Osuma
Robert Gregg
Kenton L. Longenecker
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Abbott Laboratories
Abbott Laboratories Trading (Shanghai) Company, Ltd.
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Priority to PCT/CN2010/001578 priority Critical patent/WO2012045195A1/fr
Publication of WO2012045195A1 publication Critical patent/WO2012045195A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention pertains to compounds which inhibit the activity of focal adhesion kinase (FAK) and anaphastic lymphoma kinase (ALK), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
  • FAK focal adhesion kinase
  • ALK anaphastic lymphoma kinase
  • Tyrosine kinases play a critical role in signal transduction for several cellular functions including cell proliferation, carcinogenesis, apoptosis, and cell differentiation. Inhibitors of these enzymes are useful for the treatment or prevention of proliferative diseases which are dependent of these enzymes.
  • FAK Focal adhesion kinase
  • FAK Focal adhesion kinase
  • FAK is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways.
  • FAK co-localizes with integrins in focal contact sites.
  • FAK activation and its tyrosine phosphorylation have bee shown in many cell types to be dependent on integrins binding to their extracellular ligands. Results from several studies support the hypothesis that FAK inhibitors could be useful in cancer treatment. For example, FAK-deficient cells migrate poorly in response to chemotactic signals and over-expression of C-terminal domain of FAK blocks cell spreading as well as chemotactic migration (Sieg et al, J.
  • Anaphastic lymphoma kinase (ALK), a member of the insulin receptor super family of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and non-hematopoietic tumors.
  • ALK Anaphastic lymphoma kinase
  • the aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas (Gascoyne et al, Blood, 2003, 102, 2568-2573; Griffin et al, Cancer Res., 1999, 59, 2776-2780; Lawrence et al, Am. J. Pathol, 2000, 157, 377-384). Additionally, ALK fusion proteins have occurred in anaplastic large cell lymphoma.
  • the present invention provides novel pyiTolopyrimidines that are selective inhibitors of FAK and ALK. Such compounds can be used to treat subjects suffering from cancer, and can further expand the range of treatment options available for such subjects.
  • One embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of focal adhesion kinase (FAK) and anaphastic lymphoma kinase (ALK), the compounds having Formula ( ⁇ )
  • Y is aryl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • each R 6 is independently alkyl
  • R is hydrogen or alkyl; R is alkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , SR 10 , S(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 ,
  • each R 10 is independently R 11 , R 12 , R 13 , or R 14 ;
  • R 11 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R 14 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 15 , OR 15 , SR 15 , S(0)R 15 , S0 2 R 15 , C(0)R 15 , CO(0)R 15 , OC(0)R 15 , OC(0)OR 15 , NH 2 , NHR 15 , N(R 15 ) 2 , NHC(0)R 15 , NR 15 C(0)R 15 , NHS(0) 2 R 15 , NR 15 S(0) 2 R 15 , NHC(0)OR 15 , NR 15 C(0)OR 15 ,
  • each R 15 is independently R 16 , R 17 , R 18 , or R 19 ;
  • R is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; 19
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 20 , OR 20 , SR 20 , S(0)R 20 , S0 2 R 2 °,
  • NR 20 C(O)R 20 NHS(0) 2 R 20 , NR 20 S(O) 2 R 20 , NHC(0)OR 20 , NR 20 C(O)OR 20 ,
  • each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R , R , R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected R 21 , OR 21 , SR 21 , S(0)R 21 , S0 2 R 21 , C(0)R 21 , CO(0)R 21 , OC(0)R 21 , OC(0)OR 21 , NH 2 , NHR 21 , N(R 21 ) 2 , NHC(0)R 21 , NR 21 C(0)R 21 , NHS(0) 2 R 21 , NR 21 S(0) 2 R 21 ,
  • NHC(0)OR 21 NR 21 C(0)OR 21 , NHC(0)NH 2 , NHC(0)NHR 21 , NHC(0)N(R 21 ) 2 , NR 21 C(0)NHR 21 , NR 21 C(0)N(R 21 ) 2 , C(0)NH 2 , C(0)NHR 21 , C(0)N(R 21 ) 2 ,
  • each R 21 is independently R 22 , R 23 , R 24 , or R 25 ;
  • R 22 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 26 , OR 26 , SR 26 , S(0)R 26 , S0 2 R 26 , C(0)R 26 , CO(0)R 26 , OC(0)R 26 , OC(0)OR 26 , NH 2 , NHR 26 , N(R 26 ) 2 , NHC(0)R 26 , P T/CN2010/001578
  • OCF 3 OCF 2 CF 3 , F, CI, Br, or I;
  • each R is independently alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected NH 2 , C(0)NH 2 , C(0)NHOH,
  • X is NHCH 2 .
  • X is NHCH 2 ; and Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 .
  • X is NHCH 2 ; and Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 .
  • X is NHCH 2 ; Y is aryl; wherein the aryl is substituted withNR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • X is NHCH 2 ; Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • X is NHCH 2 ; Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 , R 2 , R 4 , and R s , are hydrogen; and R 3 is C(0)NHR 10 .
  • X is NHCH 2 ; Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 , R 3 , R 4 , and R 5 , are hydrogen; and R 2 is C(0)NHR 10 .
  • X is NHCH 2 ; Y is aryl; wherein the aryl is substituted with R 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 , R 4 , and R 5 are hydrogen; R 1 is OR 10 ; and R 3 is R 10 or C(0)NHR 10
  • Still another embodiment pertains to compounds having Formula (I), which are 4- ⁇ [4-( ⁇ 2-[methyl(methylsulfonyl)amino]benzyl ⁇ amino)-7H-pyrrolo[2,3-d]pyrimidin-2- yl]amind ⁇ -N-(3-morpholin-4-ylpropyl)benzamide;
  • Another embodiment pertains to a composition for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of a compound of Formula (1).
  • Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I).
  • Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • Variable moieties herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.
  • variable moiety herein may be the same or different as another specific embodiment having the same identifier.
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-burynyl, 2-penrynyl, and 1-butynyl.
  • aryl means phenyl, a bicyclic aryl or a tricyclic aryl.
  • the bicyclic aryl is naphthyl, or a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl, or a phenyl fused to a monocyclic heteroaryl ring as defined herein, or a phenyl fused to a monocyclic heterocycle as defined herein.
  • the bicyclic aryl of the present invention must be attached to the parent molecular moiety through any available carbon atom contained within the phenyl ring.
  • bicyclic aryl examples include, but are not limited to, 2,3-dihydro-l,4-benzodioxin-5-yl, 2,3-dihydro-l,4- benzodioxin-6-yl, 3,4-dihydro-2H-l,5-benzodioxepin-6-yl, dihydroindenyl, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl.
  • the tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or a bicyclic aryl fused to a phenyl.
  • the tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the tricyclic aryl.
  • Representative examples of tricyclic aryl ring include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.
  • cycloalkenyl as used herein, means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring system containing from 3 to 12 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • monocyclic ring systems include, but are not limited to, 2- cyclohexen-l-yl, 3-cyclohexen-l-yl, 2,4-cyclohexadien-l-yl and 3-cyclopenten-l-yl.
  • Bicyclic ring systems are exemplified by a monocyclic cycloalkenyl ring system which is fused to another monocyclic cycloalkyl ring as defined herein, a monocyclic aryl ring as defined herein, a monocyclic heterocycle as defined herein or a monocyclic heteroaryl as defined herein.
  • bicyclic ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the cycloalkenyl ring.
  • Representative examples of bicyclic ring systems include, but are not limited to, 4,5-dihydro-benzo[l,2,5]oxadiazole, 3a, 4, 5, 6, 7, 7a-hexahydro-lH-indenyl, 1, 2, 3, 4, 5, 6-hexahydro-pentalenyl, 1, 2, 3, 4, 4a, 5, 6, 8a-octahydro-pentalenyl.
  • cycloalkyl as used herein, means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring system containing a saturated cyclic hydrocarbon group containing from 3 to 12 carbon atoms.
  • monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl groups of the present invention are exemplified by a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused cycloalkenyl, or a monocyclic cycloalkyl ring fused to a phenyl ring, or a monocyclic cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein, or a monocyclic cycloalkyl ring fused to a monocyclic heterocycle as defined herein.
  • the bicyclic cycloalkyl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the monocycloalkyl ring.
  • heteroaryl means a monocyclic heteroaryl, a bicyclic heteroaryl, or a tricyclic heteroaryl.
  • the monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from O, N, or S.
  • the 5 membered ring contains two double bonds may contain one, two, three or four heteroatoms.
  • the 6 membered ring contains three double bonds may contain one, two, three or four heteroatoms.
  • the 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring as defined herein, another monocyclic heteroaryl or a monocyclic heterocycle ring as defined herein.
  • the bicyclic heteroaryl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the heteroaryl ring.
  • the bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl.
  • bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine and thienopyridinyl.
  • heterocycle refers to a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring system that contains at least one heteroatom.
  • the monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, isoindoline-l,3-dione, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetraliydrofur
  • the bicyclic heterocycle of the present invention is defined as a monocyclic heterocycle fused to a phenyl group, a cycloalkylgroup as defined herein, a cycloalkenyl group as defined herein, another monocyclic heterocycle group as defined herein, or a spirocyclic ring wherein one carbon atom of the monocyclic heterocycle is bridged by two ends of an alkylene chain.
  • bicyclic heterocycle of the present invention is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclic ring.
  • Representative examples of bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 3,4-dihydro-lH- isochromen-4-yl, 2,3-dihydro-lH-indolyl, succinmimidyl, and
  • the tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle.
  • the tricyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle.
  • tricyclic heterocycle include, but are not limited to, 2,3,4,4a,9,9a-hexahydro- lH-carbazolyl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a- hexahydrodibenzo [b,d]thienyl.
  • heterocycloalkyl means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged heterocycle, as defined herein, wherein the 5 membered ring contains zero double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S, and the 6 or 7 membered ring contains zero double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • heterocycloalkenyl means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged heterocycle, as defined herein, wherein the 5 membered ring contains one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S, and the 6 or 7 membered ring contains one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • phenyl as used herein, means a monovalent radical formed by removal of a hydrogen atom from benzene.
  • spiroalkyl means a spirocyclic cycloalkyl as defined herein.
  • spirocyclic means a ring system wherein one atom is common to two different rings.
  • bridged means a ring system wherein the rings share at least two common non-adjacent atoms.
  • NH protecting group means trichloroethoxycarbonyl, tribronioethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl,
  • ortho-bromobenzyloxycarbonyl chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbony 1, para-methoxybenzyloxycarbony 1, 3 ,4-dimethoxy benzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,
  • diphenylmethoxycarbonyl 1, 1-dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, para- toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthyl-methylene, 3-hydroxy-4- pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,
  • 2-ethoxycarbonylcyclopentylidene 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclo- hexylidene, diphenylphosphoiyl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-l,3-dioxol-4- yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.
  • C(0)OH protecting group means methyl, ethyl, n-propyl, isopropyl, 1 , 1 -dimethylpropyl, n-buryl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para- methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoyhnethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclo
  • 2,2,2-trichloro-ethoxymethyl 2-(trimethylsilyl)ethoxymethy I, 1 -ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
  • Geometric isomers may exist in the present compounds.
  • Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher order substituents on the same side of the carbon-carbon or carbon- nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules.
  • the compounds of this invention may also exist as a mixture of "E” and "Z" isomers.
  • Substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration.
  • the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system.
  • Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuration.
  • C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760 see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.
  • Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms "R” and “S” are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.
  • Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%.
  • this invention includes racemic mixtures, relative and absolute
  • prodrug-forming moieties may have attached thereto prodrug-forming moieties.
  • the prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed hydroxyl, amino or carboxylic acid in vivo.
  • Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.
  • Compounds of this invention can exist in an isotopic form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 14 C, 3 P, 35 S, 18 F, 36 C1, and 12S I, respectively.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • Compounds containing tritium ( 3 H) and 14 C radioisotopes are preferred in general for their ease in preparation and detectability for radiolabeled compounds.
  • Isotopically labeled compounds of this invention can be prepared by the general methods well known to persons having ordinaiy skill in the art. Such isotopically labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Suitable groups for X, Y, R 1 , R 2 , R 3 , R 4 , and R s in compounds of Formula (I) are independently selected.
  • the described embodiments of the present invention may be combined. Such combination is contemplated and within the scope of the present invention.
  • embodiments for any of X, Y, R 1 , R 2 , R 3 , R 4 , and R 5 can be combined with embodiments defined for any other ofX, Y, R 1 , R 2 , R 3 , R 4 and R s .
  • One embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of focal adhesion kinase (FAK) and anaphastic lymphoma kinase (ALK), the compounds having Formula (I)
  • Y is aryl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • each R 6 is independently alkyl;
  • R 7 is hydrogen or alkyl;
  • R 8 is alkyl
  • R 1 , R 2 , R 3 , R 4 , R s , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , SR 10 , S(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 ,
  • each R 10 is independently R 11 , R 12 , R 13 , or R 14 ;
  • R 11 is aryl
  • R is heteroaryl
  • R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R 14 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 15 , OR 15 , SR 15 , S(0)R 15 , S0 2 R 15 , C(0)R 15 , CO(0)R 15 , OC(0)R 15 , OC(0)OR 15 , NH 2 , NHR 15 , N(R I5 ) 2 , NHC(0)R 15 , NR 15 C(0)R 15 , NHS(0) 2 R 15 , NR 15 S(0) 2 R 15 , NHC(0)OR 15 , NR 15 C(0)OR 15 ,
  • each R 15 is independently R 16 , R 17 , R 18 , or R 19 ;
  • R is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 20 , OR 20 , SR 20 , S(0)R 2 °, S0 2 R 2 °, C(0)R 20 , CO(0)R 20 , OC(0)R 20 , OC(0)OR °, NH 2 , NHR 20 , N(R 20 ) 2 , NHC(0)R 20 , NR 20 C(O)R 20 , NHS(0) 2 R 2 °, NR 20 S(O) 2 R 2 °, NHC(0)OR 2 °, NR 20 C(O)OR 20 ,
  • each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R , R , R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected R 21 , OR 21 , SR 21 , S(0)R 21 , S0 2 R 21 , C(0)R 21 , CO(0)R 21 , OC(0)R 21 , OC(0)OR 21 , NH 2 , NHR 21 , N(R 1 ) 2 , NHC(0)R 21 , NR 21 C(0)R 21 , NHS(0) 2 R 21 , NR 21 S(0) 2 R 21 ,
  • NHC(0)OR 21 NR 21 C(0)OR 21 , NHC(0)NH 2 , NHC(0)NHR 21 , NHC(0)N(R 21 ) 2 , NR 21 C(0)NHR 21 , NR 21 C(0)N(R 21 ) 2 , C(0)NH 2 , C(0)NHR 21 , C(0)N(R 1 ) 2 ,
  • each R 21 is independently R 22 , R 23 , R 24 , or R 25 ;
  • R 22 is aryl
  • R is heteroaryl
  • R 24 is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 26 , OR 26 , SR 26 , S(0)R 26 , S0 2 R 26 , C(0)R 26 , CO(0)R 26 , OC(0)R 26 , OC(0)OR 26 , NH 2 , NHR 26 , N(R 26 ) 2 , NHC(0)R 26 , NR 26 C(0)R 26 , NHS(0) 2 R 26 , NR 26 S(0) 2 R 26 , NHC(0)OR 26 , NR 26 C(0)OR 26 ,
  • each R is independently alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • the moieties represented by R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected N3 ⁇ 4, C(0)NH2, C(0)NHOH, SO2NH2, CF 3 , CF2CF3, C(0)H, C(0)OH, C(N)NH 2 , OH, (O), CN, N 3 , N0 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, CI, Br, or I.
  • Y is aryl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • R 7 is hydrogen or alkyl
  • R 8 is alkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH;
  • each R 10 is independently R 11 , R 13 , or R 14 ;
  • R 11 is aiyl
  • R is cycloalkyl, or heterocycloalkyl
  • R 14 is alkyl, which is unsubstituted or substituted with R 15 , OR 15 , N(R 15 ) 2 , or CN; each R 15 is independently R 17 , R 18 , or R 19 ;
  • R is heteroaryl;
  • R is cycloalkyl, or heterocycloalkyl;
  • R 19 is alkyl
  • R 11 , R 13 and R 18 are unsubstituted or substituted with one or two or three or four of independently selected R 21 , OR 21 , CO(0)R 21 ;
  • each R is independently R ;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with R 26 ;
  • each R 26 is aryl.
  • X is CH 2 NH.
  • X is CH 2 HCH 2 .
  • X is NHCH 2 .
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is heteroaryl; wherein the heteroaiyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl, and X is NHCH 2 .
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; and X is HCH 2 .
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; and X is NHCH 2 .
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; and X is HCH 2 .
  • One embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of focal adhesion kinase (FAK) and anaphastic lymphoma kinase (ALK), the compounds having Formula (II)
  • Y is aryl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • R is hydrogen or alkyl
  • R 8 is alkyl
  • R 2 , R 3 , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , SR 10 , S(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(0)R 10 , NR 10 C(O)R 10 , NHS(0) 2 R 10 , NR 10 S(O) 2 R 10 ,
  • NHC(0)OR 10 NR 10 C(O)OR 10 , NHC(0) H 2 , NHC(0)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(0)NH 2 , C(0)NHR 10 , C(O)N(R 10 ) 2 ,
  • each R 10 is independently R U , R 12 , R 13 , or R 14 ;
  • R 11 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R 14 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 15 , OR 15 , SR 15 , S(0)R 15 , S0 2 R 15 , C(0)R 15 , CO(0)R 15 , OC(0)R 15 , OC(0)OR 15 , NH 2 , NHR 15 , N(R I5 ) 2 , NHC(0)R 15 , NR 15 C(0)R 15 , NHS(0) 2 R 15 , NR 15 S(0) 2 R 15 , NHC(0)OR 15 , NR 15 C(0)OR 15 , NR 15 C(0)OR 15 ,
  • each R 15 is independently R 16 , R 17 , R 18 , or R 19 ;
  • R 16 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 20 , OR 20 , SR 20 , S(O)R 20 5 S0 2 R 2 °,
  • NR 20 C(O)R 20 NHS(0) 2 R 20 , NR 20 S(O) 2 R 20 , NHC(0)OR 20 , NR 20 C(O)OR 20 ,
  • each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R , R , R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected R 21 , OR 21 , SR 21 , S(0)R 21 , S0 2 R 21 , C(0)R 21 , CO(0)R 21 , OC(0)R 21 , OC(0)OR 21 , NH 2 , NHR 21 , N(R 21 ) 2 , NHC(0)R 21 , NR 21 C(0)R 21 , NHS(0) 2 R 21 , NR 21 S(0) 2 R 21 ,
  • NHC(0)OR 21 NR 21 C(0)OR 21 , NHC(0)NH 2 , NHC(0)NHR 21 , NHC(0)N(R 21 ) 2 , NR 21 C(0)NHR 21 , NR 2I C(0)N(R 21 ) 2 , C(0)NH 2 , C(0)NHR 21 , C(0)N(R 1 ) 2 ,
  • each R 21 is independently R 22 , R 23 , R 24 , or R 25 ;
  • R 22 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 26 , OR 26 , SR 26 , S(0)R 26 , S0 2 R 26 , C(0)R 26 , C0(0)R 26 , OC(0)R 26 , 0C(0)0R 26 , NH 2 , NHR 26 , N(R 6 ) 2 , NHC(0)R 26 , NR 6 C(0)R 26 , NHS(0) 2 R 26 , NR 26 S(0) 2 R 26 , NHC(0)0R 26 , NR 26 C(0)0R 26 ,
  • each R is independently alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • the moieties represented by R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected NH 2 , C(0)NH 2 , C(0)NHOH, S0 2 NH 2 , CF 3 , CF 2 CF 3 , C(0)H, C(0)OH, C(N)NH 2 , OH, (O), CN, N 3 , N0 2 , CF 3 , CF 2 CF 3 , OCF 3 , 0CF 2 CF 3 , F, CI, Br, or I.
  • Y is aryl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • R is hydrogen or alkyl
  • R 8 is alkyl
  • R 2 , R 3 , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)MIR 10 , C(O)N(R 10 ) 2 , or C(0)OH;
  • each R 10 is independently R 11 , R 13 , or R 14 ;
  • R 11 is aryl
  • R is cycloalkyl, or heterocycloalkyl
  • R 14 is alkyl, which is unsubstituted or substituted with R 15 , OR 15 , N(R 15 ) 2 , or CN; each R 15 is independently R 17 , R 18 , or R 19 ;
  • R 17 is heteroaryl
  • R is cycloalkyl, or heterocycloalkyl
  • R 19 is alkyl
  • each R is independently R ;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with R 26 ;
  • each R is aryl.
  • Y is aryl; wherein the aryl is substituted with R 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R I0 ) 2 , or C(0)OH.
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S(3 ⁇ 4R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is C(0)NHR 10 .
  • Y is phenyl; wherein the phenyl is substituted with
  • NR 7 S0 2 R 8 R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is C(0)NHR 10 .
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is C(0)NHR 10 .
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 2 is hydrogen; and R 3 is C(0)NHR 10 .
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is heteroaiyl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is R 10 , OR 10 , C(0)R 10 , HR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH.
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is C(0)NHR 10 .
  • Y is phenyl; wherein the phenyl is substituted with
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is C(0) HR 10
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 3 is hydrogen; and R 2 is C(0)NHR 10 .
  • One embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of focal adhesion kinase (FAK) and anaphastic lymphoma kinase (ALK), the compounds having Formula (III)
  • Y is aryl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • R 7 is hydrogen or alkyl
  • R 8 is alkyl;
  • R 1 , R 3 , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , SR 10 , S(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(0)R 10 , NR 10 C(O)R 10 , NHS(0) 2 R 10 , NR 10 S(O) 2 R 10 ,
  • each R 10 is independently R 11 , R 12 , R 13 , or R 14 ;
  • R 11 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R 14 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 15 , OR 15 , SR 15 , S(0)R 15 , S0 2 R 15 , C(0)R 15 , CO(0)R 15 , OC(0)R 15 , OC(0)OR 15 , NH 2 , NHR 15 , N(R 15 ) 2 , NHC(0)R 15 , NR 15 C(0)R 15 , NHS(0) 2 R 15 , NR 15 S(0) 2 R 15 , NHC(0)OR 15 , NR 15 C(0)OR 15 ,
  • each R 15 is independently R 16 , R 17 , R 18 , or R 19 ;
  • R 16 is aryl
  • R is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 20 , OR 20 , SR 20 , S(0)R 20 , S0 2 R 20 , C(0)R 20 , CO(0)R 20 , OC(0)R 20 , OC(0)OR 2 °, NH 2 , NHR 20 , N(R 20 ) 2 , NHC(0)R 2 °, NR 20 C(O)R 20 , NHS(0) 2 R 20 , NR 20 S(O) 2 R 20 , NHC(O)OR 20 5 NR 20 C(O)OR 20 ,
  • each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R , R , R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected R 21 , OR 21 , SR 21 , S(0)R 21 , S0 2 R 21 , C(0)R 21 , CO(0)R 21 , OC(0)R 21 , OC(0)OR 21 , NH 2 , NHR 21 , N(R 21 ) 2 , NHC(0)R 21 , NR 21 C(0)R 21 , NHS(0) 2 R 21 , NR 21 S(0) 2 R 21 ,
  • NHC(0)OR 21 NR 21 C(0)0R 21 , NHC(0)NH 2 , NHC(0)NHR 21 , NHC(0)N(R 21 ) 2 , NR 21 C(0)NHR 2 ', NR 21 C(0)N(R 21 ) 2 , C(0)NH 2 , C(0)NHR 21 , C(0)N(R 21 ) 2 ,
  • each R 21 is independently R 22 , R 23 , R 24 , or R 25 ;
  • R 22 is aryl
  • R is heteroaryl
  • R 24 is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 26 , OR 26 , SR 26 , S(0)R 26 , S0 2 R 26 , C(0)R 26 , CO(0)R 26 , 0C(0)R 26 , OC(0)OR 26 , NH 2 , NHR 26 , N(R 26 ) 2 , NHC(0)R 26 , NR 26 C(0)R 26 , NHS(0) 2 R 26 , NR 26 S(0) 2 R 26 , NHC(0)OR 26 , NR 26 C(0)OR 26 ,
  • each R is independently alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • the moieties represented by R , R , and R are unsubstituted or substituted with one or two or three or four of independently selected N3 ⁇ 4, C(0)N3 ⁇ 4, C(0)NHOH, S0 2 NH 2 , CF 3 , CF 2 CF 3 , C(0)H, C(0)OH, C(N)NH 2 , OH, (O), CN, N 3 , N0 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, CI, Br, or I.
  • Y is aiyl or heteroaryl; wherein the aryl or heteroaryl is substituted with
  • R 7 is hydrogen or alkyl
  • R 8 is alkyl
  • R 1 , R 3 , and R 9 are independently selected from the group consisting of hydrogen, R 10 , OR 10 , C(0)R 10 , NHR 10 , C(0)NHR 10 , C(O)N(R 10 ) 2 , or C(0)OH;
  • each R 10 is independently R 11 , R 13 , or R 14 ;
  • R 1 1 is aryl
  • R is cycloalkyl, or heterocycloalkyl
  • R 14 is alkyl, which is unsubstituted or substituted with R 15 , OR 15 , N(R 15 ) 2 , or CN; each R 15 is independently R 17 , R 18 , or R 19 ;
  • R is heteroaryl
  • R is cycloalkyl, or heterocycloalkyl
  • R 19 is alkyl; wherein the moieties represented by R , R and R are unsubstituted or
  • each R is independently R ;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with R 26 ;
  • each R 26 is aryl.
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; and R 8 is alkyl.
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 or C(0)NHR 10 .
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 or C(0)NHR 10 .
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 or C(0)NHR 10 .
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 or C(0)NHR 10 .
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 .
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 .
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is R 10 .
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR ; and R 3 is R 10
  • Y is aryl; wherein the aryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is C(0)NHR 10 .
  • Y is phenyl; wherein the phenyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is C(0) HR 10 .
  • Y is heteroaryl; wherein the heteroaryl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is C(0)NHR 10 .
  • Y is pyridinyl; wherein the pyridinyl is substituted with NR 7 S0 2 R 8 ; R 7 is alkyl; R 8 is alkyl; R 1 is OR 10 ; and R 3 is C(0)NHR 10 .
  • Another embodiment comprises pharmaceutical compositions comprising a compound having Formula (I) and an excipient.
  • Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).
  • compositions for treating diseases during which focal adhesion kinase is expressed comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
  • Still another embodiment pertains to methods of treating disease in a patient during which focal adhesion kinase and anaphastic lymphoma kinase (ALK) are expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
  • ALK focal adhesion kinase and anaphastic lymphoma kinase
  • Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
  • Still another embodiment pertains to methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
  • Still another embodiment pertains to compositions for treating diseases during which focal adhesion kinase and anaphastic lymphoma kinase (ALK) are expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • ALK focal adhesion kinase and anaphastic lymphoma kinase
  • Still another embodiment pertains to methods of treating disease in a patient during which focal adhesion kinase and anaphastic lymphoma kinase (ALK) are expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • ALK focal adhesion kinase and anaphastic lymphoma kinase
  • Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • Still another embodiment pertains to methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with focal adhesion kinase and anaphastic lymphoma kinase (ALK).
  • ALK anaphastic lymphoma kinase
  • Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have utility for treating diseases associated with expression of focal adhesion kinase and anaphastic lymphoma kinase (ALK).
  • ALK anaphastic lymphoma kinase
  • Compounds having Formula (I) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during isolation or following purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid.
  • Basic addition salts of the compounds are those derived from the reaction of the compounds with the hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
  • the compounds having Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.
  • Therapeutically effective amounts of compounds having Formula (I) depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
  • the amount of a compound of this invention having Formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight.
  • Single dose compositions contain these amounts or a combination of submultiples thereof.
  • Compounds having Formula (I) may be administered with or without an excipient.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • Excipients for preparation of compositions comprising a compound having Formula (I) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil,
  • Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof.
  • Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered osmotically include, for example,
  • Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.
  • Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
  • Compounds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-l) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (ELD AC) inhibitors, honnonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), inter
  • BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
  • Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the
  • T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B.
  • SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical
  • siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing.
  • a double-stranded siRNA can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs).
  • the overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3'-ends of a given strand.
  • Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies.
  • the term "multispecific binding protein” means a binding protein capable of binding two or more related or unrelated targets.
  • Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's.
  • Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites.
  • Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
  • Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE ® (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA ® (bendamustine), treosulfan, rofosfamide and the like.
  • Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
  • Tie-2 endothelial-specific receptor tyrosine kinase
  • EGFR epidermal growth factor receptor
  • IGFR-2 insulin growth factor-2 receptor
  • MMP-2 matrix metalloproteinase-2
  • MMP-9 matrix metalloproteinase-9
  • PDGFR platelet-derived growth factor receptor
  • VEGFR vascular endothelial growth factor receptor tyrosine
  • Antimetabolites include ALIMTA ® (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA ® (capecitabine), carmofur, LEUSTAT ® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-l- -D-ribofuranosylimidazole-4- carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR ® (gemcitabine), hydroxyurea,
  • ALKERAN ® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-l, tiazofurin, tegafur, TS-1, vidarabine, LIFT and the like.
  • Antivirals include ritonavir, hydroxychloroquine and the like.
  • Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors and the like.
  • Bcl-2 protein inhibitors include AT- 101 ((-)gossypol), GENASENSE (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro( 1 , 1 '-biphenyl)-2-y l)methyl)piperazin- 1 -y l)benzoyl)-4-((( 1 R)-3 -(dimethylamino)- 1 -((phenylsulfanyl)methyl)propyl)amino)-3 -nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 - yl)benzoyi)-4-((( 1
  • Bcr-Abl kinase inhibitors include DASATINIB ® (BMS-354825), GLEEVEC ® (imatinib) and the like.
  • CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
  • COX-2 inhibitors include ABT-963, ARCOXIA ® (etoricoxib), BEXTRA ® (valdecoxib), BMS347070, CELEBREX ® (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX ® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4- sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX ® (rofecoxib) and the like.
  • EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX ® (cetuximab), HR3, IgA antibodies, IRESSA ® (gefitinib), TARCEVA ® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB ® (lapatinib) and the like.
  • ErbB2 receptor inhibitors include CP-724-714, CI- 1033 (canertinib),
  • HERCEPTI ® (trastuzumab), TYKERB ® (lapatinib), OM ITARG ® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI- 166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
  • Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
  • HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB ® (human recombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
  • Inhibitors of inhibitors of apoptosis proteins include HGS1029, GDC-0145, GDC- 0152, LCL-161, LBW-242 and the like.
  • Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC- MMAE, anti-CD22-MCC-DMl, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN- 19Am SGN-35, SGN-75 and the like
  • Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab,
  • conatumumab conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029, LBY-135, PRO- 1762 and trastuzumab.
  • Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.
  • JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCBO 18424 and the like.
  • MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
  • mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.
  • Non-steroidal anti-inflammatory drugs include AMIGESIC ® (salsalate),
  • DOLOBID ® (diflunisal), MOTRIN ® (ibuprofen), ORUDIS ® (ketoprofen), RELAFEN ® (nabumetone), FELDENE ® (piroxicam), ibuprofen cream, ALEVE ® (naproxen) and NAPROSYN ® (naproxen), VOLTAREN ® (diclofenac), INDOCIN ® (indomethacin), CLINORIL ® (sulindac), TOLECTIN ® (tolmetin), LODINE ® (etodolac), TORADOL ® (ketorolac), DAYPRO ® (oxaprozin) and the like.
  • PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
  • Platinum chemotherapeutics include cisplatin, ELOXATIN ® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN ® (carboplatin), satraplatin, picoplatin and the like.
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Phosphoinositide-3 kinase (PI3K) inhibitors include ortmannin, LY294002, XL- 147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
  • Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
  • VEGFR inhibitors include AVASTIN ® (bevacizumab), ABT-869, AEE-788, ANGIOZYMETM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG-13736), AZD-2171, CP- 547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR ® (sorafenib, BAY43- 9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT ® (sunitinib, SU-11248), VEGF trap, ZACTIMATM (vandetanib, ZD-6474) and the like.
  • AVASTIN ® bevacizumab
  • ABT-869 ABT-869
  • AEE-788 ANGIOZY
  • Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE ® (bleomycin), daunorubicin, CAELYX ® or MYOCET ® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS ® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR ® (valrubicin), zinostatin and the like.
  • Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR ® (irinotecan
  • camptothecin hydrochloride
  • camptothecin CARDIOXANE ® (dexrazoxine), diflomotecan, edotecarin, ELLENCE ® or PHARMORUBICIN ® (epirubicin), etoposide, exatecan,
  • Antibodies include AVASTIN ® (bevacizumab), CD40-specific antibodies, chTNT-l/B, denosumab, ERBITUX ® (cetuximab), HUMAX-CD4 ® (zanolimumab), IGFlR-specific antibodies, lintuzumab, PANOREX ® (edrecolomab), RENCAREX ® (WX G250), RITUXAN ® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.
  • Hormonal therapies include ARIMIDEX ® (anastrozole), AROMASIN ®
  • NILANDRONTM nilutamide
  • NOLVADEX ® tamoxifen citrate
  • Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN ® (aliretinoin), ATRAGEN ® (liposomal tretinoin), TARGRETIN ® (bexarotene), LGD-1550 and the like.
  • PARP inhibitors include ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
  • Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
  • Proteasome inhibitors include VELCADE ® (bortezomib), MG132, NPI-0052, PR-171 and the like.
  • immunologicals examples include interferons and other immune-enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- la, ACTIMMUNE ® (interferon gamma- lb) or interferon gamma-nl, combinations thereof and the like.
  • Other agents include
  • GRANOCYTE ® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
  • MYLOTARGTM (gemtuzumab ozogamicin), NEUPOGEN ® (filgrastim), OncoVAC-CL, OVAREX ® (oregovomab), pemtumomab (Y-muHMFGl), PROVENGE ® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS ® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)),
  • PROLEUKIN ® (aldesleukin), ZADAXIN ® (thymalfasin), ZENAPAX ® (daclizumab), ZEVALIN ® (90Y-Ibritumomab tiuxetan) and the like.
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
  • Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA ® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR ® (gemcitabine), TOMUDEX ® (ratitrexed), TROXATYLTM (triacetyluridine troxacitabine) and the like.
  • Purine analogs include LANVIS ® (thioguanine) and PURI-NETHOL ®
  • Antimitotic agents include batabulin, epothilone D ( OS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3 -yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE ® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
  • Ubiqutin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.
  • Radiosensitizers that enhance the efficacy of radiotherapy.
  • radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
  • compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANETM (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN ® (Ad5CMV-p53 vaccine), ALTOCOR ® or
  • MEVACOR ® (lovastatin), AMPLIGEN ® (poly Lpoly C12U, a synthetic RNA), APTOSYN ® (exisulind), AREDIA ® (pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3,17-dione-androsta-l,4-diene), AVAGE ® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC ® (cancer vaccine), CELEUK ® (celmoleukin), CEPLENE (histamine dihydrochloride), CERVARIX (human papillomavirus vaccine), CHOP ® (C: CYTOXAN ® (cyclophosphamide); H: ADRIAMYCIN ®
  • TAXOPREXIN ® DHA-paclitaxel
  • TELCYTA ® canfosfamide, TLK286)
  • TEMODAR ® temozolomide
  • tesmilifene thalidomide
  • THERATOPE ® STn-KLH
  • thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride
  • TNFERADETM adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER ® or ZAVESCA ® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX ® (arsenic trioxide), VIRULIZIN ® , ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3
  • Focal adhesion kinase (recombinant human FAK fragment, amino acids 411-686; Millipore cat. no. 14-720) activity was measured using the HTRF assay format (Cisbio HTRF KinEASE-TK kit, cat. no. 62K0PEB). The assay was run in a 20 ul volume, in 384 well plates (Corning 384-well, white, low-volume NSB plate, cat. no. 3673).
  • Reaction conditions consisted of 4 nM FAK, 50 ⁇ ATP, and 0.2 uM TK substrate- biotin in a buffer containing 50 mM Tris pH 7.5, 10 mM magnesium chloride, 2 mM manganese chloride, 2.5 mM dithiothreitol, 100 uM sodium orthovanadate, and 0.01 percent bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the reaction was carried out for 1 hour at room temperature, and terminated with 10 ⁇ /well Stop Buffer, consisting of 20 mM HEPES, 240 mM potassium fluoride, 0.05 percent BSA, 0.005 percent Tween 20, 0.025 uM TK-StreptXL665, and lxTK-Ab- Cryptate. After a 1.25 hour incubation, the fluorescence was measured on a Perkin Elmer Envision plate reader at 320 nm excitation/620 nm and 665 nm emissions. The ratio of 665/620 was used to calculate specific signal for each well. IC50s were calculated using the standard 4-parameter curve fit model. Results are shown in Table 1.
  • Example Human - IC50 Example Human - IC50
  • Assays were performed in a total volume of 40 in black 384-well plates using 3 nM ALK (Millipore) and 50 mM ATP in assay buffer (50 mM Hepes aOH, pH 7.4, 10 mM MgCl 2 ,2 mM MnCl 2 ,0.01% BSA,100 ⁇ sodium orthovanadate, with 1 mM DTT added before use).
  • Compounds are diluted in 10% DMSO/buffer and the final concentration of DMSO was 2.5%.
  • the reaction was started initialized by addition of substrate (0.5 ⁇ biotin LCK-peptide, biotin-Ahx-G AEEEIYAAFF A-COOH) .
  • Example Human - IC50 Example Human - IC50
  • the data in table 3 shows the necessity of NR S0 2 R , wherein R and R 8 are alkyl, on FAK activity.
  • ADDP means l,l'-(azodicarbonyl)dipiperidine
  • AD-mix- ⁇ means a mixture of (DHQD) 2 PHAL, K 3 Fe(CN) 6 , K 2 C0 3 , and K 2 S0 4
  • 9-BBN means 9-borabicyclo(3.3.1 )nonane
  • Boc means tert-butoxycarbonyl
  • (DHQD) 2 PHAL means hydroquinidine 1,4-phthalazinediyl diethyl ether
  • DBU means l,8-diazabicyclo[5.4.0]undec-7-ene
  • DIBAL means
  • DIEA diisobutylaluminum hydride
  • DIEA diisopropylethylamine
  • DMAP means ⁇ , ⁇ -dimethylaminopyridine
  • DMF means ⁇ , ⁇ -dimethylformamide
  • dmpe means 1 ,2-bis(dimethylphosphino)ethane
  • DMSO means dimethylsulfoxide
  • dppb means l,4-bis(diphenylphosphino)-butane
  • dppe means l,2-bis(diphenylphosphino)ethane
  • dppf means l,l'-bis(diphenylphosphino)ferrocene
  • dppm means
  • EDAC-HCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • Fmoc means fluorenylmethoxycarbonyl
  • HATU means 0-(7-azabenzotriazol- 1 -yl)-N,NTSW'-te1xamethyluronium hexafluorophosphate
  • HMPA means hexamethylphosphoramide
  • IPA means isopropyl alcohol
  • MP-BH3 means macroporous triethylammonium methylpolystyrene cyanoborohydride
  • TEA means triethylamine
  • TFA means trifluoroacetic acid
  • THF means tetrahydrofuran
  • NCS means N-chlorosuccinimide
  • NMM means N-methylmorpholine
  • NMP means
  • N-methylpyrrolidine; PPh 3 means triphenylphosphine.
  • compounds of formula (1) can be reacted with a compound of formula NH (CH 2 ) n Y, wherein n is 0 or 1 and Y is as described herein, and a reducing agent such as but not limited to sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxyborohydride (NaBH(OCOCH 3 )3 to provide a compound of formula (2).
  • a reducing agent such as but not limited to sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxyborohydride (NaBH(OCOCH 3 )3 to provide a compound of formula (2).
  • Acetic acid may be used to facilitate the reaction, which is typically performed at room temperature in a solvent such as but not limited to dichloromethane, methanol, tetrahydrofuran, and the like, or mixtures thereof.
  • Compounds of formula (3) wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as described herein, can be prepared by reacting a compound of formula (2) with a compound of formula (2A), using Buchwald-Hartwig coupling conditions described herein, known to those skilled in the art, and readily available in the literature.
  • Compounds of formula (3) can be reacted with tetrabutyl ammonium fluoride and ethylenediamine to provide compounds of formula (4), which are representative of the compounds of this invention.
  • the reaction is typically performed in a solvent such as but not limited to tetrahydrofuran at an elevated temperature.
  • Compounds of formula (5) can be converted to compounds of formula (6) wherein Y is as described herein, using Heck coupling conditions described herein, known to those skilled in the art, and readily available in the literature.
  • Compounds of formula (7) wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as described herein, can be prepared by reacting a compound of formula (6) with a compound of formula (2A), using Buchwald- Hartwig coupling conditions described herein, known to those skilled in the art, and readily available in the literature.
  • Compounds of formula (7) can be reacted with tetrabutyl ammonium fluoride and ethylenediamine to provide compounds of formula (8), which are representative of the compounds of this invention. The reaction is typically performed in a solvent such as but not limited to tetrahydrofuran at an elevated temperature.
  • Compounds of formula (15), wherein X, Y, and R are as described herein, can be prepared by coupling compounds of formula (14) with compounds of formula NH 2 R 10 , using conditions described herein, known to those skilled in the art, and readily available in the literature.
  • Compounds of formula (16), which are representative of the compounds of this invention, can be prepared by reacting compounds of formula (15) with tetrabutyl ammonium fluoride and ethylenediamine. The reaction is typically performed in a solvent such as but not limited to tetrahydrofuran at an elevated temperature.
  • Example 1A 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine
  • Example IB In a stirred solution of Example IB (20 g, 0.12 mol) and 25% aqueous HC1 (200 ml) at 0°C was added a mixture of NaN0 2 (12.32 g, 0.17mol) and water (15 ml) slowly. The mixture was stirred at 0°C for 15 minutes. Then the mixture was added to a stirred solution of CuCl (17.8 g, 0.17 mol) and water (15 ml) at 0°C. Then it was heated to 80°C for 2 hours. After cooling to room temperature, the pH was adjusted to 8.0 with concentrated NH 4 OH, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to provide the title compound. MS (ESI)(+) m/z 188.7 (M+H) + .
  • N-(2-cyanophenyl)-N-methylmethanesulfonamide A mixture of 2-fluorobenzonitrile (5.0 ml, 47.0 mmol), N- methylmethanesulfonamide (6.16 g, 56.4 mmol), and cesium carbonate (30.6 g, 94 mmol) in N,N-dimethylacetamide (75 ml) was stirred at room temperature for 2 days. The mixture was filtered and the filtrate was poured into ice water and stirred for 0.5 hour. The precipitate was collected by filtration, and dried in a vacuum oven to give the title compound. MS (ESI)(+) m/z 223.9 (M+NH 3 ) + .
  • Example IE N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide
  • a-Ni 6.26 g, 107 mmol
  • the mixture was filtered through a nylon membrane and the filtrate was concentrated.
  • the crude material was then dissolved in ethyl acetate and treated with 2N HCl in ether. The precipitate was filtered, and air-dried to give the title compound.
  • Ethyl 4-(4-(2-(N-methylmethyIsulfonamido)benzylamino)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzoate In a 20 mL Biotage reaction vessel, a mixture of Example 1G (1.0 g, 2.02 mmol), ethyl 4-aminobenzoate and sodium t-butoxide (0.39 g, 4.04 mmol in toluene (5 ml) was degassed on a sonicator for 5 minutes.
  • Example 1H 4-(4-(2-(N-methylmethylsulfonamido)benzylamino)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzoic acid
  • 5N aqueous sodium hydroxide solution (30 ml)
  • the reaction mixture was diluted with water, and the pH was adjusted to 5 with 3N aqueous HCl.
  • the acid was dissolved in ethyl acetate and aqueous phase was extracted with ethyl acetate.
  • the combined organic phases were concentrated to obtain the title compound.
  • Example II To a solution of Example II (O.lg, 0.17 mmol)), 3-morpholinopropan-l-amine (0.34 mmol)) and benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (017g, 0.34 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.12 ml, 0.67 mmol) was added. The mixture was stirred at room temperature for 2 hours. Saturated aqueous NH 4 C1 was added and the mixture was extracted with CH2CI2. The organic layer was separated, dried (Na 2 S04), and filtered. The filtrate was concentrated to give the title compound. MS (ESI)(+) m/z 723.2 (M+H) + .
  • N-(3-cyanophenyl)-N-methylmethanesulfonamide To a mixture of N-(3-cyanophenyl)metlmnesuIfonamide (2.0 g, 10.19 mmol) and potassium carbonate (2.82 g, 20.38 mmol) in N,N-dimethylformamide (25 ml) was added iodomethane (0.91 ml, 11.21 mmol) and the reaction mixture was stirred at room temperature overnight. The suspension was diluted with ethyl acetate and filtered. The filtrate was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude material was triturated with hexane to give the title compound. MS ESI (-) m/z 208.8 [M-H] ⁇ .
  • N-(2-cyano-3-methylphenyl)-N-methylmethanesulfonamide A mixture of 2-fluoro-6-methylbenzonitrile (1.00 g, 7.40 tnmol), N- methylmethanesulfonamide (0.808 g, 7.40 mmol) and potassium carbonate (2.045 g, 14.80 mmol) in N,N-dimethylformamide (10 ml) was heated at 180°C for 16 hours. The suspension was cooled and poured into ice water, then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered.
  • Example 11A To a solution of Example 11A (0.5 g, 2.229 mmol) in 7M 1 ⁇ 2-methanol (40 ml) was added to Ra-Ni (1.0 g, 17.04 mmol) and the reaction mixture was stirred for 16 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and the filtrate was concentrated. The crude material was dissolved in ethyl acetate, then 2M HC1 in ether was added. The precipitate was collected by filtration, and air-dried to give the title compound. MS ESI (+) m/z 228.9 [M+H] + .
  • Example 13 3- ⁇ [4-( ⁇ 2-[methyl(inethylsulfonyl)amino]benzyl ⁇ am io)-7H-pyrrolo[2,3-d]pyrimidin-2- yl]amino ⁇ -N-(l-methylpiperidin-4-yl)benzamide
  • the title compound was prepared as described in Examples 1A-1K, except substituting ethyl3-aminobenzoate for ethyl 4-aminobenzoate and l-methylpiperidin-4- amine for 3-morpholinopropan-l-amine. !
  • Example 16 4- ⁇ [4-( ⁇ 2-[methyI(methylsulfonyl)amino]benzyl ⁇ amino)- 7H-pyrrolo[2,3-d]pyrimidin-2- yl]amino ⁇ -N-[3-(2-oxopyrrolidin-l-yl)propyl]benzamide
  • the title compound was prepared as described in Examples 1A-1K, except substituting l-(3-aminopropyl)pyrrolidin-2-one for 3-morpholinopropan-l-amine. !
  • Example 22B N- ⁇ 2-[( ⁇ 2-[(2-methoxy-4-piperazin-l-ylphenyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4- yl ⁇ amino)methy l]phenyl ⁇ -N-methy lmethanesulfonamide
  • Pd/C 0.063 g, 0.060 mmol
  • Example 28 N-[3-(dimethylamino)propyl]-4- ⁇ [4-( ⁇ 2-[methyl(methylsulfonyl)amino]benzyl ⁇ amino)- 7H-pyrrolo [2,3 -d]pyrimidin-2-yl] amino ⁇ benzamide
  • N-(3-cyanopyridin-2-yl)methanesulfonamide To methanesulfonamide (2.57 g, 27.0 mmol) in N,N-dimethylformamide (60 ml) was added potassium tert-butoxide (3.03 g, 27.0 mmol). The mixture was stirred for 20 minutes at room temperature and 2-fluoronicotinonitrile (3.00 g, 24.6 mmol) was added. The resulting mixture was refluxed for 2 hours. The reaction was cooled and poured into water (200 ml), extracted with dichloromethane, washed with brine, dried (MgS0 4 ), filtered, and the solvent was evaporated.
  • Example ID 3.08 g, 9.68 mmol
  • sodium methanethiolate 0.82 g, 12.58 mmol
  • the reaction mixture was stirred under nitrogen at room temperature for 18 hours.
  • the solvent was evaporated and the resulting residue was diluted with CH 2 CI 2 .
  • the organic layer was washed with water, brine and dried (MgSOt).
  • the organic solution was filtered through a short silica pad and concentrated to yield the title compound.
  • Example 35D In a 20 mL Biotage reaction vial, a mixture of Example 35D (1.5 g, 4.55 mmol), Example 8B ( 1.98 g, 7.05 mmol), and sodium tert-butoxide (1.092 g, 11.37 mmol) in toluene (16 ml) was degassed for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.167 g, 0.182 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.316 g, 0.546 mmol) were added and the reaction mixture was purged with nitrogen. The suspension was heated at 110°C for 16 hours.
  • Example 35F (0.200 g, 0.375 mmol), Example 35C (0.258 g, 1.124 mmol) and N-ethyl-N-isopropylpropan-2 -amine (0.324 ml, 1.874 mmol) in t- butanol (2 ml) was heated in a microwave (Biotage Initiator Microwave Synthesizer) at 170° for 70 minutes. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel, eluting with 9/1 mixture of ethyl acetate/hexane to give the title compound. MS ESI(+) m/z 683.3 [ ⁇ +3 ⁇ 4 + .
  • N-(3-cyanopyridin-2-yl)-N-methylmethanesulfonamide To the N-methylmethanesulfonamide (1.00 g, 9.17 mmol) in N,N- dimethylformamide (20 ml) was added potassium tert-butoxide ( 1.03 g, 9.17 mmol). The mixture was stirred for 20 minutes and 2-fluoronicotinonitrile (1.12 g, 9.17 mmol) was added. The resulting mixture was refluxed for 2 hours. The reaction was cooled and poured into water (100 ml), extracted with dichloromethane, washed with brine, dried (MgS0 4 ), filtered, and the solvent was evaporated.
  • Example 40A N-(3-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide
  • 7M NH 3 -methanol 20 ml
  • Ra-Ni, water- wet 5 g, 85 mmol
  • the reaction was shaken under 30 psi of hydrogen at room temperature for 75 minutes.
  • the reaction was filtered and the filtrate was concentrated to dryness to yield the title compound.
  • N-(2-cyanophenyl)methanesulfonamide A mixture of 2-fluorobenzonitrile (5.0 g, 41.3 mmol), methanesulfonamide (3.93 g, 41.3 mmol) and potassium carbonate (11.41 g, 83 mmol) in l-methyl-2-pyrrolidinone (8.0 ml) was heated at 180°C for 16 hours. The mixture was cooled and poured into ice water, then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (10-70% ethyl acetate in hexane) to give the title compound. MS ESI (+) m/z 227.8 [M+NH4] + .
  • N-(3-bromopyridin-2-yl)methanesulfonamide To methanesulfonamide (8.5 g, 89 mmol) in 80 ml of N,N-dimethylformamide was added potassium tert-butoxide (9.5 g, 84.8 mmol). The mixture was stirred for 20 minutes and 3-bromo-2-fluoropyridine (10.0 g, 57 mmol) was added. The resulting mixture was refluxed for 2 hours. The mixture was poured into water and extracted with dichloromethane, washed with brine, dried over Na S0 4 , filtered, and concentrated to dryness. The crude residue was put through a plug of silica (0-50% ethyl acetate in petroleum ether) to yield the title compound. MS ESI(+) m/z 251.7 [M+H] + .
  • Example 63C (0.98 g, 32 mmol), Example 63B (6.14 g, 22 mmol), palladium(II) acetate (0.15 g, 0.66 mmol), tetrabutylammonium bromide (l.lg, 34mmol), and sodium bicarbonate (l.lg, 13 mmol) in dry N,N-dimethylformamide (10 ml) was heated at 90°C for 18 hours. The mixture was cooled, filtered through diatomaceous earth, washed with water, dried over MgSC>4, filtered, and concentrated. The residue was purified by chromatography on silica gel (0-70% ethyl acetate in petroleum ether) to yield the title compound. MS ESI(+) m/z 509.7 [M+H] + .
  • Example 63D 0.5g, 1.13mmol, ethyl anthranilate (0.28 g, 1.69 mmol), and CS2CO3 (1.1 lg, 3.4 mmol) in dioxane (5 ml) was degassed on a sonicator for 5 minutes. Then tris(dibenzylideneacetone)dipalladium(0) (0.104 g, 0.11 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.13 g, 0.22 mmol) were added and the vessel was evacuated and purged with nitrogen for three times.
  • N-(6-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide To methanesulfonamide (1.870 g, 19.66 mmol) in N,N-dimethylformamide (40 ml) was added potassium tert-butoxide (2.206 g, 19.66 mmol). The mixture was stirred for 20 minutes and 2-cyano-6-fluoropyridine (2.0 g, 16.38 mmol) was added. The resulting mixture was refluxed for 3.5 hours. It was poured into water and extracted with ethyl acetate, washed with brine, dried over MgS0 , filtered and concentrated to dryness.
  • N-(3-bromopyridin-2-yl)-N-methylmethanesulfonamide To N-methylmethanesulfonamide (4.6 g, 42 mmol) in 50 ml of N,N- dimethylformamide was added potassium tert-butoxide (4.7g, 41 mmol). The mixture was stirred for 20 minutes and 3-bromo-2-fluoropyridine (5.0g, 28 mmol) was added. The resulting mixture was refluxed for 2 hours. It was poured into water, extracted with dichloromethane, washed with brine, dried over Na 2 S0 4 , filtered, and concentrated to dryness. The crude residue was put through a plug of silica (0-50% ethyl acetate in petroleum ether) to yield the title compound. MS ESI(+) m/z 265.7 [M+H] + .
  • Example 69 N-[3-((E)-2- ⁇ 2-[(2-methoxy-4-morpholin-4-ylphenyl)amino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl ⁇ vinyl)pyridin-2-yl]-N-methylmethanesulfonamide
  • the title compound was prepared as described in Examples 63C-63F, except substituting Example 65A for Example 63B and Example 8B for the ethyl anthranilate to yield the title compound.

Abstract

Cette invention concerne des composés qui inhibent l'activité de la kinase d'adhérence focale (FAK) et de la kinase des lymphomes anaplasiques (ALK), des compositions les contenant, et des méthodes pour traiter les maladies au cours desquelles FAK et ALK sont exprimées. Les maladies sont, par exemple, des cancers.
PCT/CN2010/001578 2010-10-09 2010-10-09 Pyrrolopyrimidines à titre d'inhibiteurs de fak et d'alk pour le traitement des cancers et autres maladies WO2012045195A1 (fr)

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US9012461B2 (en) 2011-02-17 2015-04-21 Cancer Therapeutics Crc Pty Ltd FAK inhibitors
WO2015113451A1 (fr) * 2014-01-29 2015-08-06 Glaxosmithkline Intellectual Property Development Limited Composés
US9120761B2 (en) 2011-02-17 2015-09-01 Cancer Therapeutics Crc Pty Ltd Selective FAK inhibitors
WO2016142855A2 (fr) 2015-03-09 2016-09-15 Aurigene Discovery Technologies Limited Dérivés de pyrazolo[1,5-a][1,3,5]triazine et de pyrazolo[1,5-a]pyrimidine utilisés en tant qu'inhibiteurs de cdk
US9518052B2 (en) 2014-05-14 2016-12-13 Pfizer Inc. Pyrazolopyridines and pyrazolopyrimidines
CN107793417A (zh) * 2016-09-05 2018-03-13 复旦大学 吡咯并[2,3‑d]嘧啶类化合物及其盐，及制备方法和药用用途
US20180244676A1 (en) * 2015-02-13 2018-08-30 Dana-Farber Cancer Institute, Inc. Lrrk2 inhibitors and methods of making and using the same
US10087186B2 (en) 2014-01-29 2018-10-02 Glaxosmithkline Intellectual Property Development Limited Compounds as LRRK2 kinase inhibitors
EP3290420A4 (fr) * 2015-04-29 2018-12-05 Xiamen University Composé pyrimidine pyrrole, méthode de préparation correspondant, composition pharmaceutique, et utilisations correspondantes
WO2020023851A1 (fr) * 2018-07-26 2020-01-30 Yale University Pyrimidines substituées bifonctionnelles en tant que modulateurs du protéolyse de fak
WO2020232332A1 (fr) * 2019-05-16 2020-11-19 Dana-Farber Cancer Institute, Inc. Inhibiteurs de pyrrolopyrimidine de type sauvage et formes mutantes de lrrk2
JP2022017384A (ja) * 2014-08-25 2022-01-25 ソーク インスティテュート フォー バイオロジカル スタディーズ 新規ｕｌｋ１阻害剤およびそれを使用する方法

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WO2010007114A2 (fr) * 2008-07-16 2010-01-21 Boehringer Ingelheim International Gmbh Nouveaux composés chimiques
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US9421205B2 (en) 2011-02-17 2016-08-23 Cancer Therapeutics CRC Pty Ltd. FAK inhibitors
US9012461B2 (en) 2011-02-17 2015-04-21 Cancer Therapeutics Crc Pty Ltd FAK inhibitors
US9120761B2 (en) 2011-02-17 2015-09-01 Cancer Therapeutics Crc Pty Ltd Selective FAK inhibitors
US9174946B2 (en) 2011-02-17 2015-11-03 Cancer Therapeutics Crc Pty Ltd Selective FAK inhibitors
US9815841B2 (en) 2014-01-29 2017-11-14 Glaxosmithkline Intellectual Property Development Limited Compounds
US10087186B2 (en) 2014-01-29 2018-10-02 Glaxosmithkline Intellectual Property Development Limited Compounds as LRRK2 kinase inhibitors
CN105980388A (zh) * 2014-01-29 2016-09-28 葛兰素史密斯克莱知识产权发展有限公司 化合物
WO2015113451A1 (fr) * 2014-01-29 2015-08-06 Glaxosmithkline Intellectual Property Development Limited Composés
US10618901B2 (en) 2014-01-29 2020-04-14 Glaxosmithkline Intellectual Property Development Limited LRRK2 inhibitors for the treatment of Parkinson's disease
US9518052B2 (en) 2014-05-14 2016-12-13 Pfizer Inc. Pyrazolopyridines and pyrazolopyrimidines
US10022376B2 (en) 2014-05-14 2018-07-17 Pfizer Inc. Pyrazolopyridines and pyrazolopyrimidines
JP2022017384A (ja) * 2014-08-25 2022-01-25 ソーク インスティテュート フォー バイオロジカル スタディーズ 新規ｕｌｋ１阻害剤およびそれを使用する方法
US20180244676A1 (en) * 2015-02-13 2018-08-30 Dana-Farber Cancer Institute, Inc. Lrrk2 inhibitors and methods of making and using the same
US10913744B2 (en) * 2015-02-13 2021-02-09 Dana-Farber Cancer Institute, Inc. LRRK2 inhibitors and methods of making and using the same
WO2016142855A2 (fr) 2015-03-09 2016-09-15 Aurigene Discovery Technologies Limited Dérivés de pyrazolo[1,5-a][1,3,5]triazine et de pyrazolo[1,5-a]pyrimidine utilisés en tant qu'inhibiteurs de cdk
EP3290420A4 (fr) * 2015-04-29 2018-12-05 Xiamen University Composé pyrimidine pyrrole, méthode de préparation correspondant, composition pharmaceutique, et utilisations correspondantes
CN107793417A (zh) * 2016-09-05 2018-03-13 复旦大学 吡咯并[2,3‑d]嘧啶类化合物及其盐，及制备方法和药用用途
WO2020023851A1 (fr) * 2018-07-26 2020-01-30 Yale University Pyrimidines substituées bifonctionnelles en tant que modulateurs du protéolyse de fak
WO2020232332A1 (fr) * 2019-05-16 2020-11-19 Dana-Farber Cancer Institute, Inc. Inhibiteurs de pyrrolopyrimidine de type sauvage et formes mutantes de lrrk2

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