WO2012045194A1 - Benzodiazépinones à titre d'inhibiteurs de fak pour le traitement du cancer - Google Patents

Benzodiazépinones à titre d'inhibiteurs de fak pour le traitement du cancer Download PDF

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Publication number
WO2012045194A1
WO2012045194A1 PCT/CN2010/001577 CN2010001577W WO2012045194A1 WO 2012045194 A1 WO2012045194 A1 WO 2012045194A1 CN 2010001577 W CN2010001577 W CN 2010001577W WO 2012045194 A1 WO2012045194 A1 WO 2012045194A1
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Prior art keywords
phenyl
oxo
dihydro
dibenzo
methyl
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PCT/CN2010/001577
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English (en)
Inventor
Jennifer Van Camp
Jyoti R. Patel
Steven Swann
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Abbott Laboratories
Abbott Laboratories Trading(Shanghai) Company, Ltd.
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Priority to PCT/CN2010/001577 priority Critical patent/WO2012045194A1/fr
Publication of WO2012045194A1 publication Critical patent/WO2012045194A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention pertains to compounds which inhibit the activity of focal adhesion kinase (FAK), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
  • FAK focal adhesion 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 been 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.
  • the present invention provides novel pyrrolopyrimidines that are selective inhibitors of focal adhesion kinase. 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 (FA ), the compounds having Formula (I)
  • X is CR 10A or N
  • A is NR n S0 2 R , 2 or S0 2 NR n R 12 ;
  • R 1 1 is hydrogen or alkyl
  • R 12 is alkyl, alkenyl, alkynyl, or R 1 A ; wherein the alkyl, alkenyl, or alkynyl are unsubstituted or substituted with one or more F, CI, Br, or I;
  • R 12A is cycloalkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R I0A are independently selected from the group consisting of hydrogen, R 13 , OR 13 , SR 13 , S(0)R 13 , S0 2 R 13 , C(0)R 13 , CO(0)R 13 , OC(0)R 13 , OC(0)OR 13 , NH 2 , NHR 13 , N(R , 3 ) 2 , NHC(0)R 13 , NR 13 C(0)R 13 , NHS(0) 2 R 13 , NR 13 S(0) 2 R 13 , NHC(0)OR 13 , NR 13 C(0)OR 13 , NHC(0)NH 2 , NHC(0)NHR 13 ,
  • each R 13 is independently R 14 , R 15 , R 16 , or R 17 ;
  • R 14 is aryl
  • R 15 is heteroaryl
  • R 16 is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 18 , OR 18 , SR 18 , S(0)R 18 , S0 2 R 18 , C(0)R 18 , CO(0)R 18 , OC(0)R 18 , OC(0)OR 18 , NH 2 , NHR 18 , N(R 18 ) 2 , NHC(0)R 18 , NR 18 C(0)R 18 , NHS(0) 2 R 18 , NR 18 S(0) 2 R 18 , NHC(0)OR 18 , NR 18 C(0)OR 18 ,
  • each R 18 is independently R 19 , R 20 , R 21 or R 22 ;
  • R 19 is aryl
  • R 20 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 23 , OR 23 , SR 23 , S(0)R 23 , S0 2 R 23 , C(0)R 23 , CO(0)R 23 , OC(0)R 23 , OC(0)OR 23 , NH 2 , NHR 23 , N(R 23 ) 2 , NHC(0)R 23 , NR 23 C(0)R 23 , NHS(0) 2 R 23 , NR 3 S(0) 2 R 23 , NHC(0)OR 23 , NR 23 C(0)OR 23 ,
  • eeaacchh RR i iss iinnddeeppeennddeennttllyy aallkkyyll,, aallkkeenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
  • R 14 , R 15 , R 16 , R 18A , R 19 , R 20 , and R 21 are independently unsubstituted or substituted with one or two or three or four of independently selected R 24 , OR 24 , SR 24 , S(0)R 24 , S0 2 R 24 , C(0)R 24 , CO(0)R 24 , OC(0)R 24 , OC(0)OR 24 , NH 2 , NHR 24 , N(R 24 ) 2 , NHC(0)R 24 , NR 24 C(0)R 24 ,
  • each R 24 is independently R 25 , R 26 , R 27 or R 28 ;
  • R is aryl
  • R 26 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 29 , OR 29 , SR 29 , S(0)R 29 , S0 2 R 29 , C(0)R 29 , CO(0)R 29 , OC(0)R 29 , OC(0)OR 29 , NH 2 , NHR 29 , N(R 29 ) 2 , NHC(0)R 29 , NR 29 C(0)R 29 , NHS(0) 2 R 29 , NR 29 S(0) 2 R 29 , NHC(0)OR 29 , NR 29 C(0)OR 29 ,
  • 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;
  • the moieties represented by R , R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl, alkenyl, alkynyl, 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 , OCF 2 CF 3 , F, CI, Br or I.
  • X is CR I0A orN; and A isNR"S0 2 R 12 .
  • X is CR ,0A orN; A is NR n S0 2 R 12 ; and R 11 isalkyl.
  • X is CR 10A orN; A is NR n S0 2 R 12 ; R" is alkyl; and R 12 is alkyl.
  • X is CR I0A or N;
  • A is NR 1 'S0 2 R 12 ;
  • R 11 is alkyl;
  • R 12 is alkyl; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R ,0A are hydrogen.
  • X is CR 10A or N;
  • A is NR n S0 2 R 12 ;
  • R 11 is alkyl;
  • R 12 is alkyl; and
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 10A are hydrogen.
  • X is CR 10A or N;
  • A is NR n S02R 1 ;
  • R 11 is alkyl;
  • R 12 is alkyl; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R !0 , and R 10A are hydrogen.
  • Still another embodiment pertains to compounds having Formula (I), which are N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;
  • 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 (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 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 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-butynyl, 2-pentynyl, 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, dihydroinden l, 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.
  • the bicyclic ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the cycloalkenyl ring.
  • bicyclic ring systems include, but are not limited to, 4,5-dihydro-benzo[l ,2,5]oxadiazole, 3a, 4, 5, 6, 7, 7a-hexahydro- IH-indenyI, 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, isothiazoly!, 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, te
  • 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, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl,
  • ortho-bromobenzyloxycarbonyl chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl,
  • 2-ethoxycarbonylcyclopentylidene 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclo- hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyI-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-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para- methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl
  • 2,2,2-trichloro-ethoxymethyl 2-(trimethylsilyl)ethoxymethyl, 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,
  • 2 3 phosphorous, sulfur fluorine, chlorine, and iodine include, but are not limited to, H, H, l C, 32 P, 35 S, l8 F, 36 C1, and l25 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 ordinary 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 A, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 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.
  • any of A, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 can be combined with embodiments defined for any other of A, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 .
  • One embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are inhibitors of focal adhesion kinase (FAK), the compounds having Formula (I)
  • X is CR I UA or N;
  • A is NR 1 'S0 2 R 12 or S0 2 NR n R 12 ;
  • R n is hydrogen or alkyl
  • R 12 is alkyl, alkenyi, alkynyl, or R 1 A ; wherein the alkyl, alkenyi, or alkynyl are unsubstituted or substituted with one or more F, CI, Br, or I;
  • R 1 A is cycioalkyi
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R ,0A are independently selected from the group consisting of hydrogen, R 13 , OR 13 , SR 13 , S(0)R 13 , S0 2 R 13 , C(0)R 13 , CO(0)R 13 , OC(0)R 13 , OC(0)OR 13 , NH 2 , NHR 13 , N(R , 3 ) 2 , NHC(0)R 13 , NR 13 C(0)R 13 , NHS(0) 2 R 13 , NR , 3 S(0) 2 R 13 , NHC(0)OR 13 , NR ,3 C(0)OR 13 , NHC(0)NH 2 , NHC(0)NHR 13 ,
  • each R 13 is independently R 14 , R 15 , R 16 , or R 17 ;
  • R 14 is aryl
  • R 15 is heteroaryi
  • R 16 is cycioalkyi, cycioalkenyl, heterocycioaikyi, or heterocycioalkenyl;
  • R 17 is alkyl, alkenyi, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R , OR , SR , S(0)R , S0 2 R , C(0)R 18 , CO(0)R 18 , OC(0)R 18 , OC(0)OR 18 , NH 2 , NHR 18 , N(R 18 ) 2 , NHC(0)R 18 , NR 18 C(0)R 18 , NHS(0) 2 R 18 , NR 18 S(0) 2 R 18 , NHC(0)OR 18 , NR 18 C(0)OR 18 ,
  • each R 18 is independently R 19 , R 20 , R 21 or R 22 ;
  • R 19 is aryl;
  • R 20 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 23 , OR 23 , SR 23 , S(0)R 23 , S0 2 R 23 , C(0)R 23 , CO(0)R 23 , OC(0)R 23 , OC(0)OR 23 , NH 2 , NHR 23 , N(R 23 ) 2 , NHC(0)R 23 , NR 23 C(0)R 23 , NHS(0) 2 R 23 , NR 23 S(0) 2 R 23 , NHC(0)OR 23 , NR 23 C(0)OR 23 ,
  • each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
  • R 14 , R 15 , R 16 , R 18A , R 19 , R 20 , and R 21 are independently unsubstituted or substituted with one or two or three or four of independently selected R 24 , OR 24 , SR 24 , S(0)R 24 , S0 2 R 24 , C(0)R 24 , CO(0)R 24 , OC(0)R 24 , OC(0)OR 24 , NH 2 , NHR 24 , N(R 24 ) 2 , NHC(0)R 24 , NR 24 C(0)R 24 ,
  • each R 24 is independently R 25 , R 26 , R 27 or R 28 ;
  • R 25 is aryl
  • R 26 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 29 , OR 29 , SR 29 , S(0)R 29 , S0 2 R 29 , C(0)R 29 , CO(0)R 29 , OC(0)R 29 , OC(0)OR 29 , NH 2 , NHR 29 , N(R 29 ) 2 , NHC(0)R 29 , NR 29 C(0)R 29 , NHS(0) 2 R 29 , NR 29 S(0) 2 R 29 , NHC(0)OR 29 , NR 29 C(0)OR 29 ,
  • 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;
  • the moieties represented by R , R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl, alkenyl, alkynyl, 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 , OCF 2 CF 3 , F, CI, Br or I.
  • X is CR , 0A or ;
  • A is NR 1 'S0 2 R 12 or S0 2 NR 1 'R 12 ;
  • R 1 1 is hydrogen or alkyl
  • R 12 is alkyl, or R ,2A ; wherein the alkyl is unsubstituted or substituted with one or more F, CI, Br, or I;
  • R 12A is cycloalkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R IOA are independently selected from the group consisting of hydrogen, R 13 , C(0)R 13 , CO(0)R 13 , NH 2 , NHC(0)R 13 ,
  • NHC(0)OR' 3 C(0)NH 2 , C(0)NHR 13 , C(0)OH, and N0 2 ;
  • each R 13 is independently R 14 , R 15 , R 16 , or R 17 ;
  • R 14 is aryl
  • R 15 is heteroaryl
  • R 16 is cycloalkyl, or heterocycloalkyl
  • R is alkyl, which is unsubstituted or substituted with one or two or three of independently selected R 18 , OR 18 , NH 2 , N(R 18 ) 2 , C(0)NH 2 , or OH;
  • each R 18 is independently R 19 , R 20 , R 21 or R 22 ;
  • R is aryl
  • R 20 is heteroaryl
  • R is cycloalkyl, or heterocycloalkyl
  • R 22 is alkyl
  • R 14 , R 15 , R 16 , R 18A , R 19 , R 20 , and R 21 are independently unsubstituted or substituted with one or two or three or four of independently selected R 24 , OR 24 , C(0)R 24 , N(R 24 ) 2 , C(0)NH 2 , C(0)NHR 24 ,
  • each R 24 is independently R 26 , R 27 or R 28 ;
  • R is heteroaryl
  • R is heterocycloalkyl
  • R is alkyl, each of which is unsubstituted or substituted with one or two or three
  • each R is independently alkyl, or heterocycloalkyl
  • R the moieties represented by R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl.
  • X is CR 10A . In another embodiment of formula (I), X is N.
  • A is NR n S0 2 R 12 . In another embodiment of formula (I), A is S0 2 NR n R 12 . In another embodiment of formula (I), X is CR I0A , and A is NR n S0 2 R 12 . In another embodiment of formula (I), X is CR 10A , and A is S0 2 NR n R 12 . In another embodiment of formula (I), X is N, and A is NR U S0 2 R 12 . In another embodiment of formula (I), X is N, and A is S0 2 NR n R 12 . In one embodiment of formula (I), R is hydrogen. In another embodiment of formula (I), R 1 1 is alkyl. In another embodiment of formula (I), X is CR I 0A , A is
  • NR N S0 2 R 12 , and R 1 1 is hydrogen.
  • X is CR I0A , A is S02NR" R' 2 , and R 1 1 is hydrogen.
  • X is N, A is R" S02R 12 , and R 1 1 is hydrogen.
  • X is N, A is S0 2 NR" R 12 , and R 1 1 is hydrogen.
  • X is CR I0A , A is NR L , S0 2 R' 2 , and R U is alkyl.
  • X is CR , 0A , A is S0 2 NR U R 12 , and R N is alkyl. In another embodiment of formula (I), X is N, A is NR N S02R 12 , and R 1 1 is alkyl. In another embodiment of formula (I), X is N, A is S0 2 NR N R 12 , and R N is alkyl.
  • R 12 is alkyl. In another embodiment of formula (I), R 12 is alkyl, which is unsubstituted. In another embodiment of formula (I), R 12 is alkyl, which is substituted with three F. In another embodiment of formula (I), R 12 is R I 2A , and R 12A is cycloalkyl.
  • X is CR , 0A , A is R N S02R 12 , R 1 ' is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is CR I 0A , A is S02 R H R 1 , R" is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is N, A is NR N S0 2 R 12 , R 1 1 is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is N, A is S02 R U R 12 , R" is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is CR ,0A , A is NR N S0 2 R 12 , R 1 1 is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is CR I 0A , A is
  • R N R 12 , R" is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is N
  • A is NR N S0 2 R 12 , R 1 1 is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is N
  • A is SC ⁇ NR 1 "R 12 , R 1 1 is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is CR 10A , A is R M S02R 12 , R" is hydrogen, and R 12 is R I 2A , and R 12A is cycloalkyl.
  • X is CR , 0A , A is S0 2 NR N R 12 , R 1 1 is hydrogen, and R 12 is R I 2A , and R 12A is cycloalkyl.
  • X is N, A is NR" SC>2R 12 , R" is hydrogen, and R 12 is R 12A , and R 12A is cycloalkyl.
  • X is N, A is S0 2 NR u R 12 , R 1 1 is hydrogen, and is R I2A , and R ,2A is cycloalkyl.
  • X is CR 10A , A is NR n S0 2 R 12 , R n is alkyl, and R 12 is R , A , and R I A is cycloalkyl.
  • X is CR 10A , A is
  • S0 2 NR , , R 12 , R" is alkyl, and R 12 is R I 2A , and R 12A is cycloalkyl.
  • X is N, A is NR n S0 2 R 12 , R 1 1 is alkyl, and R 12 is R I 2A , and R I A is cycloalkyl.
  • X is N, A is S0 2 NR n R 12 , R 1 1 is alkyl, and R 12 is R I A , and R I2A is cycloalkyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R I0A are hydrogen, and X, and A are as described in embodiments herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R ,0A are hydrogen, and R 5 is selected from the group consisting of R 13 , NH 2 , NHC(0)R 13 , NHC(0)OR 13 , C(0)NH 2 , and C(0)NHR 13 and X, and A are as described in embodiments herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R I0A are hydrogen, and R 5 is selected from the group consisting of NHC(0)R 13 and C(0)NHR 13 and X, and A are as described in embodiments herein.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R I0A are hydrogen, and R 6 is selected from the group consisting of
  • R 13 , C(0)R 13 , CO(0)R 13 , NH 2 , NHC(0)R 13 , C(0)NH 2 , C(0)NHR 13 , and C(0)OH and X, and A are as described in embodiments herein.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 10A are hydrogen, and R 6 is selected from the group consisting of NHC(0)R 13 , and C(0)NHR 13 and X, and A are as described in
  • 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 (FA ), the compounds having Formula (II)
  • X is CR ,0A or N;
  • A is NR"S0 2 R 12 or S0 2 NR M R 12 ;
  • R 1 1 is hydrogen or alkyl
  • R 12 is alkyl, alkenyl, alkynyl, or R I2A ; wherein the alkyl, alkenyl, or alkynyl are unsubstituted or substituted with one or more F, CI, Br, or I;
  • R I A is cycloalkyl
  • R 5 , R 6 , R 8 , R 9 , R 10 , and R 10A are independently selected from the group consisting of hydrogen, R 13 , OR n , SR 13 , S(0)R 13 , S0 2 R 13 , C(0)R 13 , CO(0)R 13 , OC(0)R 13 , OC(0)OR 13 , NH 2 , NHR 13 , N(R 13 ) 2 , NHC(0)R 13 , NR l3 C(0)R 13 , NHS(0) 2 R 13 ,
  • each R 13 is independently R 14 , R 15 , R 16 , or R 17 ;
  • R 14 is aryl
  • R 15 is heteroaryl
  • R 16 is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
  • R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R , OR , SR , S(0)R , S0 2 R °, C(0)R 18 , CO(0)R 18 , OC(0)R 18 , OC(0)OR 18 , NH 2 , NHR 18 , N(R 18 ) 2 , NHC(0)R 18 , NR 18 C(0)R 18 , NHS(0) 2 R 18 , NR 18 S(0) 2 R 18 , NHC(0)OR 18 , NR 18 C(0)OR 18 ,
  • each R 18 is independently R 19 , R 20 , R 21 or R 22 ;
  • R 19 is aryl;
  • R 20 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 23 , OR 23 , SR 23 , S(0)R 23 , S0 2 R 23 , C(0)R 23 , CO(0)R 23 , OC(0)R 23 , OC(0)OR 23 , NH 2 , NHR 23 , N(R 23 ) 2 , NHC(0)R 23 , NR 23 C(0)R 23 , NHS(0) 2 R 23 , NR 23 S(0) 2 R 23 , NHC(0)OR 23 , NR 23 C(0)OR 23 ,
  • each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
  • R 14 , R 15 , R 16 , R 18A , R 19 , R 20 , and R 21 are independently unsubstituted or substituted with one or two or three or four of independently selected R 24 , OR 24 , SR 24 , S(0)R 24 , S0 2 R 24 , C(0)R 24 , CO(0)R 24 , OC(0)R 24 , OC(0)OR 24 , NH 2 , NHR 24 , N(R 24 ) 2 , NHC(0)R 24 , NR 24 C(0)R 24 ,
  • each R 24 is independently R 25 , R 26 , R 27 or R 28 ;
  • R 25 is aryl
  • R 26 is heteroaryl
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl
  • R is alkyl, aikenyl or aikenyl, each of which is unsubstituted or substituted with
  • each R is independently alkyl, aikenyl, aikenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
  • the moieties represented by R , R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl, aikenyl, alkynyl, 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 , OCF 2 CF 3 , F, CI, Br or I.
  • X is CR 10A or N
  • A is NR" S02R 12 or SO2 NR n R 12 ;
  • R 1 ' is hydrogen or alkyl
  • R 12 is alkyl, or R I2A ; wherein the alkyl is unsubstituted or substituted with one or more F, CI, Br, or I;
  • R , 2A is cycloalkyl
  • R 5 , R 6 , R 8 , R 9 , R 10 , and R 10A are independently selected from the group consisting of hydrogen, R 13 , C(0)R 13 , CO(0)R 13 , NH 2 , NHC(0)R 13 , NHC(0)OR 13 , C(0)NH 2 , C(0)NHR 13 , C(0)OH, and N0 2 ;
  • each R 13 is independently R 14 , R 15 , R 16 , or R 17 ;
  • R 1 is aryl
  • R 15 is heteroaryl
  • R 16 is cycloalkyl, or heterocycloalkyl
  • R 1 7 is alkyl, which is unsubstituted or substituted with one or two or three of independently selected R 18 , OR 18 , NH 2 , N(R 18 ) 2 , C(0)NH 2 , or OH;
  • each R 18 is independently R 19 , R 20 , R 21 or R 22 ;
  • R 19 is aryl
  • R 20 is heteroaryl
  • R is cycloalkyl, or heterocycloalkyl
  • R 22 is alkyl
  • R 14 , R 15 , R 16 , R 18A , R 19 , R 20 , and R 21 are independently unsubstituted or substituted with one or two or three or four of independently selected R 24 , OR 24 , C(0)R 24 , N(R 24 ) 2 , C(0)NH 2 , C(0)NHR 24 ,
  • each R 24 is independently R 26 , R 27 or R 28 ;
  • R is heteroaryl
  • R is heterocycloalkyl
  • R is alkyl, each of which is unsubstituted or substituted with one or two or three
  • each R is independently alkyl, or heterocycloalkyl
  • R the moieties represented by R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl.
  • X is CR I 0A . In another embodiment of formula (II), X is N.
  • A is NR M S0 2 R 12 . In another embodiment of formula (II), A is S0 2 NR N R 12 . In another embodiment of formula (II), X is CR 10A , and A is NR n S0 2 R 12 . In another embodiment of formula (II), X is CR , 0A , and A is
  • X is N, and A is NR n S0 2 R 12 .
  • X is N, and A is S0 2 NR N R 12 .
  • R is hydrogen.
  • R 1 1 is alkyl.
  • X is CR 10A , A is
  • X is CR 10A , A is SO2NR 1 'R 12 , and R 1 1 is hydrogen.
  • X is N, A is NR"S02R 12 , and R n is hydrogen.
  • X is N, A is S0 2 NR n R 12 , and R 1 1 is hydrogen.
  • X is CR 10A , A is NR n S0 2 R 1 , and R 1 1 is alkyl.
  • X is CR 10A , A is
  • NR"S0 2 R 12 NR"S0 2 R 12 , and R 1 1 is alkyl.
  • X is N
  • A is S0 2 NR n R 12
  • R 1 1 is alkyl.
  • R 12 is alkyl. In another embodiment of formula (II), R 12 is alkyl, which is unsubstituted. In another embodiment of formula (II),
  • R 12 is alkyl, which is substituted with three F.
  • R 12 is R 12A
  • R 12A is cycloalkyl.
  • X is CR I0A , A is NR" S0 2 R I2 , a 11 is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is CR 10A , A is S0 2 NR n R 12 , R 1 1 is hydrogen, and R 12 is alkyl, which is
  • X is N, A is NR" S02R 1 2 , R" is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is N, A is S0 2 NR n R 12 , R" is hydrogen, and R 12 is alkyl, which is unsubstituted.
  • X is CR 10A , A is NR n S0 2 R 12 , R 1 1 is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is CR I 0A ,
  • R 1020 A is S0 2 NR n R 12 , R" is alkyl, and R 12 is alkyl, which is unsubstituted.
  • R" is alkyl
  • R 12 is alkyl, which is unsubstituted.
  • X is N, A is NR"S0 2 R 12 , R 1 1 is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is N, A is S02NR n R 12 , R 1 1 is alkyl, and R 12 is alkyl, which is unsubstituted.
  • X is CR I 0A
  • A is NR N S02R 12
  • R n is
  • X is CR 10A , A is S0 2 NR n R 12 , R 1 1 is hydrogen, and R 12 is R 12A , and R 1 A is cycloalkyl.
  • X is N, A is NR"S0 2 R 12 , R 1 1 is hydrogen, and R 12 is R I 2A , and R I A is cycloalkyl.
  • X is N, A is S0 2 NR n R 12 , R 1 1 is hydrogen, and is R 12A , and R 12A is cycloalkyl.
  • X is CR 10A , A is NR M S0 2 R 12 , R 1 1 is alkyl, and R' 2 is R , 2A , and R 12A is cycloalkyl.
  • X is CR ,0A , A is S0 2 NR n R 12 , R" is alkyl, and R 12 is R I2A , and R I2A is cycloalkyl.
  • X is N, A is NR"S0 2 R 12 , R n is alkyl, and R 12 is R 12A , and R 12A is cycloalkyl.
  • X is N, A is S0 2 NR" R 12 , R 1 ' is
  • R 12 is R 12A
  • R 12A is cycloalkyl
  • R 5 , R 6 , R 8 , R 9 , R 10 , and R ,0A are hydrogen; and X and A are as described in embodiments herein.
  • R 6 , R 8 , R 9 , R 10 , R ,0A are hydrogen; and R 5 is selected from the group consisting of R 13 , NH 2 , NHC(0)R 13 , NHC(0)OR 13 , C(0)NH 2 , and C(0)NHR 13 ; and X and A are as
  • R 6 , R 8 , R 9 , R 10 , R 10A are hydrogen, and R 5 is selected from the group consisting of NHC(0)R 13 and C(0)NHR 13 ; and X and A are as described in embodiments herein.
  • R 5 , R 8 , R 9 , R 10 , R 10A are hydrogen; and R 6 is selected from the group consisting of R 13 , C(0)R 13 , CO(0)R 13 , NH 2 , NHC(0)R 13 , C(0)NH3 ⁇ 4
  • R 5 , R 8 , R 9 , R 10 , R I0A are hydrogen; R 6 is selected from the group consisting of NHC(0)R 13 and C(0)NHR 13 ; and X and A are as described in embodiments herein.
  • 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 1055 having Formula (I).
  • Still another embodiment pertains to compositions for treating diseases during which focal adhesion kinase is expressed, said compositions 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 1060 during which focal adhesion kinase is expressed, 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 bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic 1065 leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,
  • 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 1075 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).
  • compositions for treating diseases during which focal adhesion kinase is expressed comprising an excipient and 1080 a therapeutically effective amount of the compound having Formula (I) and a
  • Still another embodiment pertains to methods of treating disease in a patient during which focal adhesion kinase is expressed, said methods comprising administering 1085 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.
  • Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic 1090 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
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid.
  • 1 125 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 1 130 intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or
  • 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
  • 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
  • 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.
  • 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,
  • hydroxypropylmethyl cellulose isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil,
  • 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 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.
  • 1 165 having Formula (1) to be administered osmotically include, for example,
  • 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
  • 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.
  • alkylating agents alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl- 1 ) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, 1 180 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 deacetyiase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinas
  • Jak2 inhibitors Jak2 inhibitors, mammalian target of rapamycin inhibitors, microR A's, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, pololike kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3 ) inhibitors, proteosome
  • NSAIDs non-steroidal anti-inflammatory drugs
  • PARP poly ADP (adenosine diphosphate)-ribose polymerase
  • Plk pololike kinase
  • PI3 phosphoinositide-3 kinase
  • 1 190 inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors,
  • etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiqutin ligase inhibitors, and the like, and in combination with one or more of these agents .
  • BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells
  • the T-cell then attacks the target cancer cell.
  • BiTE antibodies include adecatumumab (Micromet MT201 ), blinatumomab (Micromet MT103) and the like.
  • adecatumumab Mert MT201
  • blinatumomab Mert MT103
  • 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
  • modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations
  • the siRNA can have varying lengths (e.g., 10-200 bps) and
  • 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
  • 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
  • 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
  • DVD Ig's Each half of a DVD Ig comprises a heavy chain DVD
  • 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,
  • 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 metal loproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor
  • PDGFR 1235
  • thrombospondin analogs vascular endothelial growth factor
  • VAGFR receptor tyrosine kinase
  • Antimetabolites include ALIMTA ® (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA ® (capecitabine), carmofur, LEUSTAT ® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, 1240 doxifluridine, eflornithine, EICAR (5-ethynyl-l-P -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, pelitrexoi, pentostatin, raltitrexed,
  • Antivirals include ritonavir, hydroxychloroquine and the like.
  • Aurora kinase inhibitors include ABT-348, AZD- 1 152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora 1250 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'- ch loro( 1 , 1 '-bipheny l)-2-y l)methy piperazin- 1 -y l)benzoy l)-4-((( 1 R)-3-(dimethy lam ino)- l -((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), 1255 N-(4-(4-((2-(4-chloropheny l)-5,5-dimethy 1- 1 -cyclohex- 1 -en- 1 -yl)methy Opiperazin- 1 -
  • Bcr-Abl kinase inhibitors include DASATIN1B ® (B S-354825), GLEEVEC ® 1260 (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 ® 1265 (valdecoxib), BMS347070, CELEBREX ® (celecoxib), COX- 189 (lumiracoxib), CT-3, DERAMAXX ® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4- sulfamoylphenyl- l H-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, 1270 EMD-7200, ERBITUX ® (cetuximab), HR3, IgA antibodies, IRESSA ® (gefitinib), TARCEVA* (eriotinib or OSl-774), TP-38, EGFR fusion protein, TYKERB (lapatinib) and the like.
  • ErbB2 receptor inhibitors include CP-724-714, CI- 1033 (canertinib),
  • HERCEPTIN ® (trastuzumab), TYKERB ® (lapatinib), OMNITARG ® (2C4, petuzumab), 1275 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,
  • Inhibitors of inhibitors of apoptosis proteins include HGS 1029, GDC-0145, GDC- 1285 0152, LCL- 161 , LBW-242 and the like.
  • Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC- MMAE, anti-CD22-MCC-DM l , CR-01 1 -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 1290 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 I CB018424 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, 1300 temsirolimus, ATP-competitive TORC 1/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 1305 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)
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Phosphoinositide-3 kinase (PI3 ) inhibitors include wortmannin, LY294002, XL- 147, CAL-120, ONC-21, AEZS- 127, ETP-45658, PX-866, GDC-0941 , BGT226,
  • 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 1320 (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG- 13736), AZD-2171 ,
  • Antibiotics include intercalating antibiotics aclarubicin, actinomycin D,
  • CAELYX ® or MYOCET ® liposomal doxorubicin
  • elsamitrucin epirbucin, glarbuicin
  • ZAVEDOS ® idarubicin
  • mitomycin C nemorubicin
  • neocarzinostatin peplomycin
  • pirarubicin rebeccamycin
  • streptozocin VALSTAR ® (valrubicin)
  • 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), IGF l R-specific antibodies, lintuzumab, PANOREX ® (edrecolomab), RENCAREX ® (WX G250), RITUXAN ® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I
  • Hormonal therapies include ARI IDEX ® (anastrozole), AROMASIN ®
  • HECTOROL ® (doxercalciferol), RENAGEL ® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE ® (megesterol), MIFEPREX ® (mifepristone),
  • NILANDRONTM nilutamide
  • NOLVADEX ® tamoxifen citrate
  • TRELSTAR ® luteinizing hormone releasing hormone (LHRH)
  • VANTAS ® Histrelin implant
  • VETORYL ® trilostane or modrastane
  • ZOLADEX ® fosrelin, goserelin
  • Deltoids and retinoids include seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide, PANRETIN ® (aliretinoin), ATRAGEN ® (liposomal tretinoin), 1355 TARGRETI ® (bexarotene), LGD-1550 and the like.
  • PARP inhibitors include ABT-888, olaparib, U-59436, AZD-2281, AG-014699, BSI-201 , BGP-15, ⁇ - 1001 , ONO-2231 and the like.
  • Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
  • 1360 Proteasome inhibitors include VELCADE (bortezomib), MG 132, NPI-0052,
  • immunologicals include interferons and other immune-enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- l a, ACTIMMU E ® (interferon gamma- lb) or
  • GRANOCYTE ® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod,
  • MYLOTARGTM (gemtuzumab ozogamicin), NEUPOGEN ® (filgrastim), OncoVAC-CL, OVAREX ® (oregovomab), pemtumomab (Y-muHMFG l ), PROVENGE ® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS ® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN ® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific
  • PROLEU JN ® (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
  • Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA ® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR ® (gemcitabine), TOMUDEX ® (ratitrexed), TROXATYLTM (triacet luridine
  • Purine analogs include LANVIS ® (thioguanine) and PURI- ETHOL ®
  • Antimitotic agents include batabulin, epothilone D ( OS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 1390 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.
  • radiotherapy examples 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
  • 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)
  • TransMID- 107RTM diphtheria toxins
  • dacarbazine dactinomycin, 5,6- dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZONTM (squalamine lactate), DIMERICINE ® (T4N5 liposome lotion), discodermolide, DX-8951 f (exatecan mesylate), enzastaurin, EPO906 (epithilone B), GARDASIL ® (quadrivalent human papillomavirus (Types 6, 1 1 , 16, 18) recombinant vaccine), GASTRIMMUNE ® ,
  • halofuginone histerelin, hydroxycarbamide, ibandronic acid, IGN-101 , IL- 13- PE38, IL- 13-PE38QQR (cintredekin besudotox), IL- 13-pseudomonas exotoxin, interferon-a, interferon- ⁇ , JUNOVANTM or MEPACTTM (mifamurtide), lonafarnib, 5, 10- methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT ® (AE-
  • NEUTREXIN ® trimetrexate glucuronate
  • NIPENT ® pentostatin
  • ONCONASE ® a ribonuclease enzyme
  • ONCOPHAGE melanoma vaccine treatment
  • ONCOVAX IL-2 Vaccine
  • ORATHECI TM rubitecan
  • OSIDEM antibody-based cell drug
  • OVAREX ® MAb murine monoclonal antibody
  • paclitaxel PANDIMEXTM (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and
  • TAXOPREXI ® DHA-paclitaxel
  • TELCYTA ® canfosfamide, TLK286)
  • TEMODAR ® temozolomide
  • tesmilifene thalidomide
  • THERATOPE ® STn- LH
  • thymitaq (2-amino-3,4-dihydro-6-methy)-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride
  • TNFERADETM adenovector: DNA carrier containing the gene for tumor necrosis factor-a
  • TRACLEER ® or ZAVESCA ® bisentan
  • tretinoin Retin-A
  • alkaloids from the greater celandine plant vitaxin (anti-alphavbeta3 antibody), XCYTRIN ® (motexafin gadolinium), XiNLAYTM (atrasentan), XYOTAXTM (paclitaxel poliglumex), YONDELIS ® (trabectedin), ZD-6126, ZI ECARD ® (dexrazoxane), ZOMETA ® (zolendronic acid), zorubicin and the like.
  • Focal adhesion kinase (recombinant human FAK fragment, amino acids 41 1-686; 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
  • Reaction conditions consisted of 4 nM FAK, 50 ⁇ ATP, and 0.2 ⁇ 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
  • ADDP means l , r-(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
  • (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 l ,2-bis(dimethyIphosphino)ethane
  • DMSO means dimethylsulfoxide
  • dppb means
  • EDAGHCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • Fmoc means fluorenylmethoxycarbonyl
  • HATU means 0-(7-azabenzotriazol- l-yl)-N,N r 'N'-tetramethyluronium hexafluorophosphate
  • HMPA HMPA
  • IPA isopropyl alcohol
  • MP-BH3 means
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • NCS N-chlorosuccinimide
  • NMM N-methylmorpholine
  • NMP means
  • N-methylpyrrolidine; PPli3 means triphenylphosphine.
  • a compound of formula (1 ), wherein X 1 is a halogen or triflate and R 1 , R 2 , and R 3 are as described herein, can be reacted with a compound of formula (2), wherein R 4 , R 5 , R 6 , and R 7 are as described herein, and copper powder to provide a compound of formula (3).
  • the reaction is typically performed at an elevated temperature in a solvent such as but not limited to chlorobenzene.
  • formula (6) which are representative of compounds of this invention, can be prepared from compounds of formula (3) and a compound of formula (4) or formula (5), wherein R 8 , R 9 , R 10 , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature.
  • compounds of formula (8) wherein X 1 is a halogen or triflate and R 1 , R 2 , and R 3 are as described herein, can be prepared from compounds of formula (7) by reacting the latter with trimethylsilyldiazomethane in methanol. The reaction is typically performed at room temperature.
  • Compounds of formula (8) can be
  • a solvent such as but not limited to methanol is typically used, and the reaction is typically performed at an elevated temperature.
  • compounds of formula (16A), wherein R 4 , R 6 , and R 7 are as described herein, can be prepared from compounds of formula (16) by reacting the latter with potassium bis(trimethylsilyl)amide, followed by di-tert-butyl carbonate. The reaction is typically conducted at a reduced temperature in a solvent such as but not limited to tetrahydrofuran.
  • Compounds of formula (16A) can be reacted with compounds 1535 of formula (8), wherein X 1 is a halogen or triflate, and R 1 , R 2 , and R 3 are as described herein, to provide compounds of formula (17) using Buchwald-Hartwig coupling conditions described herein, known to those skilled in the art, and readily available in the literature.
  • Compounds of formula (18) can be prepared form compounds of formula (17) by reacting the latter with hydrogen in the presence of a catalyst such as but not limited to
  • the reaction is typically performed under pressure at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof.
  • Compounds of formula ( 19) can be reacted with a activating group such as but not limited to O-(benzotriazol- l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate (TBTU) in the presence of a base such as but not limited to triethylamine to provide compounds of formula (20).
  • a activating group such as but not limited to O-(benzotriazol- l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate (TBTU)
  • TBTU ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate
  • the reaction is typically performed at room temperature in a solvent such as but not limited to N,N-
  • 1570 reaction is typically performed at an elevated temperature in a solvent such as but not limited to ethanol, water, or mixtures thereof.
  • Compounds of formula (27) can be reacted with a activating group such as but not limited to 0-(benzotriazol- l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU) in the presence of a base such as but not limited to N,N-diisopropylethylamine to provide compounds of formula (28).
  • TBTU 0-(benzotriazol- l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate
  • the 1575 reaction is typically performed at room temperature in a solvent such as but not limited to ⁇ , ⁇ -dimethylformamide.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are as described herein; and which can be prepared as described in US 20040254159, can be reacted with a compound of formula
  • R 9 , R 10 , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide 1595 a compound of formula (32), which are representative of the compounds of this invention.
  • compounds of formula (8) wherein X is a halogen or 1600 triflate and R 1 , R 2 , and R 3 are as described herein, can be reacted with compounds of formula (33), wherein R 4 , R 5 , R 6 , and R 7 are as described herein, to provide compounds of formula (34) using Buchwald-Hartwig coupling conditions described herein, known to those skilled in the art, and readily available in the literature.
  • Compounds of formula (35) can be prepared form compounds of formula (34) by reacting the latter with 1605 hydrogen in the presence of a catalyst such as but not limited to Raney-Nickel.
  • reaction is typically performed under pressure at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof.
  • a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof.
  • Compounds of formula (35) can be heated in the presence of an acid such as but not limited to hydrochloric acid to provide compounds of formula (36).
  • a solvent such as but not limited to methanol is
  • aqueous base such as but not limited to sodium hydroxide
  • the reaction is typically performed at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof.
  • Compounds of formula (38) can be coupled with amines of formula NH 2 R 13 or NH(R I 3 )2, wherein each R 13 is as described herein, using conditions described herein, known to those skilled in
  • Compounds of formula (45) can be converted to compounds of formula (46) by reacting the former with iron under acidic conditions. The reaction is typically performed at an elevated temperature in a solvent such as but not limited to ethanol, water, or mixtures thereof. Compounds of formula (46) can be reacted with a activating group such as but not limited to 0-(benzotriazol- l-yl)-N,N,N',N'-
  • Example I B 0.038 g, 0.1 mmol
  • Example 3 A (3.0 g, 10.12 mmol), methyl-3,4-diaminobenzoate (3.39 g, 10.12 mmol), 2 C0 3 (1.47 g, 10.63 mmol), Cu (0.648 g, 10.12 mmol) and chlorobenzene ( 100 1 735 ml) were mixed. The reaction mixture was heated to reflux ( 135°C) overnight then filtered hot through a thin layer of diatomaceous earth. The flask was rinsed and the cake was washed with CH2CI2 (100 ml).
  • Example 3C To the mixture of Example 3C ( 1.05 g, 3.47 mmol), N-(2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (2.07 g, 6.94 mmol), CsF ( 1 .58 g, 10.41 mmol) and Cy-Map (2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl) 1755 (0.406 g, 1.04 mmol) in N,N-dimethylacetamide (80 ml) and methanol (40 ml) nitrogen was bubbled, and palladium(II) acetate (0.135 g, 0.6 mmol) was added.
  • reaction mixture was refluxed for 2 days. After cooling at room temperature, the reaction mixture was filtered through a layer of diatomaceous earth. The filtrate was washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were 1760 washed with brine, dried (Na 2 S0 4 ), filtered and concentrated onto silica gel and loaded onto an Analogix SF40- 150 g column for separation (10-80%) using ethyl acetate in hexanes to yield the title compound. MS ESI(-) m/z 436.0 [M-H] "
  • Example 3D To Example 3D (1.8 g, 4.1 1 mmol) was added tetrahydrofuran ( 14 ml) and methanol (14 ml) followed by 2.5 N aqueous NaOH solution (9.4 ml). The reaction mixture was stirred at room temperature overnight. Water ( 100 ml) was added to the
  • Example 3E (0.021 g, 0.05 mmol) in N,N-dimethylformamide (0.8 ml) was 1780 added 0-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.029 g, 0.09 mmol), N,N-diisopropylethylamine (0.0097 g, 0.075 mmol) and 3-(4- methylpiperazin- l -yl)propan-l -amine (0.010 g, 0.065 mmol).
  • Example 4A 0.037 g, 0.1 10 mmol
  • 3-bromo-2-fluoropyridine 0.018 g, 1810 0.1 mmol
  • a microwave vial was added 1 ,2-dimethoxyethane (0.6 ml) and methanol (0.3 ml) followed by CsF (0.03 g, 0.2 mmol) and
  • Example 4B To Example 4B (0.02 g, 0.066 mmol) and Cs 2 C0 3 (0.043 g, 0.132 mmol) in N,N- dimethylformamide (0.5 ml) was added N-methylmethanesulfonamide (0.0079 g, 0.073 mmol) in N,N-dimethylformamide (0.5 ml). The reaction mixture was heated at 60°C for 20 hours. After cooling, the reaction mixture was filtered and concentrated. The crude
  • Example 6A 0.077 g, 0.22 mmol
  • N-(3-bromopyridin-2-yl)-N- 1880 methylmethanesulfonamide in a microwave vial was added 1,2-dimethoxyethane ( 1.2 ml) and methanol (0.6 ml) followed by CsF (0.061 g, 0.4 mmol) and
  • Example 9A The title compound was prepared as described in Example 4B, except substituting Example 9A for 3-bromo-2-fluoropyridine.
  • Example 9A The title compound was prepared as described in Example 9A, except substituting iodomethane for iodoethane and Example 4B, except substituting N-(2-bromo-3- methylphenyl)methanesulfonamide for 3-bromo-2-fluoropyridine to afford the title compound.
  • Example 9A The title compound was prepared as described in Example 9A, except substituting iodomethane for iodoethane and Example 4B, except substituting N-(2-bromo-5- methylphenyl)methanesulfonamide for 3-bromo-2-fluoropyridine to afford the title compound.
  • Example 14A 700 mg, 2.76 mmol
  • Example 3A 820 mg, 2.76 mmol
  • CS2CO3 901 mg, 2.76 mmol
  • palladium(II) acetate 31 mg, 0.14 mmol
  • 1 , l '-bis(diphenylphosphino)ferrocene 153 mg, 0.28 mmol
  • toluene 27.6 ml
  • Example 14B (740 mg, 1.75 mmol) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (5 ml) in a 250 mL stainless steel pressure bottle. Ra-Ni (740 mg, 12.6 mmol, water-wet) was added and the resulting mixture stirred at room temperature
  • Example 14E ( 1 12 mg, 0.3 1 mmol), Example 39C ( 1 16 mg, 0.37 mmol), [(t-Bu) 2 - P(OH)PdCl 2 ]2 ( 10.6 mg, 0.02 mmol), and cesium carbonate (406 mg, 1 .25 mmol), were combined in a 5 mL microwave tube containing a conical stir bar.
  • a scintillation vial (20 ml) was charged with a solution of Example 3E (23.44 mg, 0.055 mmol) in ⁇ , ⁇ -dimethylacetamide, 3-(4-methylpiperidin-l-yl)propan- l -amine ( 10.3 mg, 0.066 mmol) in ⁇ , ⁇ -dimethylacetamide, a solution of 0-(7-azabenzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate (25.26 mg, 0.066 mmol) in N,N- 2060 dimethylacetamide, and triethylamine (23.31 ⁇ , 0.166 mmol).
  • Example 39C (2.2 g, 6.94 mmol), cesium fluoride (1.6 g, 10.41 mmol), and 2'-(dicyclohexylphosphino)-N,N- dimethylbiphenyl-2-amine (0.41 g, 1.04 mmol).
  • the resulting mixture was bubbled with nitrogen gas and palladium(II) acetate (0.13 g, 0.59 mmol) was added. After heating at
  • Example 39 To a solution of Example 39 (1.77 g, 3.92 mmol) in a mixture of tetrahydrofuran ( 14ml) and methanol (14ml) was added 2.5N aqueous NaOH (9.4 ml, 23.52 mmol). After stirring at room temperature over 18 hours, the reaction mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 2N aqueous 2395 HCI until the solution reached a pH of 2. The crude product was extracted several times with ethyl acetate. The combined organic layers were dried (Na 2 S0 4 ), filtered, and concentrated to yield the title compound.

Abstract

Cette invention concerne des composés qui inhibent l'activité de la kinase d'adhérence focale, des compositions les contenant, et des méthodes pour traiter les maladies au cours desquelles la kinase d'adhérence focale est exprimée.
PCT/CN2010/001577 2010-10-09 2010-10-09 Benzodiazépinones à titre d'inhibiteurs de fak pour le traitement du cancer WO2012045194A1 (fr)

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US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
WO2020231726A1 (fr) 2019-05-10 2020-11-19 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase d'adhésion focale à petites molécules (fak)
US10987360B2 (en) 2016-09-15 2021-04-27 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US11040965B2 (en) 2017-03-13 2021-06-22 Assembly Biosciences, Inc. Process for making Hepatitis B core protein modulators
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