WO2008127594A2 - Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer - Google Patents

Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer Download PDF

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Publication number
WO2008127594A2
WO2008127594A2 PCT/US2008/004570 US2008004570W WO2008127594A2 WO 2008127594 A2 WO2008127594 A2 WO 2008127594A2 US 2008004570 W US2008004570 W US 2008004570W WO 2008127594 A2 WO2008127594 A2 WO 2008127594A2
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WIPO (PCT)
Prior art keywords
amino
phenyl
methyloxy
quinoxalin
sulfonyl
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PCT/US2008/004570
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French (fr)
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WO2008127594A3 (en
Inventor
Peter Lamb
David Matthews
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Exelixis, Inc.
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Priority to MEP-2009-304A priority Critical patent/ME00937B/en
Priority to PL08742674T priority patent/PL2139483T3/en
Priority to US12/595,236 priority patent/US8481001B2/en
Priority to BRPI0810208-2A2A priority patent/BRPI0810208A2/en
Priority to AU2008239668A priority patent/AU2008239668B2/en
Priority to EA200970935A priority patent/EA019064B1/en
Priority to DK08742674.8T priority patent/DK2139483T3/en
Priority to EP08742674.8A priority patent/EP2139483B9/en
Priority to MX2009010929A priority patent/MX2009010929A/en
Priority to ES08742674.8T priority patent/ES2438998T3/en
Priority to RS20130486A priority patent/RS53020B/en
Priority to NZ580009A priority patent/NZ580009A/en
Application filed by Exelixis, Inc. filed Critical Exelixis, Inc.
Priority to UAA200911452A priority patent/UA98141C2/en
Priority to JP2010503043A priority patent/JP5726515B2/en
Priority to CN2008800173944A priority patent/CN101959516B/en
Priority to CA002684056A priority patent/CA2684056A1/en
Priority to SI200831061T priority patent/SI2139483T1/en
Publication of WO2008127594A2 publication Critical patent/WO2008127594A2/en
Publication of WO2008127594A3 publication Critical patent/WO2008127594A3/en
Priority to IL201211A priority patent/IL201211A/en
Priority to TNP2009000399A priority patent/TN2009000399A1/en
Priority to MA32313A priority patent/MA31335B1/en
Priority to EC2009009723A priority patent/ECSP099723A/en
Priority to HK10106504.4A priority patent/HK1140141A1/en
Priority to HRP20131081AT priority patent/HRP20131081T1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965Non-condensed pyrazines
    • A61K31/497Non-condensed pyrazines containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to methods of treating cancer with a compound that inhibits lipid kinase enzymatic activity and the resultant modulation of cellular activities (such as proliferation, differentiation, programmed cell death, migration, chemoinvasion and metabolism) in combination with anticancer agents.
  • Phosphatidylinositol 3-kinase (PI3K or PIK3CA) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit.
  • the protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate Ptdlns, PtdIns4P and PtdIns(4,5)P2.
  • PTEN a tumor suppressor which inhibits cell growth through multiple mechanisms, can dephosphorylate PIP3, the major product of PIK3CA.
  • PIP3 in turn, is required for translocation of protein kinase B (AKTl, PKB) to the cell membrane, where it is phosphorylated and activated by upstream kinases.
  • AKTl protein kinase B
  • PKB protein kinase B
  • PI3K ⁇ has been implicated in the control of cytoskeletal reorganization, apoptosis, vesicular trafficking, proliferation and differentiation processes.
  • Increased copy number and expression of PIK3CA or activating mutations in the pi 10a catalytic subunit of PIK3CA are associated with a number of malignancies such as ovarian cancer (Campbell et al., Cancer Res 2004, 64, 7678-7681 ; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman, et al.
  • activation of the PI3K pathway contributes to the resistance of human tumor cells to a wide variety of chemotherapeutic agents, including microtubule stabilizing agents such as taxol (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et. al. MoI Cancer Ther 2002, 1, 101-1X1; Kraus, A. C, et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et. al. MoI Cancer Ther 2002, 1, 913-922; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440).
  • taxol Taxol
  • Taxol is widely used to treat advanced cancers including prostate carcinomas, which frequently harbor deletions in the PTEN gene, resulting in elevated signaling downstream of PI3K.
  • a number of preclinical studies suggest that inhibiting signaling downstream of PI3K restores or enhances the ability of chemotherapeutic agents such as taxol to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et. al. MoI Cancer Ther 2002, 1, 707-717; Kraus, A. C, et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et. al.
  • Rapamycin another chemotherapeutic agent, is a potent inhibitor of the mTOR/Raptor complex. Inhibition of mTOR/Raptor prevents p70S6K and S6 phosphorylation, but also leads to relief of a negative feedback loop emanating from p70S6K that serves to downregulate POK (Sarbassov, D. D., et. al. Science 2005, 307, 1098-1 101).
  • rapamycin treatment can lead to upregulation of PDK and increased phosphorylation of AKT (O'Donnell, A., et. al. paper presented at Proc Am Soc Clin Oncol. 2003; and O'Reilly, K. E., et. al. Cancer Res 2006, 66, 1500-1508).
  • combining rapamycin with inhibitors of PI3K can enhance the efficacy of rapamycin (Powis, G. et. al. Clinical Cancer Research 2006, 12, 2964-2966; Sun, S.-Y., et. al. Cancer Research 2005, 65, 7052-7058).
  • ⁇ SCLC patients with K-Ras mutations do not respond to EGFR inhibitors such as Tarceva, and thus represent a significant unmet medical need (Janne PA, et. al. J CHn Oncology 2005, 23, 3227-3234).
  • a D ⁇ A-damaging agent such as a platin in combination with an inhibitor of PI3K is desirable in light of the lack of efficacious treatments.
  • Treatments that combine an inhibitor of PI3K- ⁇ with other anti-cancer agents are desirable and needed.
  • compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities.
  • Disease states which can be treated by the methods and compositions provided herein include cancer.
  • the invention is directed to methods of treating these diseases by administering a Compound of Formula I or II in combination with one or more treatments.
  • One aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula I:
  • R ' is hydrogen or alkyl
  • R 52 is hydrogen or halo
  • R 50 , R 53 , and R 54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(O)-Ci-C 6 -alkylene-N(R 55a )R 55b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O) 2 NR 55 R 55a , or alkylcarbonylamino and where R 55 and R 55b are indepedently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R 53 and R 54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5-
  • B is phenyl substituted with R 3a and optionally further substituted with one, two, or three R 3 ; or
  • B is heteroaryl optionally substituted with one, two, or three R 3 ;
  • R 3a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R 7 )C(O)-C,-C 6 -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen, alkyl, or alkenyl and R 7a and R 7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl
  • R 19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R 20 )C(O)-Ci-C 6 -alkylene-C(O)R 20a where R 20 is hydrogen, alkyl, or alkenyl and
  • R 20a is cycloalkyl or heterocycloalkyl; p) -NR 21 S(O) 2 -C, -C 6 -alkylene-N(R 21b )R 21a where R 21 is hydrogen, alkyl, or alkenyl and
  • R 21a and R 21b are independently hydrogen, alkyl, or alkenyl; q) -N(R 22 )C(O)-C,-C 6 -alkylene-N(R 22b )-N(R 22c )(R 22a ) where R 22 , R 22a and R 22b are independently hydrogen, alkyl, or alkenyl; r) -C 0- C 6 -alkylene-N(R 23 )-C,-C 6 -alkylene-N(R 23b )R 23a where R 23 , R 23a and R 23b are independently hydrogen, alkyl, or alkenyl; or s) -NR 24 C(O)-C, .C 6 -alkylene-OR 24a where R 24 is hydrogen, alkyl, or alkenyl and R 24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and where each of the alkylene in R 3a is independently optional
  • each R 3 (when R 3 is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo; alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R 7 )C(O)-C,-C 6 -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen, alkyl, or alkenyl and R 7a and R 7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalky
  • R l9a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R 20 )C(O)-C,-C 6 -alkylene-C(O)R 20a where R 20 is hydrogen, alkyl, or alkenyl and
  • R 2Oa is cycloalkyl or heterocycloalkyl; p) -NR 21 S(O) 2 -C,-C 6 -alkylene-N(R 21b )R 21a where R 21 is hydrogen, alkyl, or alkenyl and
  • R 21a and R 21b are independently hydrogen, alkyl, or alkenyl; q) -N(R 22 )C(O)-C,-C 6 -alkylene-N(R 22b )-N(R 22c )(R 22a ), where R 22 , R 22a and R 22b are independently hydrogen, alkyl, or alkenyl; r) -C 0 -C 6 -alkylene-N(R 23 )-C,-C 6 -alkylene-N(R 23b )R 23a where R 23 , R 23a and R 23b are independently hydrogen, alkyl, or alkenyl; or s) -NR 24 C(O)-C, .C 6 -alkylene-OR 24a where R 24 is hydrogen, alkyl, or alkenyl and R 24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; wherein each of the alkylene in R 3 is independently
  • R 50 and R 52 are hydrogen, R 51 is hydrogen or methyl, R 53 is hydrogen or methoxy, and R 54 is hydrogen or methoxy, then B is not 2,3-dihydro-l,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R 3 where R 3 is halo.
  • a second aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula II:
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more of the hormone therapies, one or more of the antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation
  • A is aryl, -S(O) 2 -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, or -alkyl-N(R 7 )R 7a , where each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl and alkoxy groups, each either alone or as part of another group within A, are independently optionally substituted with one, two, three, or four R 2a ; or B 1 is aryl, arylalkyl, alkyl, heteroaryl, or heteroary alkyl, wherein each of the aryl, heteroaryl and alkyl groups are independently optionally substituted with one, two, three, or four R 3d ; each R la is independently selected from hydrogen, alkoxy, alkyl, nitro, halo, cyano, and -C 0 - C 6 -
  • R 4 is hydrogen, aryl, -C 0 -C 6 -alkyl-N(R 7 )R 7a , alkoxy, or Ci-C 6 alkyl, wherein each of the alkyl and aryl groups, either alone or as part of another group in R 4 , is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R 8 )R 8a , alkoxy, and -C(O)OR 6 ; or
  • R 4 and X 1 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein R 5a is absent when X is -N(R 5a )-, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R 7 )R 7a , alkoxy, and -C(O)OR 6 ;
  • R 5a is hydrogen, -Ci-C 6 alkyl-N(R 7 )R 7a , alkoxy, alkyl, or aryl, wherein each of the alkyl and aryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R 8 )R 8a , C r C 6 alkoxy, or -C(O)OR 6 ; or R 5a and R 4 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R 7 )R 7a , C ,-C 6 alkoxy, and -C(
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • alkenyl or "lower alkenyl” means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one double bond and includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like.
  • alkenylcarbonyl means a C(O)R group where R is alkenyl, as defined herein.
  • alkenyloxy or "lower alkenyloxy” means an -OR group where R is alkenyl, as defined herein. Representative examples include methoxy, ethoxy, l-methoxyprop-l-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • Alkoxy or "lower alkoxy” means an -OR group where R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, l-methoxyprop-l-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • Alkoxyalkyl means an alkyl group, as defined herein, substituted with one, two, or three alkoxy groups, as defined herein.
  • Akoxycarbonyl means a -C(O)OR group where R is alkyl as defined herein.
  • Alkoxyycarbonylalkyl means an alkyl group, as defined herein, substituted with one, two, or three alkoxycarbonyl groups, as defined herein.
  • Alkyl or "lower alkyl” means a linear or branched hydrocarbon group having one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, /-butyl, isobutyl, pentyl, hexyl and the like.
  • C 6 -alkyl is a covalent bond.
  • C 6 alkyl refers to, for example, n-hexyl, /s ⁇ -hexyl, and the like.
  • Alkylamino means a -NHR radical where R is alkyl as defined herein, or an
  • N-oxide derivative thereof e.g., methylamino, ethylamino, n-, /so-propylamino, «-, iso-, tert- butylamino, or methylamino-N-oxide, and the like.
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Alkylaminoalkyloxy means an -OR group where R is alkylaminoalkyl, as defined herein.
  • Alkylcarbonyl means a C(O)R group where R is alkyl, as defined herein.
  • Alkylcarbonylamino means a -NRC(O)R' group where R is hydrogen or alkyl, as defiend herein, and R' is alkyl, as defiend herein.
  • Alkylene refers to straight or branched divalent hydrocarbon, containing no unsaturation and having from two to eight carbon atoms. Examples of alkylene include eth- diyl (-CH 2 CH 2 -), prop- 1 ,3-diyl (-CH 2 CH 2 CH 2 -), 2,2-dimethylprop-l,3-diyl
  • Alkylsulfonyl means a -S(O) 2 R group where R is lakyl, as defined herien.
  • Alkylthio means a -SR group where R is alkyl, as defined herein.
  • alkylthio include methylthio and ethylthio, and the like.
  • Alkylthioalkyl means an alkyl group substituted with one or two alkylthio groups, as defined herein, e.g. 2-(methylthio)-ethyl and 2-(ethylthio)-ethyl.
  • Alkynyl or “lower alkynyl” means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
  • Amino means a -NH 2 .
  • aminoalkyl means an alkyl group subsitutted with at least one, for example one, two, or three, amino groups.
  • aminoalkyloxy means an -OR group where R is aminoalkyl, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic.
  • Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Arylalkyl means an alkyl group, as defined herein, subsituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like.
  • Aryloxy means a -OR group where R is aryl as defined herein.
  • Arylalkyloxy means a -OR group where R is arylalkyl as defined herein.
  • Arylsulfonyl means a -SO 2 R group where R is aryl as defined herein.
  • Carboxyalkyl means an alkyl group, as defined herein, substituted with one, two, or three -C(O)OH groups.
  • Carboxy ester means a -C(O)OR group where R is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.
  • Cyanoalkyl means an alkyl, alkenyl, or alkynyl radical, as defined herein, substituted with at least one, for example one, two, or three, cyano groups.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms.
  • the cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring. Cycloalkyl includes fused, bridged, and spiro ring systems.
  • radicals examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cycloalkylalkyl means alkyl group substituted with one or two cycloalkyl groups, as defined herein. Representative examples include cyclopropylmethyl and
  • Cycloalkylcarbonyl means a -C(O)R group where R is cycloalkyl as defined herein.
  • Dialkylamino means a -NRR' radical where R and R' are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,iV-methylethylamino, and the like.
  • Dialkylaminoalkyl means an alkyl group substituted with one or dialkylamino groups, as defined herein.
  • Dialkylaminoalkyloxy means an -OR group where R is dialkylaminoalkyl, as defined herein.
  • fused ring system and "fused ring” refer to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
  • "Haloalkoxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Haloalkoxyalkyl means an alkyl group, as defined herein, substituted with one, two, or three haloalkoxy, as defined herein.
  • Halogen or "halo” means fluoro, chloro, bromo and iodo.
  • Haloalkenyl means an alkenyl group, as defined herein, substituted with one or more halogens, for example one to five halo atoms.
  • Haloalkyl means an alkyl group, as defined herein, substituted with one or more halogens, for example one to five halo atoms. Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-l-fluoroethyl, and the like.
  • Heteroaryl means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, for example one, two, three, or four ring heteroatoms independently selected from -O-, -S(O) n - (n is 0, 1, or 2), -N-, -N(R")-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic.
  • R x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl.
  • Fused bicyclic radical includes bridged ring systems.
  • the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, R x is absent.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH- indol-2-yl or 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazoliny
  • heteroarylalkyl means an alkyl group substituted with one or two heteroaryl groups as defined herein.
  • Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen atom, R y is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydro
  • ⁇ eterocycloalkylalkyl means an alkyl group, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein.
  • ⁇ ydroxyalkyl means an alkyl radical, as defined herein, substituted with at least one, for example one, two, or three, hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy butyl, 2,3-dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, for example 2-hydroxyethyl, 2,3-dihydroxypropyl, or l-(hydroxymethyl)-2-hydroxyethyl, and the like.
  • ⁇ ydroxyamino means a -N ⁇ (O ⁇ ) group.
  • Optionally substituted alkyl means an alkyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl- S(O) 0-2 -, alkenyl-S(0)o -2 -, aminosulfonyl, alkylaminosulfonyl,
  • Optionally substituted alkenyl means an alkenyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O) 0-2 -, alkenyl-S(0)o -2 -, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NR c
  • Optionally substituted aryl means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -C(O)NR 5 R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 5 C(O)R" (where R' is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O) 2 R' (where R 5 is alkyl, aryl,
  • Optionally substituted heteroaryl means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, -C(O)NR 5 R" (where R 5 is hydrogen or alkyl and R 55 is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 5 C(O)R" (where R 5 is hydrogen or alkyl and R 55 is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O) 2 R 5
  • Optionally substituted heterocycloalkyl 55 means a heterocycloalkyl, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, -C(O)NR 5 R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR 5 C(O)R" (where R 5 is hydrogen or alkyl and R 55 is alkyl, aryl, heteroaryl, or heterocycloalkyl), amino, alkylamino
  • saturated bridged ring system refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system. 55
  • Spirocyclyl or "spirocyclic ring 55 refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings C and C 5 ), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring D) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • AKT inhibitor includes, for example, LY294002, PKC 412, perifosine, compounds in Table 2a, compounds in Table 2b, and compounds described in WO 2006/071819 and WO05/117909. These references also describe in vitro assays that can be used to determine the inhibitory activity of AKT.
  • Alkylating agent includes, for example, one or more of the following: Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Carmustine, Streptozocin, Fotemustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Oxaliplatin, BBR3464, Busulfan, dacarbazine, Mechlorethamine, Procarbazine, Temozolomide, ThioTEPA, and Uramustine.
  • Antibody includes, for example, one or more of the following: an IGFlR antibody (including, for example, “IGF- IR A12 MoAb, 19Dl 2, h7C10 and CP-751871), an EGFR antibody (including, for example, Cetuximab (Erbitux®) and Panitumumab), an ErbB2 antibody (including, for example, Trastuzumab (Herceptin®)), a VEGF antibody (including, for example, Bevacizumab (Avastin®)), an IgGl antibody (including, for example, Ibritumomab (tiuxetan)), a CD20 antibody (including, for example, Rituximab and Tositumomab), a CD33 antibody (including, for example, Gemtuzumab and Gemtuzumab ozogamicin), and a CD52 antibody (including, for example, Alemtuzumab).
  • an IGFlR antibody including, for example,
  • Antimetabolite include, for example, methotrexate, Pemetrexed, Raltitrexed, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Thioguanine, Capecitabine, Cytarabine, fluorouracil (administered with or without leucovorin or folinic acid), and Gemcitabine.
  • Antimicrotubule agent includes, for example, Vincristine,Vinblastine, Vinorelbine, Vinflunine, and Vindesine.
  • Aromatase inhibitor includes, for example, one or more of the following: Aminoglutethimide, Anastrozole (Arimidex®), Letrozole (Femara®), Exemestane (Aromasin®), and Formestane (Lentaron®).
  • Cancer refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancre
  • Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myel
  • “Chemotherapeutic agent” includes, but is not limited to, an AKT inhibitor, an alkylating agent, an antimetabolite, an antimicrotubule agent, an aromatase inhibitor, a c-KIT inhibitor, a cMET inhibitor, an EGFR inhibitor, an ErbB2 inhibitor, a Flt-3 inhibitor, an HSP90 inhibitor, an IGFlR inhibitor, a platin, a Raf inhibitor, rapamycin, a Rapamycin analogue, a Receptor Tyrosine Kinase inhibitor, a taxane, a topoisomerase inhibitor, a SRC and/or ABL kinase inhibitor, and a VEGFR inhibitor.
  • c-KIT inhibitor includes, for example, imatinib, sunitinib, nilotinib, AMG 706, sorafenib, compounds in Table 3b, compounds in Table 3c, compounds in Table 8, compounds in Table 9, and compounds described in WO 2006/108059, WO/2005/020921, WO/2006/033943, and WO 2005/030140.
  • cMET inhibitor includes, for example, compounds in Table 3a, compounds in Table 3b, compounds in Table 3c, compounds described in WO06/108059, WO 2006/014325, and WO 2005/030140.
  • EGFR inhibitor'Mn includes, for example, one or more of the following: pelitinib, lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474, vandetinib), AEE788 and HKI-272, EKB-569, CI-1033, N-(3,4-dichloro-2-fluorophenyl)-7- ( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine N-(4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)qui
  • ErbB2 inhibitor includes, for example, lapatinib (GW572016), PKI- 166, canertinib, CI- 1033, HKI272, and EKB-569.
  • Flt-3 inhibitor includes, for example, CEP-701, PKC 412, MLN518, sunitinib, sorafenib, compounds in Table 3a, compounds in Table 3b, compounds in Table 3c, compounds in Table 9, and compounds described in WO 2006/108059, WO/2006/033943,
  • “Hormone therapy” or “hormonal therapy” includes, for example, treatment with one or more of the following: steroids (e.g. dexamethasone), finasteride, tamoxifen, and an aromatase inhibitor.
  • HSP90 inhibitor includes, for example, 17- AAG, 17-DMAG, Geldanamycin,
  • IGFlR inhibitor includes, for example, Tyrphostin AG 1024, compounds in
  • Kinase-dependent diseases or conditions refer to pathologic conditions that depend on the activity of one or more lipid kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
  • ocular diseases diabetic retinopathy, age-related macular degeneration, and the like
  • inflammation psoriasis, rheumatoid arthritis, and the like.
  • phosphatases can also play a role in
  • kinase-dependent diseases or conditions as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example lipid substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth.
  • abnormal levels of cell proliferation i.e. tumor growth
  • apoptosis programmed cell death
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • "Patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in another embodiment the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66: 1-19 both of which are incorporated herein by reference.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, iV-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Platinum and “platin-containing agent” include, for example, cisplatin, carboplatin, and oxaliplatin.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • Raf inhibitor includes, for example, sorafenib, RAF 265 (CHIR 265), compounds in Table 6, and compounds described in WO 2005/112932. These references also describe in vitro assays that can be used to determine the inhibitory activity of RAF.
  • Ras analogue includes for example, CCI-779, AP23573, RAD 001, TAFA 93, and compounds described in WO 2004/101583 and US 7,160,867 which are each incorporated herein by reference in their entireties.
  • Receptor Tyrosine Kinase inhibitor includes, for example, inhibitors of AKT, EGFR, ErbB2, IGFlR, KIT, Met, Raf, and VEGFR2.
  • Examples of receptor tyrosine kinase inhibitors can be found in WO 2006/108059 (US Nat'l Stage Application Serial No. 11/910,720), WO 2006/074057 (US Nat'l Stage Application Serial No. 1 1/722,719), WO 2006/071819 (US Nat'l Stage Application Serial No. 11/722,291), WO 2006/014325 (US Nat'l Stage Application Serial No. 1 1/571,140), WO 2005/117909 (US Nat'l Stage Application Serial No.
  • Taxane includes, for example, one or more of the following: Paclitaxel (Taxol ® ) and Docetaxel (Taxotere ® ).
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • Topicisomerase inhibitor includes, for example, one or more of the following: amsacrine, camptothecin, etoposide, etoposide phosphate, exatecan, irinotecan, lurtotecan, and teniposide, and topotecan.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • SRC and/or ABL kinase inhibitor includes, for example, dasatinib, imatinib (Gleevec®), and compounds described in WO 2006/074057.
  • VEGFR inhibitor includes, for example, one or more of the following: VEGF Trap, ZD6474 (vandetanib, Zactima), sorafenib, Angiozyme, AZD2171 (cediranib), pazopanib, sorafenib, axitinib, SU5416 (semaxanib), PTK787 (vatalanib), AEE778, RAF 265, sunitinib (Sutent), N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3ai?,5r,6a 1 S)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N- (4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2-methylocta
  • the embodiment includes both the recited compounds as well as individual isomers and mixtures of isomers.
  • the embodiment optionally includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof.
  • the Compound of Formula I can, for example, be of Formula I(a) or be selected from a Compound in Table 1.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, where growth and/or survival of tumor cells of the cancer is enhanced, at least in part, by the activity of PBK; in combination with one or more treatments selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric carcinoma (including gastrointestinal carcinoid tumors and gastrointestinal stromal tumors), glioblastoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), melanoma, ovarian cancer, cervical cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AJvIL), chronic myelogenous leukemia (CML), non-Hodgkin's lymphoma, and thyroid carcinoma.
  • AJvIL acute myelogenous leukemia
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from prostate cancer, NSCLC, ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, and glioblastoma.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from NSCLC, breast cancer, prostate cancer, glioblastoma, and ovarian cancer.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
  • chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, cisplatin, oxaliplatin, gef ⁇ tinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), HKI-272, pelitinib, canertinib, a compound selected from Table 4, a compound in Table 7, and lapatinib.
  • chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, cisplatin, oxaliplatin, gef ⁇ tinib (Iressa®), erlotinib (Tarceva
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, trastuzumab, erlotinib, /V-(3,4-dichloro-2-fluorophenyl)-7- ( ⁇ [(3ai?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2- methyloctahydrocyclo-penta[c]pyrrol-5-y
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, paclitaxel, carboplatin, erlotinib, and N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a.S)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine.
  • chemotherapeutic agents independently selected from rapamycin, paclitaxel, carboplatin, erlotinib, and N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a.S)-2- methylocta
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from a platin and a taxane.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from carboplatin, cisplatin, oxaliplatin, and paclitaxel.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an AKT inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an AKT inhibitor selected from perifosine, PKC 412, a compound in Table 2a, and a compound in Table 2b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor selected from a compound in Table 3a, a compound in Table 3b, and a compound in Table 3c.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, a compound selected from Table 4, and a compound in Table 7.
  • a chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, a compound selected from Table 4, and a compound in
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, N-(3,4-dichloro-2-fluorophenyl)-7- ( ⁇ [(3a/?,5r,6a5')-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine N-(4-bromo-3-chloro-2-fluorophenyl)
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor selected from lapatinib, EKB-569, HKI272, CI 1033, PKI- 166, and a compound selected from Table 4.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor selected from 17- AAG, 17-DM AG, Geldanamycin, and CNF2024.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor selected from 17-AAG, 17-DMAG, and Geldanamycin.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGFlR inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGFlR inhibitor selected from Table 5a and Table 5b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a Raf inhibitor selected from sorafenib, RAF 265 (CHIR-265), and a compound in Table 6.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor selected from VEGF Trap, ZD6474 (Zactima), cediranib (AZ2171), pazopanib, sunitinib, sorafenib, axitinib, AEE788, RAF 265 (CHIR-265), a compound selected from Table 4, and a compound selected from Table 7.
  • VEGFR inhibitor selected from VEGF Trap, ZD6474 (Zactima), cediranib (AZ2171), pazopanib, sunitinib, sorafenib, axitinib, AEE788, RAF 265 (CHIR-265), a compound selected from Table 4, and a compound selected from Table
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor selected from imatinib, sunitinib, nilotinib, AMG 706, sorafenib, a compound in Table 3b, a compound in Table 3c, a compound in Table 8, and a compound in Table 9.
  • a cKIT inhibitor selected from imatinib, sunitinib, nilotinib, AMG 706, sorafenib, a compound in Table 3b, a compound in Table 3c, a compound in Table 8, and a compound in Table 9.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor selected from CEP-701, PKC 412, sunitinib, MLN518, sunitinib, sorafenib, a compound in Table 3a, a compound in Table 3b, a compound in Table 3c, and a compound in Table 9.
  • a FLT3 inhibitor selected from CEP-701, PKC 412, sunitinib, MLN518, sunitinib, sorafenib, a compound in Table 3a, a compound in Table 3b, a compound in Table 3c, and a compound in Table 9.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from rapamycin, a rapamycin analogue, PI 103, and SF 1126.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from rapamycin, CCI-779, AP23573, RAD 001, TAFA 93, PI103, and SF 1 126.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is of formula 100:
  • E is -NR 9 -, -O-, or absent and Y is -CH 2 CH 2 -, -CH 2 -, or absent provided that when E is -NR 9 - or -O-, then Y is -CH 2 CH 2 -;
  • R 2 is selected from halogen, trihalomethyl, -CN, -NO 2 , -OR 3 , and lower alkyl;
  • R 8 is selected from -H, lower alkyl, -C(O)OR 3 , -C(O)N(R 3 )R 4 , -SO 2 R 4 , and -C(O)R 3 ;
  • R 9 is hydrogen or lower alkyl;
  • R 3 is hydrogen or R 4 ;
  • R 4 is selected from lower alkyl, aryl, lower arylalkyl, heterocyclyl, and lower heterocyclylalkyl; or R 3 and R 4 , when taken together with a common nitrogen to which they are attached, form a
  • Aryl in formula 100 means an aromatic six- to fourteen-membered carbocyclic rings which include, for example, benzene, naphthalene, indane, tetralin, fluorene and the like.
  • “Lower arylalkyl” in formula 100 means a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkenylene, or alkynylene radical where the "alkyl” portion of the group has one to six carbons; examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like.
  • heterocyclyl means a stable monocyclic, bicyclic or tricyclic three- to fifteen-membered ring radical (including fused or bridged ring systems) that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur where the nitrogen, phosphorus, carbon and sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states and the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic.
  • “Lower heterocyclylalkyl” means a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkenylene, and alkynylene radical having one to six carbons.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 , in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3 a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3c.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3c.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3c.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 , in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3ai?,5r,6a5)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3ai?,5r,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichlor
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is iV-(3,4-dichloro-2-fluorophenyl)-7- ( ⁇ [(3ai?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3ai?,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro- 2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)- 6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3ai?,5r,6a5')- 2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6aS)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is jV-(3,4-dichloro-2-fluorophenyl)-7- ( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is 7V-(3,4-dichloro- 2-fluorophenyl)-7-( ⁇ [(3ai?,5r,6a J S)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl ⁇ oxy)- 6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5ac.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5a.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5b.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 6.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 6.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 6.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 7.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 7.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 , in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 7.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 8.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 8.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 8.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 9.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 9.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 9.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is paclitaxel.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is rapamycin.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is carboplatin.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is radiation.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is radiation.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two antibodies.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two antibodies independently selected from an IGFlR antibody (including, for example, ⁇ IGF-1R A12 MoAb, 0 IGF-IR 19D12 MoAb, "IGF-IR h7C10 MoAb and 0 IGF-IR CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, IGF
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two antibodies.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two antibodies independently selected from an IGFlR antibody (including, for example, ⁇ IGF-lR A12 MoAb, 0 IGF-IR 19Dl 2 MoAb, "IGF-IR h7C10 MoAb and 0 IGF-IR CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetylR
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies independently selected from an IGFlR antibody (including, for example, « IGF-1R A12 MoAb, "IGF-IR 19Dl 2 MoAb, "IGF-IR h7C10 MoAb and 0 IGF-IR CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositum
  • IGFlR antibody including,
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is surgery.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is surgery.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide), Megestrol acetate (Megace), and one or more aromatase inhibitors.
  • hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including go
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitor selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).
  • a treatment is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitor selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies independently selected from from tamoxifen and an aromatase inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two hormone therapies.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide), Megestrol acetate (Megace), and one or two aromatase inhibitors.
  • hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitors selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies independently selected from from tamoxifen and an aromatase inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from a rapamycin, rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I saccording to Formula I(a) in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
  • the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from bone marrow or peripheral blood stem cell transplantation, radiation, one or two antibodies, and one or two chemotherapeutic agents.
  • AML acute myelogenous leukemia
  • the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or t treatments where one of the treatments is one antibody selected from Gemtuzumab ozogamicin (Mylotarg), ⁇ IGF- 1 R A 12 MoAb, 0 IGF- 1 R 19D 12 MoAb, ⁇ IGF- 1 R h7C 10 MoAb, "IGF- 1 R CP-751871 MoAb and trastuzumab.
  • AML acute myelogenous leukemia
  • the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from Imatinib (i.e.
  • Gleevec® PKC 412, CEP-701, daunorubicin, doxorubicin, cytarabine (ara-C), an anthracycline drug such as daunorubicin or idarubicin (Daunomycin, Idamycin), 6-thioguanine, and a granulocyte colony-stimulating factor (such as Neupogen or Leukine).
  • the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from bone marrow or peripheral blood stem cell transplantation, radiation, one or two chemotherapeutic agents, immunotherapy, and one or two antibodies.
  • CML chronic myelogenous leukemia
  • the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents selected from Imatinib (i.e. Gleevec®), PKC 412, hydroxyurea (Hydrea), cytosine, cytosine arabinoside, dasatinib, AMN107, VX680 (MK0457), and cytarabine (ara-C).
  • Imatinib i.e. Gleevec®
  • PKC 412 hydroxyurea
  • cytosine cytosine arabinoside
  • dasatinib AMN107
  • VX680 MK0457
  • cytarabine cytarabine
  • the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from Imatinib (i.e. Gleevec®) and dasatinib.
  • CML chronic myelogenous leukemia
  • the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is interferon therapy such as interferon- ⁇ .
  • CML chronic myelogenous leukemia
  • the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery (including cryosurgery), radiation, one or two chemotherapeutic agents, one or two antibodies, and one or two hormone therapies.
  • the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody selected from "IGF-IR Al 2 MoAb, 0 IGF-IR 19Dl 2 MoAb, "IGF-IR h7C10 MoAb, and "IGF-IR CP-751871 MoAb.
  • the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents independently selected from rapamycin, mitoxantrone, prednisone, docetaxel (Taxotere), doxorubicin, etoposide, vinblastine, paclitaxel, and carboplatin.
  • chemotherapeutic agents independently selected from rapamycin, mitoxantrone, prednisone, docetaxel (Taxotere), doxorubicin, etoposide, vinblastine, paclitaxel, and carboplatin.
  • the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the hormone therapy indepependently selected from androgen deprivation therapy and androgen suppression therapy.
  • the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a taxanes.
  • the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.
  • the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two immunotherapies, one or two hormone therapies, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from an alkylating agent, a taxane, a platin, and a Raf inhibitor.
  • the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from sorafenib, Paclitaxel (Taxol ® ), Docetaxel (Taxotere ® ), dacarbazine, rapamycin, imatinib mesylate (Gleevec®), sorafenib, cisplatin, carboplatin, dacarbazine (DTIC), carmustine (BCNU), vinblastine, temozolomide (Temodar), Melphalan, and imiquimod (Aldara).
  • chemotherapeutic agents independently selected from sorafenib, Paclitaxel (Taxol ® ), Docetaxel (Taxotere ® ), daca
  • the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two immunotherapies independently selected from ipilimumab, interferon-alpha and interleukin- 2.
  • the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is hormone therapy where the hormone therapy is tamoxifen.
  • the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from local excision, electrofulguration, segmental colon resection, polypectomy, local transanal resection, low anterior resection, abdominoperineal resection, and pelvic exenteration.
  • the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin), 5-fluorouracil (5-FU), leucovorin, capecitabine (Xeloda), irinotecan (Camptosar), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), and leucovorin.
  • a platinum-containing compound including cisplatin, oxaliplatin, and carboplatin
  • 5-fluorouracil including cisplatin, oxaliplatin, and carboplatin
  • 5-fluorouracil (5-FU) 5-fluorouracil
  • leucovorin capecitabine
  • the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies independently selected from cetuximab (Erbitux) and bevacizumab (Avastin).
  • the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is selected from one or two chemotherapeutic agents independently selected from platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin), 5-fluorouracil (5-FU), gemcitabine, a taxane (including paclitaxel and docetaxel), topotecan, irinotecan, capecitabine, streptozocin, erlotinib (Tarceva), , leucovorin, and capecitabine (Xeloda).
  • platinum-containing compound including cisplatin, oxaliplatin, and carboplatin
  • 5-fluorouracil (5-FU) 5-fluorouracil
  • gemcitabine a taxane (including paclitaxel and docetaxel)
  • the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody wehre the antibody is cetuximab.
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two chemotherapeutic agents, one or two hormone therapies, and one or two antibodies.
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents independently selected from lapatinib (Tykerb ® ), Paclitaxel (Taxol ® ), docetaxel, capecitabine, Cyclophosphamide (Cytoxan), CMF (cyclophosphamide, fluoruracil, and methotrexate), methotrexate, fluorouracil, doxorubicin, epirubicin, gemcitabine, carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine), capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil), albumin-bound paclitaxel (
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analogs (including goserelin and leuprolide), Megestrol acetate (Megace), and one or more aromatase inhibitors.
  • hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analogs (
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies and one of the hormone therapies is an aromatase inhibitors selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies independently selected from "IGF- 1 R A 12 MoAb, ⁇ IGF- 1 R 19D 12 MoAb, ⁇ IGF- 1 R h7C 10 MoAb, ⁇ IGF- 1 R CP-751871 MoAb, bevacizumab (Avastin), and trastuzumab.
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is erlotinib.
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one or two of the chemotherapeutic agents are independently selected from rapamycin, lapatinib, erlotinib, N-(3,4-dichloro-2-fluorophenyl)-7- ( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, 7V-(4- bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3ai?,5r
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the antibodies.
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies and one of the antibodies is trastuzumab.
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one of the chemotherapeutic agents is selected from N-(3,4- dichloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7- ( ⁇ [(3ai?,5r,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine, N-(
  • the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one of the chemotherapeutic agents is N-(3,4-dichloro-2- fluorophenyl)-7-( ⁇ [(3ai?,5r,6a5)-2-methyloctahydrocyclopenta-[c]py ⁇ Ol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or more antibodies, and one or more chemotherapeutic agents.
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine (Gemzar®), Vinorelbine, Irinotecan, Etoposide, Vinblastine, Erlotinib (Tarceva®), gefitinib (Iressa), and Pemetrexed.
  • chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine (Gemzar®), Vinorelbine, I
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is Bevacizumab.
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Paclitaxel, Docetaxel (Taxotere®), and erlotinib (Tarceva®).
  • chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Paclitaxel, Docetaxel (Taxotere®), and erlotinib (Tarceva®).
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is carboplatin.
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is selected from N-(3,4- dichloro-2-fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7- ( ⁇ [(3ai?,5r,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine, N
  • the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is N-(3,4-dichloro-2- fluorophenyl)-7-( ⁇ [(3a/?,5r,6a5)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl ⁇ oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
  • the invention is directed to a method of treating small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapy agents independently selected from a platin (such as cisplatin, oxaliplatin, and carboplatin), gefitinib, vinorelbine, docetaxel, paclitaxel, etoposide, fosfamide, ifosfamide, cyclophosphamide, cyclophosphamide/doxorubicin/vincristine (CAV), doxorubicin, vincristine, gemcitabine, paclitaxel, vinorelbine, topotecan, irinotecan, methotrexate, and docetaxel.
  • a platin such as cisplatin, oxaliplatin, and carboplatin
  • a platin such as
  • the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, radioactive iodine therapy, one or two hormone therapies, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from thyroid hormone pills, Doxorubucin and a platin.
  • the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is hormone therapy and the hormone therapy is radioiodine ablation.
  • the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two hormone therapies, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a
  • Compound of Formula I in combination with one or more treatments where one of the treatments is one or two hormone therapies independently selected from megestrol acetate, Tamoxifen, and a progestin including medroxyprogesterone acetate (Provera) and megestrol acetate (Megace).
  • hormone therapies independently selected from megestrol acetate, Tamoxifen, and a progestin including medroxyprogesterone acetate (Provera) and megestrol acetate (Megace).
  • the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin, more for example cisplatin), a taxane (including paclitaxel), doxorubicin (Adriamycin), cyclophosphamide, fluorouracil (5-FU), methotrexate, and vinblastine.
  • a platinum-containing compound including cisplatin, oxaliplatin, and carboplatin, more for example cisplatin
  • a taxane including paclitaxel
  • doxorubicin Adriamycin
  • cyclophosphamide fluorouracil (5-FU)
  • methotrexate
  • the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is bevacizumab.
  • the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin and carboplatin), a taxane (including paclitaxel and docetaxel), topotecan, an anthracyclines (including doxorubicin and liposomal doxorubicin), gemcitabine, cyclophosphamide, vinorelbine (Navelbine), hexamethylmelamine, ifosfamide, etoposide, bleomycin, vinblastine, ifosfamide, vincristine, and cyclophosphamide.
  • a platinum-containing compound including cisplatin, oxaliplatin and carboplatin
  • the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platin and a taxane.
  • the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, paclitaxel, and docetaxel.
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two chemotherapeutic agents, one or two anti-seizure agents, and one or two agents to reduce swelling.
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation selected from external beam radiation, interstitial radiotherapy, and stereotactic radiosurgery.
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from carmustine (BCNU), Erlotinib (Tarceva), bevacizumab, gefitinib (Iressa), rapamycin, temozolomide, cisplatin, BCNU, lomustine, procarbazine, and vincristine.
  • BCNU carmustine
  • Tarceva Erlotinib
  • bevacizumab gefitinib
  • Iressa rapamycin
  • temozolomide temozolomide
  • cisplatin cisplatin
  • BCNU lomustine
  • procarbazine a method of treating glioblastoma
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an anti-seizure agent and the anti-seizure agent is diphenylhydantoin (Dilantin).
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an agents to reduce swelling and the agent is dexamethasone (Decadron).
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents.
  • the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from erlotinib and temozolomide.
  • the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selceted from cryosurgery, laser surgery, loop electrosurgical excision, conization, simple hysterectomy, and radical hysterectomy and pelvic lymph node dissection.
  • the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation selected from called external beam radiation therapy and brachytherapy.
  • the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum compound (such as cisplatin, carboplatin, and oxaliplatin), paclitaxel, topotecan, ifosfamide, gemcitabine, vinorelbine, and fluorouracil.
  • a platinum compound such as cisplatin, carboplatin, and oxaliplatin
  • paclitaxel such as cisplatin, carboplatin, and oxaliplatin
  • topotecan such as cisplatin, carboplatin, and oxaliplatin
  • paclitaxel such as cisplatin, carboplatin, and oxaliplatin
  • topotecan such as cisplatin, carbo
  • the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, immunotherapy, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from excision and electrofulguration.
  • the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cyproheptadine, SOM230, octreotide and lanreotide.
  • the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is an interferon.
  • the invention is directed to a method of treating a gastrointestinal stromal tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating a gastrointestinal stromal tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from imatinib mesylate (Gleevec), sunitinib (Sutent), and nilotinib (AMN 107).
  • chemotherapeutic agents independently selected from imatinib mesylate (Gleevec), sunitinib (Sutent), and nilotinib (AMN 107).
  • the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiofrequency ablation, ethanol ablation, cryosurgery, hepatic artery embolization, chemoembolization, radiation, and one or two chemotherapeutic agents.
  • the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from resection and transplantation.
  • the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from sorafenib, 5-fluorouracil and cisplatin.
  • the invention is directed to a method of treating non- Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from radiation, one or two chemotherapeutic agents, interferon therapy, one or two antibodies, and bone marrow or peripheral blood stem cell transplantation.
  • the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), chlorambucil, fludarabine, and etoposide.
  • CHOP cyclophosphamide, doxorubicin, vincristine and prednisone
  • the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody selected from rituximab, ibritumomab tiuxetan, tositumomab, and alemtuzumab.
  • the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the anitbody is rituximab.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation and another treatment is surgery.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation and another treatment is one or two chemotherapeutic agents.
  • the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery and another treatment is one or two chemotherapeutic agents.
  • the Compound of Formula I is selected from any of the following embodiments, including from the Representative Compounds in Table 1.
  • R 1 is hydrogen.
  • R 50 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(O)-Ci-C 6 -alkylene- N(R 55a )R 55b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O) 2 NR 55 R 553 , or alkylcarbonylamino; where R 55 and R 55b are indepedently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention.
  • R 50 is hydrogen, alkyl, alkenyl, halo, haloalky
  • Another embodiment (C) of the invention is a Compound of Formula I where R 51 is hydrogen or alkyl; and all other groups are as defined in the Summary of the Invention. In another embodiment, R 51 is alkyl, In another embodiment, R 51 is methyl.
  • Another embodiment (D) of the invention is a Compound of Formula I where R 52 is hydrogen or halo; and all other groups are as defined in the Summary of the Invention. In another embodiment R 52 is hydrogen or fluoro. In another embodiment, R 52 is hydrogen.
  • Another embodiment (E) of the invention is a Compound of Formula I where R 53 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(O)-C
  • R 53 is hydrogen, alkoxy, nitro, amino, or -N(R 55 )C(O)-Ci-C 6 -alkylene-N(R 55a )R 55b .
  • R 53 is hydrogen, methoxy, nitro, amino, or -NHC(O)CH 2 N(CH 3 ) 2 .
  • R 53 is hydrogen or methoxy.
  • Another embodiment (F) of the invention is a Compound of Formula I where R 54 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(O)-Ci-C6-alkylene- N(R 55a )R 55b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O) 2 NR 55 R 553 , or alkylcarbonylamino; where R 55 and R 55b are indepedently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention.
  • R 54 is hydrogen, alkyl, alkoxy, or halo. In another embodiment, R 54 is hydrogen, methyl, methoxy, bromo, or chloro. In another embodiment, R 54 is hydrogen, methoxy, or chloro. [00196] Another embodiment (G) of the invention is directed to a compound of Formula I where R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention.
  • R 50 , R 52 , and R 53 are hydrogen and R 54 is chloro or methoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is methoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form pyridinyl. Even more speicfically, R 50 , R 52 , and R 53 are hydrogen and R 54 is chloro or methoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is methoxy. [00197] In another embodiment (Gl) of embodiment G is a compound of Formula I where R 51 is methyl.
  • Another embodiment (H) of the invention is a compound of Formula I where B is phenyl substituted with R 3a and optionally further substituted with one, two, or three R 3 ; and all other groups are as defined in the Summary of the Invention.
  • B is phenyl substituted with R 3a .
  • the Compound is of Formula I(a):
  • B is phenyl substituted with R 3a as depicted in Ia and is not further substituted with R 3 .
  • Another embodiment of the Invention (J) is directed to a compound of Formula I where B is heteroaryl optionally substituted with one, two, or three R 3 .
  • B is thien-3-yl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, or thiazolyl, each of which is optionally substituted with one or two R 3 .
  • B is thien-3-yl, pyridin-2-yl, pyridin- 3-yl, pyridin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, imidazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3- yl, pyrazol-4-yl, or pyrazol-5-yl, each of which is optionally substituted with one or two R 3 .
  • B is thien-3-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-4-yl, or pyrazol- 4-yl, each of which is optionally substituted with one or two R 3 .
  • B is pyridin-3-yl, 2-hydroxy-pyridin-5-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R 3 .
  • Another embodiment (K) provides a compound of Formula I or Ia where R 3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialky laminoalky loxy ; -N(R 7 )C(O)-C i -C 6 -alkylene- N(R 7a )(R 7b ); -C(O)NR 8 R 83 ; -NR 9 C(O)R 93 ; -C(O)N(R 1 °)-C,-C 6 -alkylene- N(R 1Oa )R IOb ; -NR 1 1 C(O)NR 1 13 R 1 1 " where
  • R 3a is -NHC(O)CH 2 NH(CH 3 ), -NHC(O)CH 2 NH(CH 2 CH 3 ), -NHC(O)CH(CH 3 )NH 2 ,
  • the compound of Formula I or Ia is that where R 3a is hydroxyamino, -N(R 7 )C(O)-C,-C 6 -alkylene-N(R 7a )(R 7b ), -C(O)NR 8 R 83 , -NR 9 C(O)R 93 ,
  • C 6 -alkylene-OR 24a or -N(R 20 )C(O)-C,-C 6 -alkylene-
  • R 3a is -NHC(O)CH 2 NH(CH 3 ), -NHC(O)CH(CH 3 )NH 2 , -NHC(O)C(CH 3 ) 2 NH 2 , -NHC(O)CH 2 N(C
  • R 3a is hydrogen or alkyl and R 7a and R 7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention.
  • R 3a is -NHC(O)CH 2 NH(CH 3 ), -NHC(O)CH(CH 3 )NH 2 , -NHC(O)C(CH 3 ) 2 NH 2 ,
  • Embodiment (N) provides a compound of Formula I where each R 3 is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R 7 )C(O)-Ci-C 6 -alkylene-
  • each R 3 is independently methyl, bromo, chloro, fluoro, -NHC(O)CH 2 NH(CH 3 ), -NHC(O)CH 2 NH(CH 2 CH 3 ), -NHC(O)CH(CH 3 )NH 2 ,
  • -NHC(O)CH 2 (3-methyl- 1 ,2-oxazol-5- yl), -NHC(O)CH 2 NHCH 2 (3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2-yl), - ⁇ HC(O)(2- amino-tetrahydropyran-2-yl), -NHC(O)CH 2 (4-methylamino-piperidin- 1 - yl), -NHC( ⁇ Xpiperidin-l-yl), -NHC(O)(N-methyl-pyrrolidin-2yl), -NHC(O)(thien-
  • the Compound of Formula I is that where each R 3 is independently halo, alkyl, hydroxyamino, -N(R 7 )C(O)-Ci-C 6 -alkylene-
  • Ci.C 6 -alkylene-OR 24a or -N(R 20 )C(O)-C,-C 6 -alkylene-C(O)R 20a ; where each of the alkylene in R 3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the
  • each R 3 is independently methyl, chloro, -NHC(O)CH 2 NH(CH 3 ), -NHC(O)CH(CH 3 )NH 2 , -NHC(O)C(CH 3 ) 2 NH 2 ,
  • the Compound of Formula I is that where R 3 is alkyl or -N(R 7 )C(O)-Ci-C 6 -alkylene-N(R 7a )(R 7b ); and R 7 is hydrogen or alkyl and R 7a and R 7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention.
  • R 3 is independently methyl, -NHC(O)CH 2 NH(CH 3 ), -NHC(O)CH(CH 3 )NH 2 , -NHC(O)C(CH 3 ) 2 NH 2 , -NHC(O)-
  • the Compound of Formula I is that where B is phenyl
  • R 3 is not present or R 3 is halo, alkyl, or alkoxy;
  • R 3a is -C(O)NR 8 R 83 , -NR 9 C(O)R 93 , -N(R 7 )C(O)-C,-C 6 -alkylene-N(R 7a )(R 7b ), or -C(O)N(R l0 )-C,-
  • R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the
  • R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy.
  • I(a) is that where R 3 is not present or R 3 is alkyl and R 3a is -N(R 7 )C(O)-Ci-C 6 -alkylene- N(R 7a )(R 7b ), -C(O)NR 8 R 83 , -NR 9 C(O)R 93 , or -C(O)N(R 10 )-C,-C 6 -alkylene-N(R 10a )R 10b ; where each of the alkylene in R 3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention.
  • R 3 is is not present or is methyl. In another embodiment, R 3 is is not present.
  • embodiment S is that where R 7 is hydrogen or alkyl and R 7a , and R 7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R 8 is hydrogen or alkyl and R 8a is heterocycloalkyl or heterocycloalkylalkyl; R 9 is hydrogen or alkyl and R 9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; and R 10 , R IOa , and R IOb are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.
  • embodiment S2 is that where R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl.
  • R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy.
  • the Compound of Formula I is that where B is heteroaryl, one R 3 is halo, alkyl, or alkoxy and a second R 3 is -C(O)NR 8 R 83 , -NR 9 C(O)R 93 , -N(R 7 )C(O)-C,-C 6 -alkylene-N(R 7a )(R 7b ), or -C(O)N(R 10 )-C,-
  • the compound is that where R 7 is hydrogen or alkyl and R 7a , and R 7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R 8 is hydrogen or alkyl and R 8a is heterocycloalkyl or heterocycloalkylalkyl; R 9 is hydrogen or alkyl and R 9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R 10 , R IOa , and R 1Ob are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.
  • each R 3 (when R 3 is present) is independently halo, alkyl, alkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkylamino, dialkylamino, -C(O)NR 8 R 8a , -NR 9 C(O)R 93 , -N(R 7 )C(O)- C,-C 6 -alkylene-N(R 7a )(R 7b ), or -C(O)N(R 10 )-C,-C 6 -alkylene-N(R 10a )R 10b ; and all other groups are as defined in the Summary of the Invention.
  • the compound of Formula I is that where R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention.
  • R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy.
  • the compound of Formula I is that where R 51 is methyl.
  • the Compound of Formula I is that where R 7 is hydrogen or alkyl and R 7a , and R 7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
  • R 8 is hydrogen or alkyl and R 8a is heterocycloalkyl or heterocycloalkylalkyl;
  • R 9 is hydrogen or alkyl and R a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl;
  • R 10 , R IOa , and R 1Ob are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl [00221]
  • the Compound of Formula I is that whereW 1 , W 2
  • B is phenyl substituted with R 3a and optionally further substituted with one R 3 ; or B is heteroaryl optionally substituted with one or two R 3 ;
  • R 3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy ; -N(R 7 )C(O)-C i -C 6 -alkylene-
  • each of the alkylene in R 3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; each R 3 (when R 3 is present) is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R 7 )C(O)-C i -C 6 -alkylene-
  • R 3 N(R 22b )-N(R 22c )(R 22a ); -C 0- C 6 -alkylene-N(R 23 )-C,.C 6 -alkylene-N(R 23b )R 23a ; or -NR 24 C(O)-C i.C 6 -alkylene-OR 24a ; where each of the alkylene in R 3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; provided that when R 50 and R 52 are hydrogen, R 51 is hydrogen or methyl, R 53 is hydrogen or methoxy, and R 54 is hydrogen or methoxy, then B is not 2,3-dihydro-l,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R 3 where R 3 is halo.
  • Another embodiment (W) of the invention is a Compound of Formula I where R 5 , R 53 , and R 54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(O)-C,-C 6 -alkylene-N(R 55a )R 55b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O) 2 NR 55 R 55a , or alkylcarbonylamino and where R 55 and R 55b are indepedently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R 53 and R 54 together with the carbon
  • the Compounds in Table 1 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 1 can be used to practice the invention.
  • the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 1 which salt(s) are formed with one or two acids independently selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalate,
  • the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 1 which salt(s) are formed with one or two bases independently selected from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, and N-methylglucamine. Any individual compound (and any optional salt, optional solvate, and optional hydrate thereof) in Table 1 can be used in combination with any of the above embodiments.
  • the Compounds in Table 2a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 2a can be used to practice the invention.
  • the Compounds in Table 2b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 2b can be used to practice the invention.
  • the Compounds in Table 3a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3a can be used to practice the invention.
  • the Compounds in Table 3b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3b can be used to practice the invention.
  • the Compounds in Table 3c can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3c can be used to practice the invention.
  • the Compounds in Table 4 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 4 can be used to practice the invention.
  • the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 4 which salt(s) are formed with one or two acids independently selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
  • the Compounds in Table 5a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 5a can be used to practice the invention.
  • the Compounds in Table 5b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 5b can be used to practice the invention.
  • the Compounds in Table 6 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 6 can be used to practice the invention.
  • the Compounds in Table 7 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 7 can be used to practice the invention.
  • the Compounds in Table 8 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 8 can be used to practice the invention.
  • the Compounds in Table 9 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 9 can be used to practice the invention.
  • the invention provides pharmaceutical compositions comprising an inhibitor of PI3K according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration may specifically be by the oral route.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages.
  • the administration may specifically be by placing a gliadel, a dissolvable material that contains the chemotherapy drug (in particular BCNU), directly into brain tumors during an operation.
  • the compositions will include a compound of Formula I or II as the/an active agent and can include a conventional pharmaceutical carrier or excipient and in addition may include other medicinal agents and pharmaceutical agents that are generally administered to a patient being treated for cancer.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • the choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt or solvate thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydro
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt or solvate thereof, and 99% to 1 % by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt or solvate thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • Representative pharmaceutical formulations containing a compound of Formula I or II are described below in the Pharmaceutical Composition Examples.
  • Biological Example 1 and have been determined to be PI3K inhibitors.
  • compounds of Formula I are useful for treating diseases, particularly cancer in which PBKactivity contributes to the pathology and/or symptomatology of the disease.
  • cancer in which PDK activity contributes to its pathology and/or symptomatology include breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric carcinoma, glioblastoma, hepatocellular carcinoma, small cell lung cancer, non- small cell lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and thyroid carcinoma, and the like.
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • Suitable in vitro assays for measuring PBK activity and the inhibition thereof by compounds are known. Typically, the assay will measure PI3K-induced ATP consumption.
  • an in vitro assay for measuring PI3K activity see Biological Examples, Example 1 infra.
  • Cellular activity can be determined using assays as described in Biological Examples 2, 3, and 4 infra.
  • Suitable in vivo models of cancer are known to those of ordinary skill in the art.
  • Examples 5-10, infra Examples describing the administration of a Compound of Formula I in combination with anticancer agents are described in Biological Examples 1 1-14, infra. Following the examples disclosed herein, as well as that disclosed in the art, a person of ordinary skill in the art can determine what ombinations of a Compound of Formula I and anti-cancer agents would be effective for treating cancer.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
  • the compounds of the invention may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure.
  • Compounds of Formula I that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • Some of the compounds of the invention may exist as tautomers.
  • the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.
  • B can be 2-hydroxy-pyridinyl, also described as its structure:
  • Both 2-hydroxy-pyridinyl and the above structure 14 include, and are equivalent to, pyridin-2(lH)-one and its structure 15:
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I.
  • compounds of Formula I when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • compounds of Formula I When compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group” or "protective group”.
  • a comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
  • optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specif ⁇ c reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomer enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. [00267] In Compounds of Formula I
  • Compounds of Formula I can be prepared using methods known to one of ordinary skill in the art.
  • fusion of appropriate reagents at 180 0 C in the presence of a base such as K 2 CO 3 and metallic copper is known to provide intermediates of formula 1 (see S. H. Dandegaonker and C. K. Mesta, J. Med. Chem. 1965, 8, 884).
  • each LG 1 is a leaving group (in one embodiment halo, in another embodiment chloro) and all other groups are as defined in the Detailed Description of the Invention.
  • an intermediate of formula 3 can be prepared by briefly heating commercially available 2,3-dichloroquinoxaline and an intermediate of formula 2 (which are commercially available or can be prepared by one of ordinary skill in the art), a base such as K 2 CO 3 , in a solvent, such as DMF or DMSO. Upon completion (about 2 hours), the reaction mixture is then poured into water and followed by 2 N HCl. The product is then extracted into a solvent such as ethyl acetate and washed with water and brine. The organic layers are combined and dried over a drying agent such as sodium sulfate, filtered, and concentrated under vacuum.
  • a base such as K 2 CO 3
  • a solvent such as DMF or DMSO
  • quinoxaline derivatives are known to one skilled in the art and include, but are not limited to S. V. Litvinenko, V. I. Savich, D.
  • Example 1 N-(3- ⁇ [2,5-bis(methoxy)phenyl]amino ⁇ quinoxalin-2-yl)-3- nitrobenzenesulfonamide.
  • Example 3 N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide.
  • Example 4 4-chloro-yV-(3-chloroquinoxalin-2-yl)benzenesulfonamide.
  • Example 5 4-chloro-./V-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide.
  • Example 7 iV-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-4-methylphenyl)-2-(dimethylamino)acetamide.
  • LG is a leaving group such as chloro. 5 is reacted with NHR a R b or HO-Ci-C 6 -alkylene- NHR a R b where R a and R b are independently hydrogen or alkyl. The reaction is carried out in the presence of a base, such as KHCO 3 , in a solvent such as DMF.
  • a base such as KHCO 3
  • reaction is carried out in the presence of a base such as NaH in a solvent such as
  • R , 1 i 0 ⁇ 0 ⁇ in Scheme 4 is -C(O)R 9a , -C(O)NR 1 13 R 1 lb , -C(0)0R 13a , -C(O)-C, -C 6 -alkylene- N(R 18b )C(O)R 18a , -C(O)-C ,-C 6 -alkylene-C(O)R 20a , or -S(O) 2 -C, .C 6 -alkylene-N(R 21b )R a .
  • the reaction is carried out under standard amide coupling conditions known to one of ordinary skill in the art.
  • reaction is carried out in the presence of a coupling agent such as HATU, a base such as DIEA, and in a solvent such as DMF.
  • a coupling agent such as HATU
  • a base such as DIEA
  • a solvent such as DMF.
  • the N-protecting group is then removed using procedures known to one of ordinary skill in the art, such as treating with acid where PG is Boc.
  • R 7b are as defined in the Summary of the Invention can be prepared according to Scheme
  • LG is a leaving group such as bromo or chloro. 12 is reacted with NH(R 7b )R 7a in the presence of a base, such as DIEA, in a solvent such as ACN.
  • a base such as DIEA
  • LG in Scheme 6 is a leaving group such as chloro.
  • the reaction can be carried out by irradiating in a solvent such as DMA. Alternatively, the reaction can be carried out in the presence of acetic acid in a solvent such as DMA and by heating.
  • Example 10 /V-(3-(3,5-dimethoxyphenylamino)quinoxaIin-2-yl)-6- (dimethylamino)pyridine-3-sulfonamide was prepared using procedures similar to those used in Example 9.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 12.00 (br s, IH), 8.92 (br s, IH), 8.74 (d, IH), 8.10 (dd, IH), 7.38 (br s, IH), 7.54 (m, IH), 7.33 (m, 4H), 6.70 (d, IH), 6.22 (s, IH), 3.77 (s, 6H), 3.08 (s, 6H).
  • N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (100 mg, 0.21 mmol), prepared using procedures similar to those described above in Example 1, 2-(dimethylamino)ethanol (50 ⁇ L, 0.50 mmol) and dry DMF were combined and 60% NaH in oil (80 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight.
  • N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (220 mg, 0.47 mmol), prepared using procedures similar to those described above in Example 8, DMSO (5 mL), and 3N NaOH (5 mL) are combined and heated to 100 0 C overnight with stirring. Upon cooling to room temperature, the reaction mixture was diluted with H 2 O and the pH was adjusted to 7.0 with IN HCl. The resulting solid was filtered, washed with H 2 O, and air-dried.
  • Example 13 yV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-6- oxo-l,6-dihydropyridine-3-sulfonamide.
  • the title compound was prepared according to the above Example 12.
  • Example 17 Proceeding as above, 3-amino-/V-(3-(2-chloro-5-hydroxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide was prepared. MS (EI) m/z for C 20 H 16 ClN 5 O 3 S 1.0 x C 2 H 1 O 2 F 3 : 442.2, 444.2 (MH + ).
  • Example 20 3-amino-/V-(3-(2-chIoro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide.
  • Example25 vV-(2-chloro-5-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyI)-2-(methyIamino)acetamide.
  • the title compound was prepared according to the Examples above.
  • Example 26 (5)-2-amino-iV-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin- 2-yl)sulfamoyl)phenyl)propanamide hydrochloride.
  • Example 27 (S)-2-amino-/V-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin- 2-yl)sulfamoyl)phenyl)butanamide hydrochloride.
  • Example 28 (5)-N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamide hydrochloride.
  • Example 30 (R)-2-amino-7V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-hydroxypropanamide hydrochloride.
  • Example 31 /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)piperidine-3-carboxamide hydrochloride.
  • Example32 (5)-2-amino-/V-(3-(/V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)butanamide hydrochloride.
  • Example 33 (R)-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamide hydrochloride. MS (EI) m/z for C 27 H 28 N 6 O 5 S-HCl: 549.1 (MH + ).
  • Example 34 (R)-N-(3-(iV-(3-(2-chloro-5-methoxy-phenyIamino)quinoxalin-2- yl)suIfamoyl)phenyI)pyrrolidine-2-carboxamide hydrochloride. MS (EI) m/z for C 26 H 25 ClN 6 O 4 S-HCl: 553 (MH + ).
  • Example 35 (R)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)propanamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 10.2 (br s, 1 H), 8.82 (s, 1 H), 8.27 (m, 1 H), 7.75 (m, 2 H), 7.33 (m, 5 H), 7.13 (m, 2 H), 6.14 (t, 1 H), 3.77 (s, 6 H), 1.39 (d, 3 H); MS (EI) m/z for C 25 H 26 N 6 O 5 S: 523 (MH + ).
  • Example 36 /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide.
  • Example 37 (/?)-2-amino-7V-(3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin- 2-yl)sulfamoyI)phenyl)propanamide.
  • Example 38 2-amino-7V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylpropanamide.
  • Example 39 2-amino-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylpropanamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 10.33 (s, 1 H), 8.89 (s, 1 H), 8.32 (br s, 4 H), 7.92 (m, 3 H), 7.59 (m, 2 H), 7.37 (m, 4 H), 6.24 (s, 1 H), 3.76 (s, 6 H), 1.61 (s, 6 H); MS (EI) m/z for C 26 H 28 N 6 O 5 S: 537 (MH + ).
  • Example 40 /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2-yl)sulfamoyl)-4- methylphenyl)-2-(dimethylamino)acetamide.
  • Example 41 7V-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-((2-(dimethylamino)ethyl)(methyl)amino)acetamide. 1 H
  • Example 42 2-amino-iV-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 10.5 (s, 1 H), 9.48
  • Example 43 yV-(3-(/V-(3-(2-acetyl-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 12.4 (s, 1 H), 10.5 (s, 1 H), 9.27 (s, 1 H), 8.25 (s, 1 H), 8.01 (d, 1 H), 7.82 (d, 1 H), 7.71
  • Example 44 N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)formamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 12.6 (s, 1 H), 10.5
  • Example 45 2-amino-N-(5-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-2-methyIphenyl)acetamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 12.4 (s, 1
  • Example 46 N-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methyl-2-(methylamino)propanamide.
  • Example 47 (S)-/V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)propanamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 10.61 (s, 1 H), 9.47 (s, 1 H), 8.95 (s, 1 H), 8.82 (br s, 2 H), 8.27 (m, 1 H), 7.74 (m, 2
  • Example 48 3-amino-iV-(5-(7V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-2-methylphenyl)propanamide.
  • 1 H NMR 400 MHz, DMSO- ⁇ 6 ) ⁇ 12.25
  • Example 49 l-amino-iV-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopropanecarboxamide.
  • 1 H NMR 400 MHz, DMSO- ⁇ 6 ) ⁇ 9.54 (br s, 1 H), 9.42 (s, 1 H), 8.91 (s, 1 H), 8.21 (s, 1 H), 8.20 (br s, 2 H), 7.81 (m, 2
  • Example 51 l-amino-iV-(3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopentanecarboxamide.
  • Example 52 /V-(5-(7V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyI)-2-methylphenyl)-2-(dimethylamino)acetamide.
  • Example 53 l-amino-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclobutanecarboxamide.
  • Example 54 /V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(3-(2- (dimethylamino)ethyl)ureido)benzenesulfonamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 8.91 (br s, 1 H), 8.81 (s, 1 H), 8.08 (s, 1 H), 7.60 (s, 1 H), 7.38 (m, 9 H), 6.28 (m, 1 H),
  • Example 55 l-amino-7V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopentanecarboxamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 12.40 (br s, 1 H), 10.58 (s, 1 H), 8.46 (m, 4 H), 7.80 (m, 3 H), 7.59 (m, 2 H), 7.34 (m, 4
  • Example 56 l-amino-./V-(3-(./V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopropanecarboxamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 9.54 (br s, 1 H), 8.84 (s, 1 H), 8.29 (s, 1 H), 7.75 (m, 2 H), 7.39 (m, 6 H), 7.17 (m, 2 H),
  • Example 57 2-(dimethylamino)ethyl 3-(N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenylcarbamate.
  • Example 58 4-amino-/V-(3-( ⁇ r -(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)tetrahydro-2H-pyran-4-carboxamide.
  • Example 59 ⁇ f -(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)- ⁇ 3-(2- (dimethylamino)ethyl)benzene-l,3-disulfonamide.
  • 1 H NMR 400 MHz, DMSO-J 6 ) ⁇ 9.35 (m, 2 H), 8.92 (m, 1 H), 8.64 (s, 1 H), 8.30 (m, 1 H), 8.1 1 (s, 1 H), 7.86 (m, 1 H), 7.68 (m, 1 H), 7.49 (s, 1 H), 7.42 (m, 2 H), 7.21 (m, 2 H), 6.61 (m, 1 H), 3.82 (s, 3 H),
  • Example 60 ⁇ H3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-/V3-(3-
  • Example 66 (/?)-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)propanamide.
  • Example 70 N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-(dimethylamino)piperidin-l-yl)acetamide.
  • Example 71 /V-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide.
  • Example 72 /V-(3-(/V-(3-(2-chloro-5-methoxy-phenyIamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(ethylamino)acetamide.
  • Example 73 2-(azetidin-l-yl)-/V-(3-(N-(3-(2-chloro-5- methoxyphenyIamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide.
  • Example 74 N-(3-(N-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide.
  • the title compound was prepared according to the Examples above. 1 H NMR (400 MHz, DMSO) ⁇ 10.6 (s, IH), 9.5 (s,
  • Example 75 2-(dimethylamino)- ⁇ '-(3-( ⁇ L (3-(6-methoxy-quinolin-8- ylamino)quinoxalin-2-yl)sulfamoyl)phenyI)acetamide.
  • the title compound was prepared according to the Examples above.
  • Example 76 7V-(3-(7V-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide.
  • 1 H NMR 400 MHz, DMSO) ⁇ 10.6 (s, IH), 9.4 (s, IH), 8.9 (s, IH), 8.25 (s, IH), 7.78 (d, IH), 7.70 (d, IH), 7.54 (d, IH), 7.48 (d, IH), 7.40 (t, 2H), 6.56 (d, IH), 4.02 (s, 2H), 3.82 (s, 3H), 2.80 (s, 6H).
  • Example 77 /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-nuoroethylamino)acetamide.
  • Example 78 iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)formamide.
  • 1 H NMR 400 MHz, DMSO) ⁇ 12.4 (br s, IH), 10.5 (s, IH), 8.90 (s, IH), 8.3 (s, IH), 7.9 (br s, IH), 7.85 (d, IH), 7.75 (d, IH), 7.5-7.6 (m, 2H), 7.3-7.4 (m, 4H), 6.2 (s, IH), 3.8 (s, 3H).
  • Example 79 /V-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-(dimethyIamino)azetidin-l-yl)acetamide.
  • Example 80 N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2-(pyrrolidin-l-yl)acetamide.
  • Example 81 N-(3-(jV-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyI)phenyl)-2-(ethyl(methyI)amino)acetamide.
  • Example 82 7V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2-(3-(piperidin-l-yl)azetidin-l-yl)acetamide.
  • Example 83 /V-(3-(/V-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide.
  • Example 84 iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-methylpiperidine-4-carboxamide. MS (EI) m/z for
  • Example 85 /V-(3-(/V-(3-(3-methoxyphenylamino)quiiioxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide.
  • Example 86 /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2,2,2-trifluoroethylamino)acetamide.
  • Example 88 /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-(dimethylamino)butanamide.
  • Example 90 /V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(piperidin-l-yl)acetamide.
  • Example 91 2-(dimethylamino)-/V-(3-(7V-(3-(3-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide.
  • 1 H NMR 400 MHz, DMSO
  • Example 92 /V-(3-(N-(3-(2-chloro-5-hydroxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide.
  • Example 94 /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z for C 24 H 23 N 5 O 5 S: 494.0 (MH + ).
  • Example 97 2-amino-7V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-4-methylphenyl)-2-methylpropanamide. MS (EI) m/z for
  • Example 102 3-(/V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-methyI-l-(piperidin-l-yl)propan-2-yl)benzamide.
  • Example 103 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-methyl-l-oxo-l-(piperidin-l-yl)propan-2-yl)benzamide.
  • reaction was stirred for 15 min before N, iV-dimethylethane- 1 ,2-diamine (73 mg, 0.83 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL), 1.0 N aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL).
  • Example 105 5-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-2-methoxybenzamide.
  • Example 106 5-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-N-(2-(dimethylamino)ethyl)-2-fluorobenzamide.
  • Example 108 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-/V-methylbenzamide. MS (EI) m/z for
  • Example 110 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)benzamide.
  • Example 111 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-morpholinoethyl)benzamide.
  • Example 112 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-/V-methyIbenzamide.
  • Example 113 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)-iV-morpholinobenzamide.
  • Example 116 jV-(3-(2-chIoro-5-methoxyphenylamino)quinoxalin-2-yl)-3- cyanobenzenesulfonamide. MS (EI) m/z for C 22 Hi 6 ClN 5 O 3 S: 465.9 (MH + ).
  • Example 117 3-cyano-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 23 Hi 9 N 5 O 4 S: 462.3 (MH + ).
  • Example 118 /V-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- fluorobenzenesulfonamide. MS (EI) m/z for C 22 H 19 FN 4 O 4 S: 456.0 (MH + ).
  • Example 119 3-bromo-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 22 H 19 BrN 4 O 4 S: 516.9 (MH + ).
  • Example 120 3-bromo-N-(3-(2,5-dimethoxy-phenylamino)quinoxaIin-2- yl)benzenesulfonamide. MS (EI) m/z for C 22 Hi 9 BrN 4 O 4 S: 516.9 (MH + ).
  • Example 121 7V-(3-(3-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide. MS (EI) m/z for C 21 H 18 N 4 O 3 S: 407.0 (MH + ).
  • Example 122 iV-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 2 ,H, 7 FN 4 O 3 S: 425.0 (MH + ).
  • Example 123 7V-(3-(2,5-dimethoxy-phenylamino)quinoxaIin-2-yl)-4- methoxybenzenesulfonamide. MS (EI) m/z for C 23 H 22 N 4 O 5 S: 467.0 (MH + ).
  • Example 124 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yI)-4- methoxybenzenesulfonamide. MS (EI) m/z for C 23 H 22 N 4 O 5 S: 467.0 (MH + ).
  • Example 125 /V-(3-(4-chloro-3-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 2 iH 17 ClN 4 O 3 S: 440.9 (MH + ).
  • Example 126 /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)thiophene-2- sulfonamide. MS (EI) m/z for C 20 H 18 N 4 O 4 S 2 : 443.0 (MH + ).
  • Example 127 /V-(3-(6-methoxyquinolin-8-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 24 H 18 N 6 O 5 S: 502.95 (MH + ).
  • Example 128 3-nitro-ZV-(3-(pyridin-4-ylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for Ci 9 H 14 N 6 O 4 S: 423.2 (MH + ).
  • Example 129 /V-(3-(2-chloropyridin-4-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonam.de. MS (EI) m/z for Ci 9 H 13 ClN 6 O 4 S: 456.93, 458.90 (MH + ).
  • Example 130 /V-(3-(4,6-dimethoxypyrimidin-2-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 20 H 17 N 7 O 6 S: 484.03 (MH + ).
  • Example 131 7V-(3-(4-hydroxy-6-methoxypyrimidin-2-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for Ci 9 Hi 5 N 7 O 6 S: 469.97 (MH + ).
  • Example 132 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2- fluorobenzenesulfonamide. MS (EI) m/z for C 22 Hi 9 FN 4 O 4 S: 455.3 (MH + ).
  • Example 133 7V-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 2 ,H 16 BrN 5 O 5 S: 531.82, 532.84 (MH + ).
  • Example 134 /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- methylbenzenesulfonam.de. MS (EI) m/z for C 23 H 22 N 4 O 4 S: 451.0 (MH + ).
  • Example 136 /V-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- methylbenzenesulfonamide. MS (EI) m/z for C 23 H 22 N 4 O 4 S: 451.0 (MH + ).
  • Example 137 /V-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 2 iHi 6 FN 5 O 5 S: 470.0 (MH + ).
  • Example 138 4-bromo-/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)benzenesulfonamide. MS (EI) m/z for C 22 Hi 9 BrN 4 O 4 S: 516.9, 514.9 (MH + ).
  • Example 139 /V-(3-(3-methoxyphenylamino)quinoxalin-2-yl)-3-nitro- benzenesulfonamide. MS (EI) m/z for C 2 ,Hi 7 N 5 O 5 S: 451.93 (MH + ).
  • Example 140 N-(3-(2-chIoro-5-hydroxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 20 Hi 4 ClN 5 O 5 S: 472.15, 474.13 (MH + ).
  • Example 141 3-acetyl-jV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 23 H 19 ClN 4 O 4 S: 483.08 (MH + ).
  • Example 142 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin- 2-yl)benzenesulfonamide. MS (EI) m/z for C 22 H 20 N 4 O 4 S: 437.49 (MH + ).
  • Example 143 /V-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 22 H 20 N 4 O 3 S: 421.46 (MH + ).
  • Example 144 /V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 21 Hi 7 ClN 4 O 3 S: 440.59 (MH + ).
  • Example 145 N-(3-(2,5-dimethoxy-phenylamino)quinoxalin- 2-yl)benzenesulfonamide. MS (EI) m/z for C 22 H 20 N 4 O 4 S: 437.53 (MH + ).
  • Example 146 4-chloro-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 22 Hi 9 ClN 4 O 4 S: 470.54 (MH + ).
  • Example 147 /V-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 22 Hi 9 N 5 O 5 S: 466.32 (MH + ).
  • Example 148 /V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C 2 iH I6 ClN 5 O 5 S: 485.86 (MH + ).
  • Example 149 7V-(3-(4-chloro-2,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide.
  • Example 154 yV-(3-(2,5-dimethoxyphenylamino)-7-methylqui ⁇ oxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C 23 H 22 N 4 O 4 S: 451.0 (MH + ).
  • Example 157 /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-((3-(diniethylamino)propyl)(methyl)amino)acetamide.
  • Example 159 tert-butyl 2-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenylcarbamoyl)piperidine-l-carboxylate.
  • Example 161 /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- ureidobenzenesulfonamide. MS (EI) m/z for C 23 H 22 N 6 O 5 S: 495.40 (MH + ).
  • Example 163 /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-methyIpiperazin-l-yl)acetamide.
  • Example 164 2-acetamido-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide.
  • Example 165 tert-butyl 2-(3-(ZV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenylamino)-2-oxoethylcarbamate.

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Abstract

The present invention provides methods of treating cancer by administering a compound of Formula I, optionally as a pharmaceutically acceptable salt, solvate and/or hydrate thereof, in combination with other cancer treatments.

Description

METHODS OF TREATING BY INHIBITING WITH QUINAXOLINE INHIBITORS
OF PI3K-ALPHA Cross-Reference to Related Applications
[0001] The Applicants claim priority under 35 U.S.C. 1 19(e) to copending Provisional Application No. 60/923,164 filed on April 11, 2007, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to methods of treating cancer with a compound that inhibits lipid kinase enzymatic activity and the resultant modulation of cellular activities (such as proliferation, differentiation, programmed cell death, migration, chemoinvasion and metabolism) in combination with anticancer agents.
BACKGROUND OF THE INVENTION
[0003] Improvements in the specificity of agents used to treat various disease states such as cancer, metabolic, and inflammatory diseases is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.
[0004] Phosphatidylinositol 3-kinase (PI3K or PIK3CA) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate Ptdlns, PtdIns4P and PtdIns(4,5)P2. PTEN, a tumor suppressor which inhibits cell growth through multiple mechanisms, can dephosphorylate PIP3, the major product of PIK3CA. PIP3, in turn, is required for translocation of protein kinase B (AKTl, PKB) to the cell membrane, where it is phosphorylated and activated by upstream kinases. The effect of PTEN on cell death is mediated through the PIK3CA/AKT1 pathway.
[0005] PI3Kα has been implicated in the control of cytoskeletal reorganization, apoptosis, vesicular trafficking, proliferation and differentiation processes. Increased copy number and expression of PIK3CA or activating mutations in the pi 10a catalytic subunit of PIK3CA are associated with a number of malignancies such as ovarian cancer (Campbell et al., Cancer Res 2004, 64, 7678-7681 ; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman, et al. Cancer Biol Ther 2004, 3, 772-775; Levine, et al., supra; Li et al., Breast Cancer Res Treat 2006, 96, 91-95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer (Samuels, et al. Science 2004, 304, 554; Velho et al. Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al. Cancer Res. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., Int J Cancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee et al., id.), small and non- small cell lung cancer (Tang et al., Lung Cancer 2006, 51, 181-191; Massion et al., Am J Respir Crit Care Med 2004, 170, 1088-1094), thyroid carcinoma (Wu et al., J Clin Endocrinol Metab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels et al., supra).
[0006] In view of the important role of PI3K-α in biological processes and disease states, inhibitors and/or modulators of this lipid kinase are desirable. In addition, it is well established that combining treatments with different mechanisms of action often leads to enhanced anti-tumor activity as compared to single treatments administered alone. This is true for combinations of chemotherapies (e.g. Kyrgiou M. et. al. J Natl Cancer Inst 2006, 98, 1655) and combinations of antibodies and chemotherapy (e.g. Pasetto LM et. al. Anticancer Res 2006, 26, 3973.
[0007] For example, activation of the PI3K pathway contributes to the resistance of human tumor cells to a wide variety of chemotherapeutic agents, including microtubule stabilizing agents such as taxol (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et. al. MoI Cancer Ther 2002, 1, 101-1X1; Kraus, A. C, et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et. al. MoI Cancer Ther 2002, 1, 913-922; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440). Taxol is widely used to treat advanced cancers including prostate carcinomas, which frequently harbor deletions in the PTEN gene, resulting in elevated signaling downstream of PI3K. A number of preclinical studies suggest that inhibiting signaling downstream of PI3K restores or enhances the ability of chemotherapeutic agents such as taxol to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et. al. MoI Cancer Ther 2002, 1, 707-717; Kraus, A. C, et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et. al. MoI Cancer Ther 2002, /, 913-922; and Saga, Y., et. al. Clin Cancer Res 2002, 8, 1248-1252). [0008] Rapamycin, another chemotherapeutic agent, is a potent inhibitor of the mTOR/Raptor complex. Inhibition of mTOR/Raptor prevents p70S6K and S6 phosphorylation, but also leads to relief of a negative feedback loop emanating from p70S6K that serves to downregulate POK (Sarbassov, D. D., et. al. Science 2005, 307, 1098-1 101). As a result, rapamycin treatment can lead to upregulation of PDK and increased phosphorylation of AKT (O'Donnell, A., et. al. paper presented at Proc Am Soc Clin Oncol. 2003; and O'Reilly, K. E., et. al. Cancer Res 2006, 66, 1500-1508). Thus, combining rapamycin with inhibitors of PI3K can enhance the efficacy of rapamycin (Powis, G. et. al. Clinical Cancer Research 2006, 12, 2964-2966; Sun, S.-Y., et. al. Cancer Research 2005, 65, 7052-7058).
[0009] A growing body of clinical and preclinical data indicates that activation of the PI3K pathway confers resistance to EGFR inhibitors such as erlotinib (Bianco, R., et. al. Oncogene 2003, 22, 1'&U-l'ill; Chakravarti, A., et. al. Cancer Res 2002, 62, 200-207; and Janmaat, M. L., et. al. Clin Cancer Res 2003, P, 2316-2326). Both NSCLC patients with K-Ras mutations and glioblastoma patients with PTEN deletions fail to respond to erlotinib, potentially because of genetic activation of the PI3K pathway (Mellinghoff, I. K., et. al. N. Eng. J Med. 2006, 353, 2012-2024). Preclinical studies have shown that downregulation of PI3K signaling in EGFR-expressing tumor cells confers increased sensitivity to EGFR inhibitors (IhIe, Ν. T., et. al. MoI Cancer Ther 2005, 4, 1349-1357). Thus, treating cancer with a PI3K inhibitor in combination with an EGFR inhibitor, such as erlotinib, is desirable. [0010] Activation of the PI3K pathway also contributes to the resistance of human tumor cells to DΝA damaging agents, such as platins. A number of preclinical studies suggest that inhibiting signaling downstream of PI3K restores or enhances the ability of chemotherapeutic agents such as platins to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61, 3986- 3997; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440). Carboplatin is widely used to treat advanced cancers including non-small cell lung carcinomas (ΝSCLC), which frequently harbor activating mutations in the K-Ras gene, resulting in activation of PI3K (Aviel-Ronen S., et. al. Clin Lung Cancer 2006, 8, 30-38). ΝSCLC patients with K-Ras mutations do not respond to EGFR inhibitors such as Tarceva, and thus represent a significant unmet medical need (Janne PA, et. al. J CHn Oncology 2005, 23, 3227-3234). Thus, treating ΝSCLC with a DΝA-damaging agent such as a platin in combination with an inhibitor of PI3K is desirable in light of the lack of efficacious treatments. [0011] Treatments that combine an inhibitor of PI3K-α with other anti-cancer agents are desirable and needed. SUMMARY OF THE INVENTION
[0012] The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this specification and the references incorporated by reference, the express disclosure of this specification shall control.
[0013] The compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities. Disease states which can be treated by the methods and compositions provided herein include cancer. The invention is directed to methods of treating these diseases by administering a Compound of Formula I or II in combination with one or more treatments.
[0014] One aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula I:
Figure imgf000005_0001
I or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof; or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation, where the Compound of Formula I is that wherein: W1, W2, W3, and W4 are -C(R1)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; and where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino;
R ' is hydrogen or alkyl;
R52 is hydrogen or halo;
R50, R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-Ci-C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl;
B is phenyl substituted with R3a and optionally further substituted with one, two, or three R3; or
B is heteroaryl optionally substituted with one, two, or three R3;
R3a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R8a where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9a where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-C6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R10)-Ci-C6-alkylene-N(R10a)R10b where R1Oa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R10 and RIOb are independently hydrogen, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl; e) -NR1 1C(O)NR1 '3R1 lb where R1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R11 and Rl lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl; h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C,-C6-alkylene-N(R153)R15b where R15, R15a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-Cι-C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and
R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; 1) -N(R17)-C(=N(R17b)(R17a))(NR17cR17d) where R17, R17a, R17b, R17c, and R17d are independently hydrogen, alkyl, or alkenyl; m) -N(R18)C(O)-C,-C6-alkylene-N(R18b)C(O)Rl8a where Rl8a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and Rl 8b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(R19)-C,-C6-alkylene-C(O)R19a where R19 is hydrogen, alkyl, or alkenyl and
R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-Ci-C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and
R20a is cycloalkyl or heterocycloalkyl; p) -NR21 S(O)2-C, -C6-alkylene-N(R21b)R21a where R21 is hydrogen, alkyl, or alkenyl and
R21a and R21b are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C,-C6-alkylene-N(R22b)-N(R22c)(R22a) where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-C,-C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C, .C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3,
4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and each R3 (when R3 is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo; alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R83 where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9a where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-C6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R10)-C,-C6-alkylene-N(R10a)R10b where R1Oa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or hydroxyalkyl and R10 and R10b are independently hydrogen, alkyl, alkenyl, haloalkyl, or hydroxyalkyl; e) -NR1 1C(O)NR1 laR* lb where R1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R1 ' and R1 lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminooalkyl, dialkylaminoalkyl ; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl); h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C,-C6-alkylene-N(R15a)R15b where R15, Rl5a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C,-C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and
R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; 1) -N(Rl7)-C(=N(Rl 7b)(R17a))(NRl 7cRl 7d) where R17, R17a, Rl 7b, R17c, and R17d are independently hydrogen, alkyl, or alkenyl; m) -N(R18)C(O)-C,-C6-alkylene-N(Rl8b)C(O)R18a where R18a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and R18b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(R19)-Ci-C6-alkylene-C(O)Rl9a where R19 is hydrogen, alkyl, or alkenyl and
Rl9a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C,-C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and
R2Oa is cycloalkyl or heterocycloalkyl; p) -NR21S(O)2-C,-C6-alkylene-N(R21b)R21a where R21 is hydrogen, alkyl, or alkenyl and
R21a and R21b are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C,-C6-alkylene-N(R22b)-N(R22c)(R22a), where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-C,-C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C, .C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; wherein each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3,
4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and provided that when R50 and R52 are hydrogen, R51 is hydrogen or methyl, R53 is hydrogen or methoxy, and R54 is hydrogen or methoxy, then B is not 2,3-dihydro-l,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R3 where R3 is halo.
[0015] A second aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula II:
Figure imgf000010_0001
II or a pharmaceutically acceptable salt or solvate, thereof; or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more of the hormone therapies, one or more of the antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation wherein the Compound of Formula I is that wherein: W1, W2, W3, and W4 are -C(Rla)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1 a)=; X1 is -N(R5a)-;
A is aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, or -alkyl-N(R7)R7a, where each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl and alkoxy groups, each either alone or as part of another group within A, are independently optionally substituted with one, two, three, or four R2a; or B1 is aryl, arylalkyl, alkyl, heteroaryl, or heteroary alkyl, wherein each of the aryl, heteroaryl and alkyl groups are independently optionally substituted with one, two, three, or four R3d; each Rla is independently selected from hydrogen, alkoxy, alkyl, nitro, halo, cyano, and -C0- C6-alkyl-N(R7)R7a, wherein each of the alkyl and alkoxy groups is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, and -C(O)OR6; each R2a (when R2a is present) is independently selected from alkyl, alkenyl, -alkenyl- C(O)OR6, -OR6, -N(R7)C(O)R6, -N(R7)C(O)-C0-C6 alkyl-N(R7b)R7a, -OC(O)-C0-C6 alkyl-N(R7)R7a, -N(R7)C(O)-C,-C6 alky IC(O)OR6, C0-C6-alkyl-C(O)R6, oxo, dioxo, -S(O)2-N(R7)R7a, -C(O)OR6, -CH(R6)2-C(O)OR6, -S(O)2R6, cycloalkyl, heterocycloalkyl, heteroaryl, -C(O)N(R7)-alkyl-OR6, -C0-C6 alkyl-C(O)N(R7)-C0-C6- alkyl-C(O)OR6, -C0-C6-alkyl-C(O)N(R7)R7a, aryl, arylalkyl, -S-(C1-C6 alkyl), halo, oxo, nitro, -SCN, cyano, and -C0-C6 alkyl-N(R7)R7a, wherein each of the alkyl (including, for example the alkyl within alkoxy), aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R2, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, oxo, nitro, cyano, hydroxy, -N(R8)R8a, alkoxy, and -C(O)OR9; each R3d (when R3d is present) is independently oxo, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, C3-C6-cycloalkyl, -Co-Ce-alkyl-heterocycloalkyl, -C0-C6 alkyl- N(R7)C(O)-C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)C(0)-Co-C6-alkyl- N(R7b)C(O)R7a, -C0-C6 alkyl-C(O)-C0-C6-alkyl-N(R7)R7a, -C0-C6-alkyl-C(O)N(R7)-C0-
C6-alkyl-N(R7b)R7a, -C0-C6-alkyl-C(O)N(R7)-C,-C6alkylC(O)OR7a, -C0-C6 alkyl- N(R7)C(0)-Co-C6-alkyl-(R7a), -C0-C6 alkyl-N(R7)-Co-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl- N(R7)C(0)-Co-C6-alkyl-N(R7b)-N(R7c)R7a, -C0-C6 alkyl-N(R7)C(0)0-Co-C6-alkyl- aryl, -C0-C6 alkyl-C(O)N(R7)-C0-C6-alkyl-N(R7b)R7a, -C0-C6 alkyl-N(R7)-C0-C6 alkyl- C(=N(R7b)(R7a))(NR7cR7d), -C0-C6-alkyl-aryl, -C0-C6-alkyl-heteroaryl, -C0-C6 alkyl- heterocycloalkyl, -0-C0-C6 alkyl-N(R7)R7a, -C0-C6 alkyl-ORό, -C0-C6 ^yI-C(O)OR6, C0- C6-alkyl-N(R7)R7a, -C0-C6 alkyl-C(O)NR7R7a, -C0-C6 alkyl-
C(O)R7, -SR7, -S(O)2R7, -S(O)3R7, -S(O)R7, -SO2N(R7)R7a, -SO2N(R7)-C0-C6 alkyl- N(R7b)R7a, -C0-C6-alkyl-N(R7)-aryl, -C0-C6-alkyl-N(R7)-heteroaryl, -C0-C6-alkyl-N(R7)- heterocycloalkyl, -C0-C6-alkyl-C(0)N(R7)-Co-C6-alkyl-cycloalkyl, C0-C6-alkyl- C(0)N(R7)-Co-C6-alkyl-aryl, C0-C6 alkyl-C(O)N(R7)-C0-C6 alkyl-heteroaryl, C0-C6 alkyl-C(0)N(R7)-Co-C6-alkyl-heterocycloalkyl, -C0-C6-alkyl-N(R7)C(0)-C0-C6-alkyl- cycloalkyl, -Co-C6-alkyl-N(R7)C(0)-C0-C6-alkyl-aryl, C0-C6-alkyl-N(R7)C(0)-Co-C6- alkyl-heteroaryl, -Co-C6-alkyl-N(R7)C(0)-C0-C6-alkyl-heterocycloalkyl, Co-C6-alkyl- N(R7)C(O)-C0-C6-alkyl-heterocycloalkyl-aryl, -N(R7)C(O)OR6, or -NHC(O)H, wherein each of the alkyl, alkenyl, cycloalkyl, aryl, (including, for example the alkyl within alkoxy), heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R3d, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkenyl, -C0-C6-alkyl-OR9, cycloalkyl, halo, haloalkyl, haloalkoxy, -C(O)R9, nitro, cyano, oxo, -C0-C6-alkyl-N(R8)R8a, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)OR9, alkylthio, and hydroxyalkyl;
R4 is hydrogen, aryl, -C0-C6-alkyl-N(R7)R7a, alkoxy, or Ci-C6 alkyl, wherein each of the alkyl and aryl groups, either alone or as part of another group in R4, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, alkoxy, and -C(O)OR6; or
R4 and X1 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein R5a is absent when X is -N(R5a)-, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R7)R7a, alkoxy, and -C(O)OR6;
R5a is hydrogen, -Ci-C6 alkyl-N(R7)R7a, alkoxy, alkyl, or aryl, wherein each of the alkyl and aryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R8)R8a, CrC6 alkoxy, or -C(O)OR6; or R5a and R4 together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R7)R7a, C ,-C6 alkoxy, and -C(O)OR6; R6 and R9 are independently hydrogen, hydroxy, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, either alone or as part of another group within R6 and R9, is independently optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from amino, hydroxy, alkoxy, alkyl, and halo; and R7, R7a R7b, R7c, R7d, R8, and R8a are independently hydrogen, alkyl, alkenyl, hydroxy, alkyloxy, alkenyloxy, -0-C0-C6 alkyl-aryl, -C0-C6 alkyl-C(O)OR6, -C0-C6 alkyl-C(O)R6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either alone or part of another group within R7, R7a R7b, R7c, R7d, R8, and R8a is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, -S-Ci-C6 alkyl, cyano, nitro, hydroxy, Ci-C6 alkoxy, Ci-C6 alkyl, halo, aryl, heterocycloalkylalkyl, and heteroaryl optionally substituted with one or two Ci-C6 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0016] The following abbreviations and terms have the indicated meanings throughout: Abbreviation Meanin
Figure imgf000013_0001
Figure imgf000014_0001
Definitions for a Compound of Formula I, Ia, and II
[0017] The symbol "-" means a single bond, "=" means a double bond, "≡" means a triple bond, and "— " means a single bond and optionally a double bond. When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four.
|0018] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents
(e.g., surgery, radiation, and chemotherapy, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
[0019] "Alkenyl" or "lower alkenyl" means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one double bond and includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like.
[0020] "Alkenylcarbonyl" means a C(O)R group where R is alkenyl, as defined herein.
[0021] "Alkenyloxy" or "lower alkenyloxy" means an -OR group where R is alkenyl, as defined herein. Representative examples include methoxy, ethoxy, l-methoxyprop-l-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
[0022] "Alkoxy" or "lower alkoxy" means an -OR group where R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, l-methoxyprop-l-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
[0023] "Alkoxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three alkoxy groups, as defined herein.
[0024] "Akoxycarbonyl" means a -C(O)OR group where R is alkyl as defined herein.
[0025] "Alkoxyycarbonylalkyl" means an alkyl group, as defined herein, substituted with one, two, or three alkoxycarbonyl groups, as defined herein.
[0026] "Alkyl" or "lower alkyl" means a linear or branched hydrocarbon group having one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, /-butyl, isobutyl, pentyl, hexyl and the like. A "C0" alkyl (as in "C0-
C6-alkyl") is a covalent bond. "C6 alkyl" refers to, for example, n-hexyl, /sø-hexyl, and the like.
[0027] "Alkylamino" means a -NHR radical where R is alkyl as defined herein, or an
N-oxide derivative thereof, e.g., methylamino, ethylamino, n-, /so-propylamino, «-, iso-, tert- butylamino, or methylamino-N-oxide, and the like.
[0028] "Alkylaminoalkyl" means an alkyl group substituted with one or two alkylamino groups, as defined herein. [0029] "Alkylaminoalkyloxy" means an -OR group where R is alkylaminoalkyl, as defined herein.
[0030] "Alkylcarbonyl" means a C(O)R group where R is alkyl, as defined herein.
[0031] "Alkylcarbonylamino" means a -NRC(O)R' group where R is hydrogen or alkyl, as defiend herein, and R' is alkyl, as defiend herein.
[0032] "Alkylene" refers to straight or branched divalent hydrocarbon, containing no unsaturation and having from two to eight carbon atoms. Examples of alkylene include eth- diyl (-CH2CH2-), prop- 1 ,3-diyl (-CH2CH2CH2-), 2,2-dimethylprop-l,3-diyl
(-CH2C(CH3)2CH2-), and the like.
[0033] "Alkylsulfonyl" means a -S(O)2R group where R is lakyl, as defined herien.
[0034] "Alkylthio" means a -SR group where R is alkyl, as defined herein. Examples of alkylthio include methylthio and ethylthio, and the like.
[0035] "Alkylthioalkyl" means an alkyl group substituted with one or two alkylthio groups, as defined herein, e.g. 2-(methylthio)-ethyl and 2-(ethylthio)-ethyl.
[0036] "Alkynyl" or "lower alkynyl" means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
[0037] "Amino" means a -NH2.
[0038] "Aminoalkyl" means an alkyl group subsitutted with at least one, for example one, two, or three, amino groups.
[0039] "Aminoalkyloxy" means an -OR group where R is aminoalkyl, as defined herein.
[0040] "Aryl" means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenyl, naphthyl, and indanyl, and the like.
[0041] "Arylalkyl" means an alkyl group, as defined herein, subsituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like.
[0042] "Aryloxy"means a -OR group where R is aryl as defined herein.
[0043] "Arylalkyloxy" means a -OR group where R is arylalkyl as defined herein.
[0044] "Arylsulfonyl" means a -SO2R group where R is aryl as defined herein.
[0045] "Carboxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three -C(O)OH groups. [0046] "Carboxy ester" means a -C(O)OR group where R is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.
[0047] "Cyanoalkyl" means an alkyl, alkenyl, or alkynyl radical, as defined herein, substituted with at least one, for example one, two, or three, cyano groups.
[0048] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms. The cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring. Cycloalkyl includes fused, bridged, and spiro ring systems.
Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0049] "Cycloalkylalkyl" means alkyl group substituted with one or two cycloalkyl groups, as defined herein. Representative examples include cyclopropylmethyl and
2-cyclobutyl-ethyl, and the like.
[0050] "Cycloalkylcarbonyl" means a -C(O)R group where R is cycloalkyl as defined herein.
[0051] "Dialkylamino" means a -NRR' radical where R and R' are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,iV-methylethylamino, and the like.
[0052] "Dialkylaminoalkyl" means an alkyl group substituted with one or dialkylamino groups, as defined herein.
[0053] "Dialkylaminoalkyloxy" means an -OR group where R is dialkylaminoalkyl, as defined herein.
[0054] "Fused ring system" and "fused ring" refer to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups. [0055] "Haloalkoxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
[0056] "Haloalkoxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three haloalkoxy, as defined herein.
[0057] "Halogen" or "halo" means fluoro, chloro, bromo and iodo. [0058] "Haloalkenyl means an alkenyl group, as defined herein, substituted with one or more halogens, for example one to five halo atoms.
[0059] "Haloalkyl" means an alkyl group, as defined herein, substituted with one or more halogens, for example one to five halo atoms. Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-l-fluoroethyl, and the like. [0060] "Heteroaryl" means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, for example one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)n- (n is 0, 1, or 2), -N-, -N(R")-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Rx is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, Rx is absent. In another embodiment, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH- indol-2-yl or 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like), pyrrolo[3,2- c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof. [0061] "Ηetereoarylalkyl" means an alkyl group substituted with one or two heteroaryl groups as defined herein. [0062] "Heterocycloalkyl" means a saturated or partially unsaturated monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, for example one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)n- (n is 0, 1, or 2), -N=, -N(Ry)- (where Ry is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen atom, Ry is absent. In another embodiment the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof and N-oxide or a protected derivative thereof.
[0063] "Ηeterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein.
[0064] "Ηydroxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, for example one, two, or three, hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy butyl, 2,3-dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, for example 2-hydroxyethyl, 2,3-dihydroxypropyl, or l-(hydroxymethyl)-2-hydroxyethyl, and the like. [0065] "Ηydroxyamino" means a -NΗ(OΗ) group.
[0066] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted " refers to all subsequent modifiers in a term. So, for example, in the term "optionally substituted arylCi _g alkyl," both the "Ci_8 alkyl" portion and the "aryl" portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of "substituted." [0067] "Optionally substituted alkyl" means an alkyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl- S(O)0-2-, alkenyl-S(0)o-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc- (where R° is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxy alky loxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).
[0068] "Optionally substituted alkenyl" means an alkenyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)0-2-, alkenyl-S(0)o-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc- (where Rc is hydrogen, optionally substituted alkyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, optionally substituted alkyl, alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy). [0069] "Optionally substituted aryl" means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -C(O)NR5R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR5C(O)R" (where R' is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)2R' (where R5 is alkyl, aryl, or heteroaryl). [0070] "Optionally substituted heteroaryl" means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, -C(O)NR5R" (where R5 is hydrogen or alkyl and R55 is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR5C(O)R" (where R5 is hydrogen or alkyl and R55 is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)2R5 (where R5 is alkyl, aryl, or heteroaryl). [0071] "Optionally substituted heterocycloalkyl55 means a heterocycloalkyl, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, -C(O)NR5R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR5C(O)R" (where R5 is hydrogen or alkyl and R55 is alkyl, aryl, heteroaryl, or heterocycloalkyl), amino, alkylamino, dialkylamino, and -NHS(O)2R5 (where R5 is alkyl, aryl, or heteroaryl).
[0072] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system.55
[0073] "Spirocyclyl" or "spirocyclic ring55 refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a ring atom of a saturated bridged ring system (rings C and C5), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring D) attached thereto. A spirocyclyl can be carbocyclic or heteroalicyclic.
Figure imgf000022_0001
[0074] "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.
Definitions for the Compound of formula 100
[0075] The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage Application Serial No. 10/522,004) which is herein incorporated by reference. For example "optionally substituted alkyl" for formula 100 has the meaning given in WO 2004/006846 (US Nat'l Stage Application Serial No. 10/522,004). Whenever a compound of formula 100 is described in this application, whether by structure or by use of the term "formula 100," the terms used to describe that compound are defined by WO 2004/006846 (US Nat'l Stage Application Serial No. 10/522,004).
Other Definitions
[0076] "AKT inhibitor" includes, for example, LY294002, PKC 412, perifosine, compounds in Table 2a, compounds in Table 2b, and compounds described in WO 2006/071819 and WO05/117909. These references also describe in vitro assays that can be used to determine the inhibitory activity of AKT.
[0077] "Alkylating agent" includes, for example, one or more of the following: Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Carmustine, Streptozocin, Fotemustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Oxaliplatin, BBR3464, Busulfan, Dacarbazine, Mechlorethamine, Procarbazine, Temozolomide, ThioTEPA, and Uramustine.
[0078] "Antibody" includes, for example, one or more of the following: an IGFlR antibody (including, for example, "IGF- IR A12 MoAb, 19Dl 2, h7C10 and CP-751871), an EGFR antibody (including, for example, Cetuximab (Erbitux®) and Panitumumab), an ErbB2 antibody (including, for example, Trastuzumab (Herceptin®)), a VEGF antibody (including, for example, Bevacizumab (Avastin®)), an IgGl antibody (including, for example, Ibritumomab (tiuxetan)), a CD20 antibody (including, for example, Rituximab and Tositumomab), a CD33 antibody (including, for example, Gemtuzumab and Gemtuzumab ozogamicin), and a CD52 antibody (including, for example, Alemtuzumab). [0079] "Antimetabolite" include, for example, methotrexate, Pemetrexed, Raltitrexed, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Thioguanine, Capecitabine, Cytarabine, fluorouracil (administered with or without leucovorin or folinic acid), and Gemcitabine.
[0080] "Antimicrotubule agent" includes, for example, Vincristine,Vinblastine, Vinorelbine, Vinflunine, and Vindesine.
[0081] "Aromatase inhibitor" includes, for example, one or more of the following: Aminoglutethimide, Anastrozole (Arimidex®), Letrozole (Femara®), Exemestane (Aromasin®), and Formestane (Lentaron®).
[0082] "Cancer" refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital rumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Adrenal Glands: neuroblastoma; and breast cancer. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above- identified conditions.
[0083] "Chemotherapeutic agent" includes, but is not limited to, an AKT inhibitor, an alkylating agent, an antimetabolite, an antimicrotubule agent, an aromatase inhibitor, a c-KIT inhibitor, a cMET inhibitor, an EGFR inhibitor, an ErbB2 inhibitor, a Flt-3 inhibitor, an HSP90 inhibitor, an IGFlR inhibitor, a platin, a Raf inhibitor, rapamycin, a Rapamycin analogue, a Receptor Tyrosine Kinase inhibitor, a taxane, a topoisomerase inhibitor, a SRC and/or ABL kinase inhibitor, and a VEGFR inhibitor. A pharmaceutically acceptable salt, solvate, and/or hydrate of a chemotherapeutic agent can be prepared by one of ordinary skill in the art and such salt, solvate, and/or hydrates thereof can be used to practice the invention. [0084] "c-KIT inhibitor" includes, for example, imatinib, sunitinib, nilotinib, AMG 706, sorafenib, compounds in Table 3b, compounds in Table 3c, compounds in Table 8, compounds in Table 9, and compounds described in WO 2006/108059, WO/2005/020921, WO/2006/033943, and WO 2005/030140.
[0085] "cMET inhibitor" includes, for example, compounds in Table 3a, compounds in Table 3b, compounds in Table 3c, compounds described in WO06/108059, WO 2006/014325, and WO 2005/030140.
[0086] "EGFR inhibitor'Mncludes, for example, one or more of the following: pelitinib, lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474, vandetinib), AEE788 and HKI-272, EKB-569, CI-1033, N-(3,4-dichloro-2-fluorophenyl)-7- ({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-
({[(3a/?,5s,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-
(methyloxy)quinazolin-4-amine, compounds in Table 4, compounds in Table 7, and compounds described in WO 2004/006846 and WO 2004/050681.
[0087] "ErbB2 inhibitor" includes, for example, lapatinib (GW572016), PKI- 166, canertinib, CI- 1033, HKI272, and EKB-569.
[0088] "Flt-3 inhibitor" includes, for example, CEP-701, PKC 412, MLN518, sunitinib, sorafenib, compounds in Table 3a, compounds in Table 3b, compounds in Table 3c, compounds in Table 9, and compounds described in WO 2006/108059, WO/2006/033943,
WO 2006/014325, and WO 2005/030140.
[0089] "Hormone therapy" or "hormonal therapy" includes, for example, treatment with one or more of the following: steroids (e.g. dexamethasone), finasteride, tamoxifen, and an aromatase inhibitor.
[0090] "HSP90 inhibitor" includes, for example, 17- AAG, 17-DMAG, Geldanamycin,
5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(moφholinomethyl)phenyl)isoxazole-3- carboxamide [NVP-AUY922 (VER 52296)], 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2- yl)methyl)-9H-purin-2-amine (CNF2024, also named BIIB021), compounds disclosed in
WO2004072051 (which is herein incorporated by reference), compounds disclosed in
WO2005028434 (which is herein incorporated by reference), compounds disclosed in
WO2007035620 (which is herein incorporated by reference) and compounds disclosed in
WO2006091963 (which is herein incorporated by reference).
[0091] "IGFlR inhibitor" includes, for example, Tyrphostin AG 1024, compounds in
Table 5a, compounds in Table 5b, and compounds described in WO06/074057.
[0092] "Kinase-dependent diseases or conditions" refer to pathologic conditions that depend on the activity of one or more lipid kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
[0093] While not wishing to be bound to theory, phosphatases can also play a role in
"kinase-dependent diseases or conditions" as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example lipid substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. [0094] "Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure. [0095] "Patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
[0096] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66: 1-19 both of which are incorporated herein by reference. [0097] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like.
[0098] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, iV-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
[0099] "Platin," and "platin-containing agent" include, for example, cisplatin, carboplatin, and oxaliplatin.
[00100] "Prodrug" refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
[00101] "Raf inhibitor" includes, for example, sorafenib, RAF 265 (CHIR 265), compounds in Table 6, and compounds described in WO 2005/112932. These references also describe in vitro assays that can be used to determine the inhibitory activity of RAF. [00102] "Rapamycin analogue" includes for example, CCI-779, AP23573, RAD 001, TAFA 93, and compounds described in WO 2004/101583 and US 7,160,867 which are each incorporated herein by reference in their entireties.
[00103] "Receptor Tyrosine Kinase inhibitor" includes, for example, inhibitors of AKT, EGFR, ErbB2, IGFlR, KIT, Met, Raf, and VEGFR2. Examples of receptor tyrosine kinase inhibitors can be found in WO 2006/108059 (US Nat'l Stage Application Serial No. 11/910,720), WO 2006/074057 (US Nat'l Stage Application Serial No. 1 1/722,719), WO 2006/071819 (US Nat'l Stage Application Serial No. 11/722,291), WO 2006/014325 (US Nat'l Stage Application Serial No. 1 1/571,140), WO 2005/117909 (US Nat'l Stage Application Serial No. 11/568,173), WO 2005/030140 (US Nat'l Stage Application Serial No. 10/573,336), WO 2004/050681 US Nat'l Stage Application Serial No. 10/533,555), WO 2005/1 12932 (US Nat'l Stage Application Serial No. 11/568,789), and WO 2004/006846 (US Nat'l Stage Application Serial No. 10/522,004), each of which is incorporated herein by reference for all purposes. In particular, the applications cited in this paragraph are incorporated for the purpose of providing specific examples and generic embodiments (and the definitions associated with the terms used in the embodiments) of compounds that are useful in the practice of the invention. These references also describe in vitro assays useful in the practice of this invention.
[00104] "Taxane" includes, for example, one or more of the following: Paclitaxel (Taxol®) and Docetaxel (Taxotere®).
[00105] "Therapeutically effective amount" is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure. [00106] "Topoisomerase inhibitor" includes, for example, one or more of the following: amsacrine, camptothecin, etoposide, etoposide phosphate, exatecan, irinotecan, lurtotecan, and teniposide, and topotecan.
[00107] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
[00108] "SRC and/or ABL kinase inhibitor" includes, for example, dasatinib, imatinib (Gleevec®), and compounds described in WO 2006/074057.
[00109] "VEGFR inhibitor" includes, for example, one or more of the following: VEGF Trap, ZD6474 (vandetanib, Zactima), sorafenib, Angiozyme, AZD2171 (cediranib), pazopanib, sorafenib, axitinib, SU5416 (semaxanib), PTK787 (vatalanib), AEE778, RAF 265, sunitinib (Sutent), N-(3,4-dichloro-2-fluorophenyl)-7-({[(3ai?,5r,6a1S)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N- (4-bromo-3-chloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl } oxy)-6-(methyloxy)quinazolin-4-amine, N-(3 ,4-dichloro-2- fluorophenyl)-7-({[(3a/?,5s,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3a/?,5s,6a5)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, compounds in Table 7, and compounds described in WO 2004/050681 and WO 2004/006846. Embodiments of the Invention
[00110] The following paragraphs present a number of embodiments of compounds of the invention. In each instance, the embodiment includes both the recited compounds as well as individual isomers and mixtures of isomers. In addtion, in each instance, the embodiment optionally includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof. [00111] For each of the following embodiments, the Compound of Formula I can, for example, be of Formula I(a) or be selected from a Compound in Table 1. [00112] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, where growth and/or survival of tumor cells of the cancer is enhanced, at least in part, by the activity of PBK; in combination with one or more treatments selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation.
[00113] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric carcinoma (including gastrointestinal carcinoid tumors and gastrointestinal stromal tumors), glioblastoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), melanoma, ovarian cancer, cervical cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AJvIL), chronic myelogenous leukemia (CML), non-Hodgkin's lymphoma, and thyroid carcinoma. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from prostate cancer, NSCLC, ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, and glioblastoma. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from NSCLC, breast cancer, prostate cancer, glioblastoma, and ovarian cancer.
[00114] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents. [00115] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, cisplatin, oxaliplatin, gefϊtinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), HKI-272, pelitinib, canertinib, a compound selected from Table 4, a compound in Table 7, and lapatinib. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, trastuzumab, erlotinib, /V-(3,4-dichloro-2-fluorophenyl)-7- ({[(3ai?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5s,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, iV-(4-bromo-3-chloro-2-fluorophenyl)-7- ({[(3a/?,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, a compound in Table 7, and lapatinib. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, paclitaxel, carboplatin, erlotinib, and N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6a.S)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine. [00116] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from a platin and a taxane. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from carboplatin, cisplatin, oxaliplatin, and paclitaxel. [00117] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an AKT inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an AKT inhibitor selected from perifosine, PKC 412, a compound in Table 2a, and a compound in Table 2b. [00118] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor selected from a compound in Table 3a, a compound in Table 3b, and a compound in Table 3c.
[00119] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, a compound selected from Table 4, and a compound in Table 7. In another embodiment, In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, N-(3,4-dichloro-2-fluorophenyl)-7- ({[(3a/?,5r,6a5')-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3ai?,5s,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, and 7V-(4-bromo-3-chloro-2- fluorophenyl)-7-({[(3ai?,5s,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine.
[00120] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor selected from lapatinib, EKB-569, HKI272, CI 1033, PKI- 166, and a compound selected from Table 4.
[00121] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor selected from 17- AAG, 17-DM AG, Geldanamycin, and CNF2024. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor selected from 17-AAG, 17-DMAG, and Geldanamycin. [00122] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGFlR inhibitor. In another embodiment, In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGFlR inhibitor selected from Table 5a and Table 5b.
[00123] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a Raf inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a Raf inhibitor selected from sorafenib, RAF 265 (CHIR-265), and a compound in Table 6. [00124] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor selected from VEGF Trap, ZD6474 (Zactima), cediranib (AZ2171), pazopanib, sunitinib, sorafenib, axitinib, AEE788, RAF 265 (CHIR-265), a compound selected from Table 4, and a compound selected from Table 7.
[00125] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor selected from imatinib, sunitinib, nilotinib, AMG 706, sorafenib, a compound in Table 3b, a compound in Table 3c, a compound in Table 8, and a compound in Table 9. [00126) In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor selected from CEP-701, PKC 412, sunitinib, MLN518, sunitinib, sorafenib, a compound in Table 3a, a compound in Table 3b, a compound in Table 3c, and a compound in Table 9. [00127] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from rapamycin, a rapamycin analogue, PI 103, and SF 1126. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from rapamycin, CCI-779, AP23573, RAD 001, TAFA 93, PI103, and SF 1 126. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.
[00128] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is of formula 100:
Figure imgf000036_0001
100 where q is 1, 2, or 3; E is -NR9-, -O-, or absent and Y is -CH2CH2-, -CH2-, or absent provided that when E is -NR9- or -O-, then Y is -CH2CH2-; R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, and lower alkyl; R8 is selected from -H, lower alkyl, -C(O)OR3, -C(O)N(R3)R4, -SO2R4, and -C(O)R3; R9 is hydrogen or lower alkyl; R3 is hydrogen or R4; R4 is selected from lower alkyl, aryl, lower arylalkyl, heterocyclyl, and lower heterocyclylalkyl; or R3 and R4, when taken together with a common nitrogen to which they are attached, form a five- to seven-membered heterocyclyl, said five- to seven-membered heterocyclyl optionally containing one or more additional heteroatom selected from N, O, S, and P; or a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, additionally optionally as a solvate, and additionally as a hydrate thereof. The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage Application Serial No. 10/522,004) which is herein incorporated by reference. Whenever a compound of formula 100 is described in this application, whether by structure or by use of the term "formula 100," the terms used to describe that compound are defined by WO 2004/006846 (US Nat'l Stage Application Serial No. 10/522,004). In particular, "alkyl" in formula 100 is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively; "lower alkyl" means alkyl groups of from one to six carbon atoms. "Aryl" in formula 100 means an aromatic six- to fourteen-membered carbocyclic rings which include, for example, benzene, naphthalene, indane, tetralin, fluorene and the like. "Lower arylalkyl" in formula 100 means a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkenylene, or alkynylene radical where the "alkyl" portion of the group has one to six carbons; examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. In formula 100, "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic three- to fifteen-membered ring radical (including fused or bridged ring systems) that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur where the nitrogen, phosphorus, carbon and sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states and the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. "Lower heterocyclylalkyl" means a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkenylene, and alkynylene radical having one to six carbons. [00129] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 , in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a.
[00130] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2b.
[00131] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3 a.
[00132] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3b.
[00133] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3c. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3c. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 3c. [00134] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 , in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4.
[00135] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3ai?,5r,6a5)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5r,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2- fluorophenyl)-7-({[(3a/?,5s,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, or N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3a/?,5s,6aiS)- 2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is iV-(3,4-dichloro-2-fluorophenyl)-7- ({[(3ai?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, or N-(4-bromo-3-chloro-2-fluorophenyl)- 7-({[(3ai?,5s,6a5)-2-methyloctahydrocyclo-penta[c]pyiτol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro- 2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)- 6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5r,6a5')- 2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5s,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, or N-(4-bromo-3-chloro-2-fluorophenyl)- 7-({[(3a/?,5s,6aiS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. [00136] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6aS)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is jV-(3,4-dichloro-2-fluorophenyl)-7- ({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is 7V-(3,4-dichloro- 2-fluorophenyl)-7-({[(3ai?,5r,6aJS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)- 6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. [00137] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5ac. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5a.
[00138] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 5b. [00139] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 6. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 6. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 6.
[00140] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 7. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 7. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 , in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 7.
[00141] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 8. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 8. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 8.
[00142] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 9. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 9. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 9.
[00143] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is paclitaxel.
[00144] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is rapamycin. [00145] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is carboplatin.
[00146] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is erlotinib.
[00147] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is lapatinib.
[00148] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is trastuzumab.
[00149] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is cetuximab.
[00150] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is panitumumab.
[00151] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is bevacizumab.
[00152] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is radiation. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is radiation. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is radiation.
[00153] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two antibodies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two antibodies independently selected from an IGFlR antibody (including, for example, ΛIGF-1R A12 MoAb, 0IGF-IR 19D12 MoAb, "IGF-IR h7C10 MoAb and 0IGF-IR CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)).
[00154] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two antibodies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two antibodies independently selected from an IGFlR antibody (including, for example, αIGF-lR A12 MoAb, 0IGF-IR 19Dl 2 MoAb, "IGF-IR h7C10 MoAb and 0IGF-IR CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)). [00155] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies independently selected from an IGFlR antibody (including, for example, «IGF-1R A12 MoAb, "IGF-IR 19Dl 2 MoAb, "IGF-IR h7C10 MoAb and 0IGF-IR CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)). [00156] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide.
[00157] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is surgery. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is surgery. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table
1 in combination with a treatment where the treatment is surgery. [00158] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide), Megestrol acetate (Megace), and one or more aromatase inhibitors. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitor selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies independently selected from from tamoxifen and an aromatase inhibitor. [00159] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two hormone therapies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide), Megestrol acetate (Megace), and one or two aromatase inhibitors. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitors selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies independently selected from from tamoxifen and an aromatase inhibitor. [00160] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from a rapamycin, rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I saccording to Formula I(a) in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
[00161] In another embodiment, the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from bone marrow or peripheral blood stem cell transplantation, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or t treatments where one of the treatments is one antibody selected from Gemtuzumab ozogamicin (Mylotarg), αIGF- 1 R A 12 MoAb, 0IGF- 1 R 19D 12 MoAb, αIGF- 1 R h7C 10 MoAb, "IGF- 1 R CP-751871 MoAb and trastuzumab. In another embodiment, the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from Imatinib (i.e. Gleevec®), PKC 412, CEP-701, daunorubicin, doxorubicin, cytarabine (ara-C), an anthracycline drug such as daunorubicin or idarubicin (Daunomycin, Idamycin), 6-thioguanine, and a granulocyte colony-stimulating factor (such as Neupogen or Leukine). [00162] In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from bone marrow or peripheral blood stem cell transplantation, radiation, one or two chemotherapeutic agents, immunotherapy, and one or two antibodies. In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents selected from Imatinib (i.e. Gleevec®), PKC 412, hydroxyurea (Hydrea), cytosine, cytosine arabinoside, dasatinib, AMN107, VX680 (MK0457), and cytarabine (ara-C). In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from Imatinib (i.e. Gleevec®) and dasatinib. In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is interferon therapy such as interferon-α. [00163] In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery (including cryosurgery), radiation, one or two chemotherapeutic agents, one or two antibodies, and one or two hormone therapies. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody selected from "IGF-IR Al 2 MoAb, 0IGF-IR 19Dl 2 MoAb, "IGF-IR h7C10 MoAb, and "IGF-IR CP-751871 MoAb. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents independently selected from rapamycin, mitoxantrone, prednisone, docetaxel (Taxotere), doxorubicin, etoposide, vinblastine, paclitaxel, and carboplatin. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the hormone therapy indepependently selected from androgen deprivation therapy and androgen suppression therapy. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a taxanes. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.
[00164] In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two immunotherapies, one or two hormone therapies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from an alkylating agent, a taxane, a platin, and a Raf inhibitor. In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from sorafenib, Paclitaxel (Taxol®), Docetaxel (Taxotere®), dacarbazine, rapamycin, imatinib mesylate (Gleevec®), sorafenib, cisplatin, carboplatin, dacarbazine (DTIC), carmustine (BCNU), vinblastine, temozolomide (Temodar), Melphalan, and imiquimod (Aldara). In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two immunotherapies independently selected from ipilimumab, interferon-alpha and interleukin- 2. In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is hormone therapy where the hormone therapy is tamoxifen.
[00165] In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from local excision, electrofulguration, segmental colon resection, polypectomy, local transanal resection, low anterior resection, abdominoperineal resection, and pelvic exenteration. In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin), 5-fluorouracil (5-FU), leucovorin, capecitabine (Xeloda), irinotecan (Camptosar), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), and leucovorin. In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies independently selected from cetuximab (Erbitux) and bevacizumab (Avastin).
[00166] In another embodiment, the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is selected from one or two chemotherapeutic agents independently selected from platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin), 5-fluorouracil (5-FU), gemcitabine, a taxane (including paclitaxel and docetaxel), topotecan, irinotecan, capecitabine, streptozocin, erlotinib (Tarceva), , leucovorin, and capecitabine (Xeloda). In another embodiment, the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody wehre the antibody is cetuximab.
[00167] In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two chemotherapeutic agents, one or two hormone therapies, and one or two antibodies. In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents independently selected from lapatinib (Tykerb®), Paclitaxel (Taxol®), docetaxel, capecitabine, Cyclophosphamide (Cytoxan), CMF (cyclophosphamide, fluoruracil, and methotrexate), methotrexate, fluorouracil, doxorubicin, epirubicin, gemcitabine, carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine), capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil), albumin-bound paclitaxel (Abraxane), AC (adriamycin and Cyclophosphamide), adriamyclin, and pamidronate or zoledronic acid (to treat bone weakness). In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analogs (including goserelin and leuprolide), Megestrol acetate (Megace), and one or more aromatase inhibitors. In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies and one of the hormone therapies is an aromatase inhibitors selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies independently selected from "IGF- 1 R A 12 MoAb, αIGF- 1 R 19D 12 MoAb, αIGF- 1 R h7C 10 MoAb, αIGF- 1 R CP-751871 MoAb, bevacizumab (Avastin), and trastuzumab.
[00168] In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is erlotinib.
[00169] In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one or two of the chemotherapeutic agents are independently selected from rapamycin, lapatinib, erlotinib, N-(3,4-dichloro-2-fluorophenyl)-7- ({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, 7V-(4- bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5r,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol- 5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, N-(3,4-dichloro-2-fluorophenyl)-7-( {[(3ai?,5s,6a5)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, and iV-(4-brorno-3-chloro-2-fluorophenyl)-7- ({[(3a/?,5s,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. [00170] In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the antibodies. In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies and one of the antibodies is trastuzumab.
[00171] In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one of the chemotherapeutic agents is selected from N-(3,4- dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7- ({[(3ai?,5r,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5s,6a5)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, and N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5s,6a5)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine; optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
[00172] In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one of the chemotherapeutic agents is N-(3,4-dichloro-2- fluorophenyl)-7-({[(3ai?,5r,6a5)-2-methyloctahydrocyclopenta-[c]pyπOl-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. [00173] In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or more antibodies, and one or more chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine (Gemzar®), Vinorelbine, Irinotecan, Etoposide, Vinblastine, Erlotinib (Tarceva®), gefitinib (Iressa), and Pemetrexed. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is Bevacizumab. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Paclitaxel, Docetaxel (Taxotere®), and erlotinib (Tarceva®).
[00174] In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is carboplatin. [00175] In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is selected from N-(3,4- dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7- ({[(3ai?,5r,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5s,6a.S)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, and 7V-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3ai?,5s,6a5}-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine; optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is N-(3,4-dichloro-2- fluorophenyl)-7-({[(3a/?,5r,6a5)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. [00176] In another embodiment, the invention is directed to a method of treating small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapy agents independently selected from a platin (such as cisplatin, oxaliplatin, and carboplatin), gefitinib, vinorelbine, docetaxel, paclitaxel, etoposide, fosfamide, ifosfamide, cyclophosphamide, cyclophosphamide/doxorubicin/vincristine (CAV), doxorubicin, vincristine, gemcitabine, paclitaxel, vinorelbine, topotecan, irinotecan, methotrexate, and docetaxel.
[00177] In another embodiment, the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, radioactive iodine therapy, one or two hormone therapies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from thyroid hormone pills, Doxorubucin and a platin. In another embodiment, the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is hormone therapy and the hormone therapy is radioiodine ablation. [00178] In another embodiment, the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two hormone therapies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a
Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies independently selected from megestrol acetate, Tamoxifen, and a progestin including medroxyprogesterone acetate (Provera) and megestrol acetate (Megace). In another embodiment, the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin, more for example cisplatin), a taxane (including paclitaxel), doxorubicin (Adriamycin), cyclophosphamide, fluorouracil (5-FU), methotrexate, and vinblastine.
[00179] In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is bevacizumab. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin and carboplatin), a taxane (including paclitaxel and docetaxel), topotecan, an anthracyclines (including doxorubicin and liposomal doxorubicin), gemcitabine, cyclophosphamide, vinorelbine (Navelbine), hexamethylmelamine, ifosfamide, etoposide, bleomycin, vinblastine, ifosfamide, vincristine, and cyclophosphamide. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platin and a taxane. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, paclitaxel, and docetaxel. [00180] In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two chemotherapeutic agents, one or two anti-seizure agents, and one or two agents to reduce swelling. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation selected from external beam radiation, interstitial radiotherapy, and stereotactic radiosurgery. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from carmustine (BCNU), Erlotinib (Tarceva), bevacizumab, gefitinib (Iressa), rapamycin, temozolomide, cisplatin, BCNU, lomustine, procarbazine, and vincristine. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an anti-seizure agent and the anti-seizure agent is diphenylhydantoin (Dilantin). In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an agents to reduce swelling and the agent is dexamethasone (Decadron). In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from erlotinib and temozolomide. [00181] In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selceted from cryosurgery, laser surgery, loop electrosurgical excision, conization, simple hysterectomy, and radical hysterectomy and pelvic lymph node dissection. In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation selected from called external beam radiation therapy and brachytherapy. In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum compound (such as cisplatin, carboplatin, and oxaliplatin), paclitaxel, topotecan, ifosfamide, gemcitabine, vinorelbine, and fluorouracil.
[00182] In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, immunotherapy, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from excision and electrofulguration. In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cyproheptadine, SOM230, octreotide and lanreotide. In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is an interferon.
[00183] In another embodiment, the invention is directed to a method of treating a gastrointestinal stromal tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating a gastrointestinal stromal tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from imatinib mesylate (Gleevec), sunitinib (Sutent), and nilotinib (AMN 107). [00184] In another embodiment, the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiofrequency ablation, ethanol ablation, cryosurgery, hepatic artery embolization, chemoembolization, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from resection and transplantation. In another embodiment, the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from sorafenib, 5-fluorouracil and cisplatin.
[00185] In another embodiment, the invention is directed to a method of treating non- Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from radiation, one or two chemotherapeutic agents, interferon therapy, one or two antibodies, and bone marrow or peripheral blood stem cell transplantation. In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), chlorambucil, fludarabine, and etoposide. In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody selected from rituximab, ibritumomab tiuxetan, tositumomab, and alemtuzumab. In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the anitbody is rituximab.
[00186] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation and another treatment is surgery.
[00187] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation and another treatment is one or two chemotherapeutic agents. [00188] In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery and another treatment is one or two chemotherapeutic agents.
[00189] For each of the foregoing embodiments, the Compound of Formula I is selected from any of the following embodiments, including from the Representative Compounds in Table 1.
[00190] One embodiment (A) of the invention is directed to a compound of Formula I where W1, W2, W3, and W4 are -C(R1)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino; and all other groups are as defined in the Summary of the Invention. In another embodiment, W1, W2, W3, and W4 are -C(R1)= and each R1 is independently hydrogen or alkyl; or one of W1 and W4 is -N= and the other is -C(H)=. In another embodiment, W1, W2, W3, and W4 are -C(R1)= where each R1 is independently hydrogen or alkyl. In another embodiment, R1 is hydrogen.
[00191] Another embodiment (B) of the invention is a Compound of Formula I where R50 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-Ci-C6-alkylene- N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R553, or alkylcarbonylamino; where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention. In another embodiment, R50 is hydrogen.
[00192] Another embodiment (C) of the invention is a Compound of Formula I where R51 is hydrogen or alkyl; and all other groups are as defined in the Summary of the Invention. In another embodiment, R51 is alkyl, In another embodiment, R51 is methyl. [00193] Another embodiment (D) of the invention is a Compound of Formula I where R52 is hydrogen or halo; and all other groups are as defined in the Summary of the Invention. In another embodiment R52 is hydrogen or fluoro. In another embodiment, R52 is hydrogen. [00194] Another embodiment (E) of the invention is a Compound of Formula I where R53 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C|-C6-alkylene- N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R553, or alkylcarbonylamino; where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention. In another embodiment, R53 is hydrogen, alkoxy, nitro, amino, or -N(R55)C(O)-Ci-C6-alkylene-N(R55a)R55b. In another embodiment, R53 is hydrogen, methoxy, nitro, amino, or -NHC(O)CH2N(CH3)2. In another embodiment, R53 is hydrogen or methoxy.
[00195] Another embodiment (F) of the invention is a Compound of Formula I where R54 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-Ci-C6-alkylene- N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R553, or alkylcarbonylamino; where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention. In another embodiment, R54 is hydrogen, alkyl, alkoxy, or halo. In another embodiment, R54 is hydrogen, methyl, methoxy, bromo, or chloro. In another embodiment, R54 is hydrogen, methoxy, or chloro. [00196] Another embodiment (G) of the invention is directed to a compound of Formula I where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention. In another embodiment, R50, R52, and R53 are hydrogen and R54 is chloro or methoxy; R50, R52, and R54 are hydrogen and R53 is methoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form pyridinyl. Even more speicfically, R50, R52, and R53 are hydrogen and R54 is chloro or methoxy; or R50, R52, and R54 are hydrogen and R53 is methoxy. [00197] In another embodiment (Gl) of embodiment G is a compound of Formula I where R51 is methyl.
[00198] Another embodiment (H) of the invention is a compound of Formula I where B is phenyl substituted with R3a and optionally further substituted with one, two, or three R3; and all other groups are as defined in the Summary of the Invention. In another embodiment, B is phenyl substituted with R3a. In another embodiment the Compound is of Formula I(a):
Figure imgf000066_0001
I(a).
In another embodiment, B is phenyl substituted with R3a as depicted in Ia and is not further substituted with R3.
[00199] Another embodiment of the Invention (J) is directed to a compound of Formula I where B is heteroaryl optionally substituted with one, two, or three R3. In another embodiment, B is thien-3-yl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, or thiazolyl, each of which is optionally substituted with one or two R3. In another embodiment, B is thien-3-yl, pyridin-2-yl, pyridin- 3-yl, pyridin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, imidazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3- yl, pyrazol-4-yl, or pyrazol-5-yl, each of which is optionally substituted with one or two R3. In another embodiment, B is thien-3-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-4-yl, or pyrazol- 4-yl, each of which is optionally substituted with one or two R3. In another embodiment, B is pyridin-3-yl, 2-hydroxy-pyridin-5-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R3.
[00200] Another embodiment (K) provides a compound of Formula I or Ia where R3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialky laminoalky loxy ; -N(R7)C(O)-C i -C6-alkylene- N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R93; -C(O)N(R1 °)-C,-C6-alkylene- N(R1Oa)RIOb; -NR1 1C(O)NR1 13R1 1" where
Rl la; -C(O)R12; -NR13C(O)OR133; -C(O)N(R14)N(R14a)(R14b); -S(O)2N(R15)-C,-C6-alkylene- N(R15a)R15b; -C(O)N(R16)-Ci-C6-alkylene-C(O)OR16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)- C(=N(R17b)(R17a))(NRl 7cR17d); -N(R18)C(O)-C,-C6-alkylene-N(R18b)C(O)R18a; -C(O)N(R19)- C , -C6-alkylene-C(O)R' 9a; -N(R22)C(O)-C , -C6-alkylene-N(R22b)-N(R22c)(R22a); -C0-C6- alkylene-N(R23)-C,-C6-alkylene-N(R23b)R23a; or -NR24C(O)-Ci.C6-alkylene-OR24a; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and all other groups are as defined in the Summary of the Invention.
[00201] In another embodiment, R3a is -NHC(O)CH2NH(CH3), -NHC(O)CH2NH(CH2CH3), -NHC(O)CH(CH3)NH2,
-NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC
(O)CH(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH(CH3)NH(CH3),
-NHC(O)CH2NH2, -NHC(O)H, -NHC(O)CH2(azetidin-l-yl), -NHC(O)(pyrrolidin-2- yl), -NHC(O)CH(NH2)CH2OH, -NHC(0)(azetidin-4-yl), -NHC(O)C(CH3)2NH(CH3), -NH2,
-NHC(O)CH2NH(CH2CH2CH3), -NHC(O)CH2CH2NH2, -NHOH, -NHC(0)(piperidin-3- yl), -NHC(O)CH2(4-methyl- 1 ,4-diazepan- 1 -yl), -NHC(O)CH(NH2)(CH2CH3),
-NHC(O)CH2NH(CH2CH(OH)(CH3)), -NHC(O)CH2NHCH2CH2F,
-NHC(O)CH2NH(OCH2CH(CH3)2), -NHC(0)( 1 -aminocycloprop-
1-yl), -NHC(0)CH2NH(CH2cyclopropyl), -NHC(0)CH2(3-(dimethylamino)-azetidin-l-yl),
-NHC(O)(piperidin-2-yl), -NHC(O)(moφholin-4-yl), -NHC(O)CH2(pyrrolidin- 1 -yl),
-NHC(O)CH(NH2)CH2CH2CH2CH2N(CH3)2, -NHC(O)CH2N(CH3)(CH2CH3),
-NHC(O)CH2(imidazol-5-yl), -NHC(0)( 1 -aminocyclopent- 1 -yl),
-NHC(O)CH2NH(CH2CH(CH3)2), -NHC(O)CH2N(CH3)(CH2CH3),
-NHC(0)(7V-(imidazol-4-ylmethy l)-azetidin-3 -yl), -NHC(0)(N-ethyl-azetidin-3 - yl), -NHCH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH2N(CH3)(N-methyl-pyrrolidin-3- yl), -NHC(O)CH2N(CH3)(CH2CH2N(CH3)2), -NHC(O)CH2(3 -hydroxy-pyrrolidin- 1 - yl), -NHC(O)(I -amino-cyclobut-1-yl), -NHC(O)CH2NH(CH2)3CH3,
-NHC(O)CH2(3-piperidin- 1 -ylazetidin- 1 yl), -NHC(O)NH2,
-NHC(OX 1 -hydroxycyclopropyl), -NHC(O)CH2NHN(CH3)2, -NHC(O)NH(CH2)2N(CH3)2,
-NHC(O)CH2OH, -NHC(O)(pyridazin-4-yl), -NHC(0)(N-methyl-piperidin-4- yl), -NHC(O)CH2NHCH(CH3)3, -NHC(O)CH2(3-dimethylamino-pyrrolidin-
1 yl), -NHC(O)CH2NH(CH2)2N(CH3)2, -NHC(0)( 1 -cyclopropylmethyl-azetidin-3- yl), -NHC(O)CH2NH(CH3)3, -NHC(O)(imidazol-2-yl), -NHC(O)(imidazol-4- yl), -NHC(O)(1, 2-oxazol-5-yl), -NHC(O)CH2NHCH2CF3, -NHC(O)CH2CH2(piperidin-l- yl), -NHC(O)(3-oxo-cyclopent-l-yl), -NHC(O)(2-hydroxy-pyridin-6-yl), -NHC(O)CH2NH(3- fluoro-4-hydroxyphenyl), -NHC(O)(CH2)3N(CH3)2, -NHC(0)( 1 -(furan-2-ylmethyl)-azetidin-
3-yl), -NHC(0)(pyrimidin-5-yl), -NHC(O)(pyrrol-2-yl), -NHC(O)CH2N(CH3)CH(CH3)2,
-NHC(O)CH2N(CH2CH3)2, -NHC(O)CH2(3-methyl- 1 ,2-oxazol-5- yl), -NHC(O)CH2NHCH2(3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2-yl), -NHC(0)(2- amino-tetrahydropyran-2-yl), -NHC(O)CH2(4-methylamino-piperidin- 1 - yl), -NHC(OXpiperidin-l-yl), -NHC(O)(7V-methyl-pyrrolidin-2yl), -NHC(O)(thien-
3yl), -NHC(O)(N-(cycloproρylcarbonyl)azetidin-3-yl), -NHC(O)CH2(4-methylpiperazin- 1 - yl), -NHC(O)(N-benzylazetidin-3-yl), -ΝHC(O)(2-chloro-pyridin-3- yl), -NHC(O)CH2(pyridin-4-yl), -NHC(O)CH2N(CH3)(CH2CH=CH2),
-NHC(O)CH2NH(benzyl), -NHC(O)CH2OCH3, -NHC(0)[ 1 -(C(O)CH2CH3)-azetidin-3- yl], -NHC(O)(pyridin-3-yl), -NHC(O)CH2NHCH2CH2OCH3,
-NHC(OX 1 -[C(O)CH3]piperidin-4-yl), -NHC(O)CH2(2-methyl-pyrrolidin- 1 - yl), -NHC(O)(furan-3-yl), -NHC(O)CH2N(CH3)2, -NHC(O)(2-chloro-pyridin-5- yl), -NHC(O)(2-chlorophenyl), -NHC(O)CH2(pyridin-2-yl), -NHC(O)CH2(3-dimethylamino- azetidin-1-yl), -NHC(O)CH2(pyridin-3-yl), -NHC(O)CH2(2- chlorophenyl), -NHC(O)CH2N(CH3)CH2CH2CH2N(CH3)2, -NHC(O)CH2N(CH2CH3)CH2CH
20H, -NHC(O)CH2(2-benzyl-pyrrolidin-l-yl), -NHC(0)(furan-2-yl, -NHC(O)(2-chloro- pyridin-4-yl), -NHC(O)CH2NHC(O)CH3, -NHC(O)CH2CH2CH3, -NHC(O)(4-chlorophenyl),
-NHC(0)(4-methyl-phenyl), -NHC(O)CH2NHC(O)O(CH3)3, -NHC(O)(benzo[d] [ 1 ,3]dioxol-
5-yl), -NHC(O)CH2NHOCH2(2-methoxyphenyl), -NHC(0)(pyridin-4-yl), -NHC(O)CH2[4-
(3,4-dichlorophenyl)-piperazin-l-yl], -NHC(O)CH2CH2(pyridin-3- yl), -NHC(O)(tetrahydrofuran-3-yl), -NHC(O)CH2NHCH2^- methylphenyl), -NHC(O)CH(CH3)CH2CH3, -NHC(O)CH2(3- fluorophenyl), -NHC(O)CH2C(CH3)2phenyl, -NHC(O)(2-methyl-cycloprop- 1 - yl), -NHC(O)(2-methyl-4-methoxyphenyl), -NHC(O)(2-methylpyridin-3-yl), -NHC(0)(4- methoxyphenyl), -NHC(O)CH2(4-ethylpiperazin-l-yl), -NHC(0)(thien-2-yl), -NHC(0)(3- fluoro-2-methylphenyl), -NHC(0)(2-bromo-thien-3-yl), -NHC(O)(4- fluorophenyl), -NHC(O)CH2(3-methylpiperidin- 1 -yl), -NHC(O)CH(CH3)2,
-NHC(O)(CH2)3CH3, -NHC(O)CH2OCH2CH3, -NHC(O)CH2NH(2- fluorophenyl), -NHC(O)(3-dimethylaminophenyl), -NHC(O)CH2(4-methylpiperidin- 1 - yl), -NHC(O)CH2NH(2-n-propylphenyl), -NHC(O)phenyl, -NHC(O)(pyrazin2- yl), -NHC(O)(3-fluoro-4-methoxyphenyl), -NHC(O)C(CH3)2CH2CH3,
-NHC(O)CH2O(4-fluorophenyl), -NHC(0)( 1 -methylcarbonyl-azetidin-3- yl), -NHC(O)CH2NH(4-methylphenyl), -NHC(O)CH2NH(phenyl), -NHC(O)CH2(4-allyl- piperazin-1-yl), -NHC(0)(2-methylphenyl), -NHC(O)CH2CH2OCH3, -NHC(0)(3-methyl- furan-2-yl), -NHC(O)C(CH3)3, -NHC(O)CH2NHObenzyl, -NHC(O)CH2NH(3-chlorophenyl),
-NHC(O)cyclobutyl, -NHC(O)CH2(3-methoxyphenyl), -NHC(0)( 1 -methylcycloprop- 1 -yl),
-NHC(O)(3-flurophenyl), -NHC(0)(4-dimethylaminophenyl), -NHC(O)(3 ,4- dichlorophenyl), -NHC(O)CH2NHCH2(2-methylthiophenyl), -NHC(O)CH2(2-fluorophenyl), -NHC(O)CH2N(CH2CH3)CH(CH3)2, -NHC(O)(thiazol-4-yl), -NHC(O)CH2N(CH3)benzyl, -NHC(O)CH2NHCH2(thien-2-yl), -NHC(O)CH2NHCH2(pyridin-2-yl), -NHC(O)(3- methoxyphenyl), -NHC(O)CH2NHCH2(3-chloro-4-methylphenyl), -NHC(O)CH(CH3)CH2CH2CH3, -NHC(O)CH2(4-chlorophenyl), -NHC(O)(3-fluoro-4- methylphenyl), -NHC(O)CH2O(2-methylphenyl), -NHC(O)CH2(cyclohexyl), -NHC(0)(2- phenyl-cycloprop-1-yl), -NHC(O)(3-chlorophenyl), -NHC(O)CH2(2- methoxyphenyl), -NHC(O)CH2CH2(3-methoxyphenyl), -NHC(O)CH2NH(2-fluoro-4-methyl- phenyl), -NHC(O)CH2NHCH2(3-fluoro-phenyl), -NHC(O)CH2(4-methoxy- phenyl), -NHC(O)benzyl, -NHC(0)(2,4-dichlorophenyl), -NHC(O)(3-oxo-cyclohex-l- yl), -NHC(O)CH2NH(3-fluorophenyl), -NHC(O)CH2(3-chlorophenyl), -NHC(O)CH2NHCH2CH(CH3)phenyl, -NHC(O)CH2NHCH2(2,4-dimethylphenyl), -NHC(O)CH2(2-methyl-piperidin- 1 -yl), -NHC(O)CH2NH(2- methoxyphenyl), -NHC(O)CH2(1 ,2,3,4-tetrahydroisoquinolin-2- yl), -NHC(O)CH2CH2CH=CH2, -NHC(O)CH2NH(2-methylphenyl), -NHC(O)CH2(4-oxo- piperidin-1-yl), -NHC(O)(2-fluorophenyl), -NHC(O)CH2NHCH(CH3)phenyl, -NHC(0)(2- fluoro-6-methoxyphenyl), -NHC(O)CH2NH(2-isopropylphenyl), -NHC(O)CH2CH2(2- methoxyphenyl), -NHC(O)CH2CH2CH(CH3)2, -NHC(O)CH2(2-phenyl-moφholin-4- yl), -NHC(O)CH2CH2(4-methoxyphenyl), -NHC(O)CH2N(allyl)cyclopentyl, -NHC(O)CH2N(CH3)CH2CH2OCH35 -NHC(O)CH2CH2C(O)CyClOPrOPyI, -NHC(O)CH2NH(3-tert-butylphenyl), -NHC(O)CH2N(n- propyl)(cyclopropylmethyl), -NHC(O)CH2(2-oxo-cyclopentyl), -NHC(O)CH2NH(4- chlorophenyl), -NHC(O)CH2(4-piperidin- 1 -ylpiperidin- 1 -yl), -NHC(O)CH2(4- cyclopentylpiperazin- 1 -yl), -NHC(O)CH2(2-methylphenyl), -NHC(O)CH2NHCH2(3-fluoro- 6-methylphenyl), -NHC(O)CH2C(CH3)3, -NHC(O)CH2NH(2-chlorophenyl), -NHC(0)(3- fluoro-6-methylphenyl), -NHC(O)(4-fluoro-3-methylphenyl), -NHC(O)(2,3- dichlorophenyl), -NHC(O)CH2Ophenyl, -NHC(O)CH2NH(2,3-dimethylphenyl), -NHC(0)(2- fluoro-5-methylphenyl), -NHC(O)CH2NHOCH2(4-methylphenyl), -NHC(O)CH2(4- isopropylpiperazin- 1 -yl), -NHC(O)CH2(4-fluorophenyl), -NHC(O)CH2CH(CH3)2, -NHC(O)(2-methoxy-4-methylphenyl), -NHC(O)CH2(4-«-propylpiperidin- 1 - yl), -NHC(O)CH2O(3-methylphenyl), -NHC(O)(tetrahydrofuran-2-yl), -NHC(O)CH2(3- hydroxymethylpiperidin- 1 -yl), -NHC(0)( 1 -tert-butoxycarbonylpiperidin-2- yl), -NHC(O)CH2N(CH3)CH2(pyridin-3-yl), -NHC(O)CH2N(CH2CH3)phenyl, -NHC(O)CH2OCH2CH2OCH3, -NHC(O)CH2CH2(cyclopentyl), -NHC(O)(2,5- dichlorophenyl), -NHC(O)CH2(4-methylcarbonylpiperazin- 1 -yl), -NHC(O)(5-fluoro-2- methoxyphenyl), -NHC(O)CH2N(CH2CH3)cyclohexyl, -NHC(O)(5-methyl-l,2-oxazol-3- yl), -NHC(O)(3-methylpyridin-3-yl), -NHC(O)(2-methoxypyridin-3-yl), -NHC(O)(3,5- dichlorophenyl), -NHC(O)CH2(thiazolidin3-yl), -NHC(O)CH2(4-[C(O)H]-piperazin-l- yl), -NHC(O)CH2(2-pyridin-4-ylpiperidin- 1 -yl), -NHC(O)(2-methoxyphenyl), -NHC(O)CH2N(CH3)CH2CH(CH3)2, -NHC(O)CH2(4- [C(O)H] -homopiperazin- 1 - yl), -NHC(O)( 1 -phenylcycloprop- 1 -yl), -NHC(O)CH2(2,6-dimethylmorpholin-4-yl), NHC(O)CH2(2-phenylpyrrolidin- 1 -yl), -NHC(O)CH2(morpholin-4-yl), -C(O)NHCH(CH3)CH2N(CH3)2, -C(O)NHCH2CH2N(CH3)2, -C(O)NH(pyrrolidin-3-yl), -C(O)NHCH2CH2(pyrrolidin- 1 -yl), -C(O)NHCH2CH2NH2, -C(O)N(CH3)CH2CH2N(CH3)2, -C(O)NHCH2(piperidin-2-yl), -C(0)NH( 1 -methylazetidin-3-yl), -C(O)NHCH2CH2(piperidin- 1-yl), -C(O)NHCH2CH2N(CH2CH3)2, -C(O)NH(I -methylpiperidin-3- yl), -C(O)NH(piperidin-3-yl), -C(O)NHCH2(I -methylpiperidin-3-yl), -C(O)NHCH2CH2N(CH2CH2OH)2, -C(0)NH(l-ethylpiperidin-3-yl), -C(O)NH2, -C(0)(3- aminopyrrolidin- 1 -yl), -C(O)(3-methylaminopyrrolidin- 1 -yl), -C(O)OH, -C(O)NHCH2CH2(moφholin-4-yl), -C(0)NHCH2( 1 -ethylpyrrolidin-2-yl), -C(O)(4-amino- 3-oxo-pyrazolidin-l-yl), -C(O)NHCH3, -C(O)(3-aminocyclobut-l-yl), -C(O)NHCH2(pyridin- 3-yl), -C(O)NHCH2CH2OH, -C(O)NH(3-oxo-pyrazolidin-4-yl), -NHCH2CH2(imidazol-4- yl), -C(O)(3-dimethylaminopyrrolidin-l-yl), -C(O)NHCH2(pyridin-4-yl), -C(O)N(CH3)(I- methyl-pyrrolidin-3-yl), -C(O)(3-diethylaminopyrrolidin-l-yl), -C(O)NH(pyrrol-l-yl), -C(O)NHCH2CH2CH2(pyrrolidin- 1 -yl), -C(O)N(CH3)CH2CH2CN, -C(O)NHCH2CH2OCH3, -C(O)N(CH2CH3)CH2CH2CN, -C(O)(3-aminopiperidin- 1 -yl), -C(O)NHCH2CH2CH2N(CH3);!, -C(O)NH(morpholin-4-yl), -C(O)NHN(CH3)2, -C(O)NHCH2CH2CH2(imidazol- 1 -yl), -C(O)NHCH2CH2CH2N(CH2CH3)2, -C(O)NHCH2CH2CN, -C(O)NHCH2CH2C(O)OCH3, -C(O)NHCH2CH2SCH3, -C(O)NHCH2CH2SCH2CH3, -C(O)N(CH2CH3)CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2(2- oxo-pyrrolidin- 1 -yl), -C(O)NHCH2CH2(pyridin-4-yl), -C(O)NHCH2CH2CH2OCH2CH3, -C(O)NHCH2CH2CH2(moφholin-4-yl), -C(O)NHCH2CH2CH2OCH3, -C(O)N(CH3)CH2CH2CH2N(CH3)Z1 -C(O)NHCH2CH2CH2OCH2CH2CH3, -C(O)NHCH2CH2C(O)OCH2CH3, -C(O)NHCH2CH2CH2OCH(CH3)2, -C(O)NHC(CH3)2CH2(piperidin- 1 -yl), -C(O)N(CH3)CH2CH2CH3, -C(O)NH(piperidin- 1 - yl), -C(O)NHCH(CH3)CH2OCH3, -C(0)NHC(CH3)2CH2(morpholin-4-yl), -C(0)(2- dimethylaminomethylpiperidin- 1 -yl), -C(O)NH(CH2)3O(CH2)3CH3, -C(O)NHCH(CH3)(CH2)3N(CH2CH3)2, -C(O)NHC(CH3)2C(O)(piperidin- 1 -yl), -C(0)(4- methylpiperazin- 1 -yl), -C(0)(2-piperidin- 1 -ylmethyl-piperidin- 1 -yl), cyano, -NHCH3, -CH(CH3)NHCH2CH2N(CH3)2, -C(O)CH3, -S(O)2NHCH2CH2N(CH3)2, -S(
O)2NH(CH2)3N(CH3)2, 5-(N,N-dimethylaminomethyl)- 1 ,3,4-oxadiazol-2- yl, -ΝHCH2CH2Ν(CH3)2, -N(CH3)2, -OCH2CH2N(CH3)2, -NHC[N(CH3)2][=N(CH3)2], -OCH
F2, -S(O)2CH3, -OCF3, or -NHC(O)CH2(4-dimethylaminopiperidin-l-yl).
[00202] In another embodiment (L), the compound of Formula I or Ia is that where R3a is hydroxyamino, -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b), -C(O)NR8R83, -NR9C(O)R93,
-C(O)N(R10)-C,-C6-alkylene-N(R10a)R10b, -NR1 1C(O)NR1 '3R1 lb, -N(R22)C(O)-C,-C6- alkylene-N(R22b)-N(R22c)(R22a), -NR13C(O)OR13a, -N(R18)C(O)-C , -C6-alkylene-
N(R18b)C(O)R18a , -NR24C(O)-C1. C6-alkylene-OR24a, or -N(R20)C(O)-C,-C6-alkylene-
C(O)R20a; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention. In another embodiment, R3a is -NHC(O)CH2NH(CH3), -NHC(O)CH(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2N(C
H3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH(NH2)CH2CH3, -NHC(O)CH2N(C
H3)CH2CH2N(CH3)2, -NHC(O)CH(CH3)NH(CH3), -NHC(O)H, -NHC(O)CH2(azetidin- 1 - yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH2)CH2OH, -NHC(0)(azetidin-4- yl), -NHC(O)C(CH3)2NH(CH3), -NH2, -NHC(O)CH2NH(CH2CH2CH3),
-NHC(O)CH2CH2NH2, -NHOH, or -NHC(O)(piperidin-3-yl).
[00203] In another embodiment (M) the compound is of Formula I or Ia and
R3a -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b); and R7 is hydrogen or alkyl and R7a and R7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention. In another embodiment, R3a is -NHC(O)CH2NH(CH3), -NHC(O)CH(CH3)NH2, -NHC(O)C(CH3)2NH2,
-NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH(NH2)CH2CH3,
-NHC(O)CH2N(CH3)CH2CH2N(CH3)2, or -NHC(O)CH(CH3)NH(CH3).
[00204] Embodiment (N) provides a compound of Formula I where each R3 is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R7)C(O)-Ci-C6-alkylene-
N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R93; -C(O)N(R10)-C,-C6-alkylene-
N(R1Oa)RIOb; -NR1 1C(O)NR1 13R1 lb where Rl la; -C(O)R12; -NR13C(O)OR138;
-C(O)N(R14)N(R14a)(R14b); -S(O)2N(Rl5)-C,-C6-alkylene-N(R15a)R15b; -C(O)N(R16)-C,-C6- alkylene-C(O)OR16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)-C(=N(R17b)(R17a))(NR17cR17d); -N(RI8)C(O)-
C,-C6-alkylene-N(R18b)C(O)R18a; -C(O)N(R19)-C,-C6-alkylene-C(O)R19a; -N(R22)C(O)- C,-C6-alkylene-N(R22b)-N(R22c)(R22a); -Co-C6-alkylene-N(R23)-C,-C6-alkylene-N(R23b)R23a; or -NR24C(O)-C i.C6-alkylene-OR24a; where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and all other groups are as defined in the Summary of the
Invention.
[00205] In another embodiment, each R3 is independently methyl, bromo, chloro, fluoro, -NHC(O)CH2NH(CH3), -NHC(O)CH2NH(CH2CH3), -NHC(O)CH(CH3)NH2,
-NHC(O)C(CH3)2NH2, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)Z,
-NHC(O)CH(NH2)CH2CH3, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2,
-NHC(O)CH(CH3)NH(CH3), -NHC(O)CH2NH2, -NHC(O)H, -NHC(O)CH2(azetidin-l- yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH2)CH2OH, -NHC(O)(azetidin-4- yl), -NHC(O)C(CH3)2NH(CH3), -NH2, -NHC(O)CH2NH(CH2CH2CH3),
-NHC(O)CH2CH2NH2, -NHOH, -NHC(0)(piperidin-3-yl), -NHC(O)CH2(4-methyl-l,4- diazepan- 1 -yl), -NHC(O)CH(NH2)(CH2CH3), -NHC(O)CH2NH(CH2CH(OH)(CH3)),
-NHC(O)CH2NHCH2CH2F, -NHC(O)CH2NH(OCH2CH(CH3)2), -NHC(O)(I- aminocycloprop- 1 -yl), -NHC(O)CH2NH(CH2cyclopropyl), -NHC(O)CH2(3-
(dimethylamino)-azetidin- 1 -yl), -NHC(0)(piperidin-2-yl), -NHC(O)(morpholin-4- yl), -NHC(O)CH2(pyrrolidin- 1 -yl), -NHC(O)CH(NH2)CH2CH2CH2CH2N(CH3);:,
-NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2(imidazol-5-yl), -NHC(0)( 1 -aminocyclopent-
1-yl), -NHC(O)CH2NH(CH2CH(CH3)2), -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)(N-
(imidazol-4-ylmethyl)-azetidin-3-yl), -NHC(O)(N-ethyl-azetidin-3-yl),
-ΝHCH2Ν(CH3)CH2CH2Ν(CH3)2, -ΝHC(O)CH2Ν(CH3)(N-methyl-pyrrolidin-3- yl), -ΝHC(O)CH2Ν(CH3)(CH2CH2Ν(CH3)2), -NHC(O)CH2(3-hydroxy-pyrrolidin- 1 - yl), -NHC(O)(I -amino-cyclobut-1-yl), -NHC(O)CH2NH(CH2)3CH3, -NHC(O)CH2Q- piperidin-1-ylazetidin-lyl), -NHC(O)NH2, -NHC(O)(I- hydroxycyclopropyl), -NHC(O)CH2NHN(CH3)2, -NHC(O)NH(CH2)2N(CH3)2, -NHC(O)CH2
OH, -NHC(0)(pyridazin-4-yl), -NHC(0)(N-methyl-piperidin-4- yl), -NHC(O)CH2NHCH(CH3)3, -NHC(O)CH2(3-dimethylamino-pyrrolidin-
1 yl), -NHC(O)CH2NH(CH2)2N(CH3)2, -NHC(0)( 1 -cyclopropylmethyl-azetidin-3- yl), -NHC(O)CH2NH(CH3)3, -NHC(O)(imidazol-2-yl), -NHC(O)(imidazol-4- yl), -NHC(OX l,2-oxazol-5-yl), -NHC(O)CH2NHCH2CF3, -NHC(O)CH2CH2(piperidin-l- yl), -NHC(O)(3-oxo-cyclopent- l-yl), -NHC(O)(2-hydroxy-pyridin-6-yl), -NHC(O)CH2NH(3- fluoro-4-hydroxyphenyl), -NHC(O)(CH2)3N(CH3)2, -NHC(0)( 1 -(furan-2-ylmethyl)-azetidin-
3-yl), -NHC(0)(pyrimidin-5-yl), -NHC(O)(pyrrol-2-yl), -NHC(O)CH2N(CH3)CH(CH3)2, -NHC(O)CH2N(CH2CH3);!, -NHC(O)CH2(3-methyl- 1 ,2-oxazol-5- yl), -NHC(O)CH2NHCH2(3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2-yl), -ΝHC(O)(2- amino-tetrahydropyran-2-yl), -NHC(O)CH2(4-methylamino-piperidin- 1 - yl), -NHC(θXpiperidin-l-yl), -NHC(O)(N-methyl-pyrrolidin-2yl), -NHC(O)(thien-
3yl), -NHC(O)(N-(cyclopropylcarbonyl)azetidin-3-yl), -NHC(O)CH2(4-methylpiperazin-l- yl), -NHC(O)(Λf-benzylazetidin-3-yl), -NHC(O)(2-chloro-pyridin-3- yl), -NHC(O)CH2(pyridin-4-yl), -NHC(O)CH2N(CH3)(CH2CH=CH2),
-NHC(O)CH2NH(benzyl), -NHC(O)CH2OCH3, -NHC(O)[I -(C(O)CH2CH3)-azetidin-3- yl], -NHC(0)(pyridin-3-yl), -NHC(O)CH2NHCH2CH2OCH3,
-NHC(0)( 1 -[C(O)CH3]piperidin-4-yl), -NHC(O)CH2(2-methyl-pyrrolidin- 1 - yl), -NHC(0)(furan-3-yl), -NHC(O)CH2N(CH3)2, -NHC(O)(2-chloro-pyridin-5- yl), -NHC(O)(2-chlorophenyl), -NHC(O)CH2(pyridin-2-yl), -NHC(O)CH2(3-dimethylamino- azetidin-1-yl), -NHC(O)CH2(pyridin-3-yl), -NHC(O)CH2(2- chlorophenyl), -NHC(O)CH2N(CH3)CH2CH2CH2N(CH3)2,
-NHC(O)CH2N(CH2CH3)CH2CH2OH, -NHC(O)CH2(2-benzyl-pyrrolidin- 1 - yl), -NHC(0)(furan-2-yl, -NHC(O)(2-chloro-pyridin-4-yl), -NHC(O)CH2NHC(O)CH3,
-NHC(O)CH2CH2CH3, -NHC(0)(4-chlorophenyl), -NHC(0)(4-methyl- phenyl), -NHC(O)CH2NHC(O)O(CH3)3, -NHC(O)(benzo[d][l,3]dioxol-5- yl), -NHC(O)CH2NHOCH2(2-methoxyphenyl), -NHC(0)(pyridin-4-yl), -NHC(O)CH2[4-
(3 ,4-dichlorophenyl)-piperazin- 1 -yl] , -NHC(O)CH2CH2(pyridin-3 -yl),
-NHC(O)(tetrahydrofuran-3-yl), -NHC(O)CH2NHCH2(2-methylphenyl),
-NHC(O)CH(CH3)CH2CH3, -NHC(O)CH2(3-fluorophenyl), -NHC(O)CH2C(CH3)2phenyl,
-NHC(O)(2-methyl-cycloprop- 1 -yl), -NHC(O)(2-methyl-4-methoxyphenyl), -NHC(0)(2- methylpyridin-3-yl), -NHC(O)(4-methoxyphenyl), -NHC(O)CH2(4-ethylpiperazin- 1 - yl), -NHC(0)(thien-2-yl), -NHC(O)(3-fluoro-2-methylphenyl), -NHC(O)(2-bromo-thien-3- yl), -NHC(O)(4-fluorophenyl), -NHC(O)CH2(3-methylpiperidin-
1-yl), -NHC(O)CH(CH3)2, -NHC(O)(CH2)3CH3, -NHC(O)CH2OCH2CH3, -NHC(0)CH2NH(
2-fluorophenyl), -NHC(O)(3-dimethylaminophenyl), -NHC(O)CH2(4-methylpiperidin- 1 - yl), -NHC(O)CH2NH(2-«-propylphenyl), -NHC(O)phenyl, -NHC(0)(pyrazin2- yl), -NHC(O)(3-fluoro-4-methoxyphenyl), -NHC(O)C(CH3)2CH2CH3,
-NHC(O)CH2O(4-fluorophenyl), -NHC(0)( 1 -methylcarbonyl-azetidin-3- yl), -NHC(O)CH2NH(4-methylphenyl), -NHC(O)CH2NH(phenyl), -NHC(O)CH2(4-allyl- piperazin-1-yl), -NHC(0)(2-methylphenyl), -NHC(O)CH2CH2OCH3, -NHC(0)(3-methyl- furan-2-yl), -NHC(O)C(CH3)3, -NHC(O)CH2NHObenzyl, -NHC(O)CH2NH(3-chlorophenyl), -NHC(O)cyclobutyl, -NHC(O)CH2(3-methoxyphenyl), -NHC(O)( 1 -methylcycloprop- 1 - yl), -NHC(O)(3-flurophenyl), -NHC(O)(4-dimethylaminophenyl), -NHC(O)(3,4- dichlorophenyl), -NHC(O)CH2NHCH2(2-methylthiophenyl), -NHC(O)CH2(2- fluorophenyl), -NHC(O)CH2N(CH2CH3)CH(CH3)2, -NHC(O)(thiazol-4- yl), -NHC(O)CH2N(CH3)benzyl, -NHC(O)CH2NHCH2(thien-2-yl),
-NHC(O)CH2NHCH2(pyridin-2-yl), -NHC(O)(3-methoxyphenyl), -NHC(O)CH2NHCH2(3- chloro-4-methylphenyl), -NHC(O)CH(CH3)CH2CH2CH3, -NHC(O)CH2(4-chlorophenyl), -NHC(O)(3-fluoro-4-methylphenyl), -NHC(O)CH2O(2-methylphenyl), -NHC(O)CH2(cyclohexyl), -NHC(O)(2-phenyl-cycloprop- 1 -yl), -NHC(0)(3- chlorophenyl), -NHC(O)CH2(2-methoxyphenyl), -NHC(O)CH2CH2(3- methoxyphenyl), -NHC(O)CH2NH(2-fluoro-4-methyl-phenyl), -NHC(O)CH2NHCH2(3- fluoro-phenyl), -NHC(O)CH2(4-methoxy-phenyl), -NHC(O)benzyl, -NHC(O)(2,4- dichlorophenyl), -NHC(O)(3-oxo-cyclohex-l-yl), -NHC(O)CH2NH(3- fluorophenyl), -NHC(O)CH2(3-chlorophenyl), -NHC(O)CH2NHCH2CH(CH3)phenyl, -NHC(O)CH2NHCH2(2,4-dimethylphenyl), -NHC(O)CH2(2-methyl-piperidin- 1 - yl), -NHC(O)CH2NH(2-methoxyphenyl), -NHC(0)CH2( 1 ,2,3,4-tetrahydroisoquinolin-2- yl), -NHC(O)CH2CH2CH=CH2, -NHC(O)CH2NH(2-methylphenyl), -NHC(O)CH2(4-oxo- piperidin-1-yl), -NHC(O)(2-fluorophenyl), -NHC(O)CH2NHCH(CH3)phenyl, -NHC(0)(2- fluoro-6-methoxyphenyl), -NHC(O)CH2NH(2-isopropylphenyl), -NHC(O)CH2CH2(2- methoxyphenyl), -NHC(O)CH2CH2CH(CH3)2, -NHC(O)CH2(2-phenyl-moφholin-4- yl), -NHC(O)CH2CH2(4-methoxyphenyl), -NHC(O)CH2N(allyl)cyclopentyl, -NHC(O)CH2N(CH3)CH2CH2OCH35 -NHC(O)CH2CH2C(O)CyClOPrOPyI, -NHC(O)CH2NH(3-tert-butylphenyl), -NHC(O)CH2N(«-propyl)(cyclopropylmethyl), -NHC(O)CH2(2-oxo-cyclopentyl), -NHC(O)CH2NH(4-chlorophenyl), -NHC(O)CH2(4- piperidin- 1 -ylpiperidin- 1 -yl), -NHC(O)CH2(4-cyclopentylpiperazin- 1 -yl), -NHC(O)CH2(2- methylphenyl), -NHC(O)CH2NHCH2(3-fluoro-6-methylphenyl), -NHC(O)CH2C(CH3)3, -NHC(O)CH2NH(2-chlorophenyl), -NHC(O)(3-fluoro-6-methylphenyl), -NHC(O)(4-fluoro- 3-methylphenyl), -NHC(O)(2,3-dichlorophenyl), -NHC(O)CH2Ophenyl, -NHC(O)CH2NH(2,3-dimethylphenyl), -NHC(O)(2-fluoro- 5-methylphenyl), -NHC(O)CH2NHOCH2(4-methylphenyl), -NHC(O)CH2(4- isopropylpiperazin- 1 -yl), -NHC(O)CH2(4-fluorophenyl), -NHC(O)CH2CH(CH3)2, -NHC(O)(2-methoxy-4-methylphenyl), -NHC(O)CH2(4-«-propylpiperidin- 1 - yl), -NHC(O)CH2O(3-methylphenyl), -NHC(O)(tetrahydrofuran-2-yl), -NHC(O)CH2(3- hydroxymethylpiperidin- 1 -yl), -NHC(0)( 1 -/ert-butoxycarbonylpiperidin-2- yl), -NHC(O)CH2N(CH3)CH2(pyridin-3-yl), -NHC(O)CH2N(CH2CH3)phenyl, -NHC(O)CH2OCH2CH2OCH3, -NHC(O)CH2CH2(cyclopentyl), -NHC(O)(2,5- dichlorophenyl), -NHC(O)CH2(4-methylcarbonylpiperazin- 1 -yl), -NHC(O)(5-fluoro-2- methoxyphenyl), -NHC(O)CH2N(CH2CH3)cyclohexyl, -NHC(0)(5 -methyl- 1 ,2-oxazol-3- yl), -NHC(O)(3-methylpyridin-3-yl), -NHC(O)(2-methoxypyridin-3-yl), -NHC(O)(3,5- dichlorophenyl), -NHC(O)CH2(thiazolidin3-yl), -NHC(O)CH2(4-[C(O)H]-piperazin-l- yl), -NHC(O)CH2(2-pyridin-4-ylpiperidin- 1 -yl), -NHC(0)(2-methoxyphenyl), -NHC(O)CH2N(CH3)CH2CH(CH3)2, -NHC(O)CH2(4-[C(O)H]-homopiperazin- 1 - yl), -NHC(0)( 1 -phenylcycloprop- 1 -yl), -NHC(O)CH2(2,6-dimethylmorpholin-4-yl), NHC(O)CH2(2-phenylpyrrolidin- 1-yl), -NHC(O)CH2(morpholin-4- yl), -C(O)NHCH(CH3)CH2N(CH3)2, -C(O)NHCH2CH2N(CH3)2, -C(O)NH(pyrrolidin-3- yl), -C(O)NHCH2CH2(pyrrolidin-l-yl), -C(O)NHCH2CH2NH2,
-C(O)N(CH3)CH2CH2N(CH3)2, -C(O)NHCH2(piperidin-2-yl), -C(0)NH( 1 -methylazetidin-3- yl), -C(O)NHCH2CH2(piperidin-l-yl), -C(O)NHCH2CH2N(CH2CH3)2, -C(O)NH(I- methylpiperidin-3-yl), -C(0)NH(piperidin-3-yl), -C(O)NHCH2(I -methylpiperidin-3- yl), -C(O)NHCH2CH2N(CH2CH2OH)2, -C(O)NH(I -ethylpiperidin-3-yl), -C(O)NH2, -C(0)(3- aminopyrrolidin- 1 -yl), -C(O)(3-methylaminopyrrolidin- 1 -yl), -C(O)OH, -C(O)NHCH2CH2(morpholin-4-yl), -C(O)NHCH2( 1 -ethylpyrrolidin-2-yl), -C(O)(4-amino- 3-oxo-pyrazolidin-l-yl), -C(O)NHCH3, -C(O)(3-aminocyclobut-l-yl), -C(O)NHCH2(pyridin- 3-yl), -C(O)NHCH2CH2OH, -C(O)NH(3-oxo-pyrazolidin-4-yl), -NHCH2CH2(imidazol-4- yl), -C(O)(3-dimethylaminopyrrolidin-l-yl), -C(O)NHCH2(pyridin-4-yl), -C(O)N(CH3)(I- methyl-pyrrolidin-3-yl), -C(0)(3-diethylaminopyrrolidin-l-yl), -C(O)NH(pyrrol-l- yl), -C(O)NHCH2CH2CH2(pyrrolidin-l-yl), -C(O)N(CH3)CH2CH2CN, -C(O)NHCH2CH2OCH3, -C(O)N(CH2CH3)CH2CH2CN, -C(O)(3-aminopiperidin- 1 - yl), -C(O)NHCH2CH2CH2N(CH3);!, -C(O)NH(morpholin-4-yl), -C(O)NHN(CH3)2, -C(O)NHCH2CH2CH2(imidazol- 1 -yl), -C(O)NHCH2CH2CH2N(CH2CH3)2, -C(O)NHCH2CH2CN, -C(O)NHCH2CH2C(O)OCH3, -C(O)NHCH2CH2SCH3, -C(O)NHCH2CH2SCH2CH3, -C(O)N(CH2CH3)CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2(2- oxo-pyrrolidin- 1 -yl), -C(O)NHCH2CH2(pyridin-4-yl), -C(O)NHCH2CH2CH2OCH2CH3, -C(O)NHCH2CH2CH2(moφholin-4-yl), -C(O)NHCH2CH2CH2OCH3, -C(O)N(CH3)CH2CH2CH2N(CH3)2, -C(O)NHCH2CH2CH2OCH2CH2CH3, -C(O)NHCH2CH2C(O)OCH2CH3, -C(O)NHCH2CH2CH2OCH(CH3)2, -C(O)NHC(CH3)2CH2(piperidin- 1 -yl), -C(O)N(CH3)CH2CH2CH3, -C(O)NH(piperidin- 1 - yl), -C(O)NHCH(CH3)CH2OCH3, -C(O)NHC(CH3)2CH2(morpholin-4-yl), -C(0)(2- dimethylaminomethylpiperidin- 1 -yl), -C(O)NH(CH2)3O(CH2)3CH3,
-C(O)NHCH(CH3)(CH2)3N(CH2CH3)2, -C(O)NHC(CH3)2C(O)(piperidin- 1 -yl), -C(O)(4- methylpiperazin- 1 -yl), -C(0)(2-piperidin- 1 -ylmethyl-piperidin- 1 -yl), cyano, -NHCH3, -CH(CH3)NHCH2CH2N(CH3)2, -C(O)CH3, -S(O)2NHCH2CH2N(CH3)2, -S(
O)2NH(CH2)3N(CH3)2, 5-(MN-dimethylaminomethyl)-l,3,4-oxadiazol-2- yl, -NHCH2CH2N(CH3)2, -N(CH3)2, -OCH2CH2N(CH3)2, -NHC[N(CH3)2][=N(CH3)2], -OCH
F2, -CF3, -S(O)2CH3, -OCF3, -NHC(O)CH2(4-dimethylaminopiperidin-l-yl), or methoxy.
[00206] In another embodiment (P), the Compound of Formula I is that where each R3 is independently halo, alkyl, hydroxyamino, -N(R7)C(O)-Ci-C6-alkylene-
N(R7a)(R7b), -C(O)NR8R83 , -NR9C(O)R93, -C(O)N(R IO)-C, -C6-alkylene-
N(R1Oa)R1Ob-NR' 1C(O)NR1 '3R1 lb, -N(R22)C(O)-C,-C6-alkylene-N(R22b)-
N(R22c)(R22a), -NR13C(O)OR133, -N(R18)C(O)-C,-C6-alkylene-N(R18b)C(O)R18a , -NR24C(O)-
Ci.C6-alkylene-OR24a, or -N(R20)C(O)-C,-C6-alkylene-C(O)R20a; where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the
Invention. In another embodiment, each R3 is independently methyl, chloro, -NHC(O)CH2NH(CH3), -NHC(O)CH(CH3)NH2, -NHC(O)C(CH3)2NH2,
-NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH(NH2)CH2CH3,
-NHC(O)CH2N(CH3)CH2CH2N(CH3)2, -NHC(O)CH(CH3)NH(CH3), -NHC(O)H,
-NHC(O)CH2(azetidin- 1 -y 1), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH2)CH2OH,
-NHC(0)(azetidin-4-yl), -NHC(O)C(CH3)2NH(CH3), -NH2, -NHC(O)CH2NH(CH2CH2CH3),
-NHC(O)CH2CH2NH2, -NHOH, or -NHC(0)(piperidin-3-yl).
[00207] In another embodiment (Q), the Compound of Formula I is that where R3 is alkyl or -N(R7)C(O)-Ci-C6-alkylene-N(R7a)(R7b); and R7 is hydrogen or alkyl and R7a and R7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention. In another embodiment, each
R3 is independently methyl, -NHC(O)CH2NH(CH3), -NHC(O)CH(CH3)NH2, -NHC(O)C(CH3)2NH2, -NHC(O)-
CH2N(CHj)2, -NHC(O)CH2N(CH3)CH2CH2N(CH-O2, -NHC(O)CH(NH2)CH2CH3, -NHC(O)
CH2N(CH3)CH2CH2N(CH3)2, or -NHC(O)CH(CH3)NH(CH3).
[00208] In another embodiment (R), the Compound of Formula I is that where B is phenyl,
R3 is not present or R3 is halo, alkyl, or alkoxy; R3a is -C(O)NR8R83, -NR9C(O)R93, -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b), or -C(O)N(Rl0)-C,-
C6-alkylene-N(R10a)R10b where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention.
[00209) In another embodiment (Rl) of embodiment R, the compound is that where R50,
R52, and R53 are hydrogen and R54 is halo or alkoxy; R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the
Summary of the Invention. In another embodiment, R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy.
[00210] In another embodiment of (R2) of embodiment R, the compound is that where R51 is methyl.
[00211] In another embodiment (S), the compound of Formula Ia:
Figure imgf000077_0001
I(a) is that where R3 is not present or R3 is alkyl and R3a is -N(R7)C(O)-Ci-C6-alkylene- N(R7a)(R7b), -C(O)NR8R83 , -NR9C(O)R93, or -C(O)N(R10)-C,-C6-alkylene-N(R10a)R10b; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention. In another embodiment, R3 is is not present or is methyl. In another embodiment, R3 is is not present.
[00212] In another embodiment (Sl) of embodiment S is that where R7 is hydrogen or alkyl and R7a, and R7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R8 is hydrogen or alkyl and R8a is heterocycloalkyl or heterocycloalkylalkyl; R9 is hydrogen or alkyl and R9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; and R10, RIOa, and RIOb are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.
[00213] In another embodiment (S2) of embodiment S is that where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl. In another embodiment, R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy.
[00214] In another embodiment of (S3) of embodiment S, the compound is that where R51 is methyl.
[00215] In another embodiment (T), the Compound of Formula I is that where B is heteroaryl, one R3 is halo, alkyl, or alkoxy and a second R3 is -C(O)NR8R83, -NR9C(O)R93, -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b), or -C(O)N(R 10)-C,-
C6-alkylene-N(R10a)Rl0b where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention.
[00216] In another embodiment (Tl) of embodiment T, the compound is that where R7 is hydrogen or alkyl and R7a, and R7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R8 is hydrogen or alkyl and R8a is heterocycloalkyl or heterocycloalkylalkyl; R9 is hydrogen or alkyl and R9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R10, RIOa, and R1Ob are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.
[00217] In another embodiment U, the compound of Formula I is that where B is
Figure imgf000078_0001
; each R3 (when R3 is present) is independently halo, alkyl, alkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkylamino, dialkylamino, -C(O)NR8R8a, -NR9C(O)R93, -N(R7)C(O)- C,-C6-alkylene-N(R7a)(R7b), or -C(O)N(R10)-C,-C6-alkylene-N(R10a)R10b; and all other groups are as defined in the Summary of the Invention.
[00218] In another embodiment (Ul) of embodiment U, the compound of Formula I is that where R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; R50, R52, and R54 are hydrogen and R53 is alkoxy; or R50 and R52 are hydrogen and R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention. In another embodiment, R50, R52, and R53 are hydrogen and R54 is halo or alkoxy; or R50, R52, and R54 are hydrogen and R53 is alkoxy. [00219] In another embodiment (U2) of embodiment Ul, the compound of Formula I is that where R51 is methyl. [00220] In another embodiment (U3) of embodiment U, the Compound of Formula I is that where R7 is hydrogen or alkyl and R7a, and R7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R8 is hydrogen or alkyl and R8a is heterocycloalkyl or heterocycloalkylalkyl; R9 is hydrogen or alkyl and R a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R10, RIOa, and R1Ob are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl [00221] In another embodiment of the Invention (V) the Compound of Formula I is that whereW1, W2, W3, and W4 are -C(H)=; or W2 and W3 are -C(H)= and one of W1 and W4 is -N= and the other is -C(H)=; R50 is hydrogen; R51 is hydrogen or alkyl; R is hydrogen; R53 is hydrogen, alkoxy, nitro, amino, or -N(R55)C(O)-C,-C6-alkylene-N(R55a)R55b; and R54 is hydrogen, alkyl, alkoxy, or halo; or R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl;
B is phenyl substituted with R3a and optionally further substituted with one R3; or B is heteroaryl optionally substituted with one or two R3; R3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy ; -N(R7)C(O)-C i -C6-alkylene-
N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R9a; -C(O)N(R1 °)-Ci -C6-alkylene-
N(R1Oa)R1Ob; -NR1 1C(O)NR1 13R1 lb where Rl la; -C(O)R12; -NR13C(O)OR133;
-C(O)N(R14)N(R14a)(R14b); -S(O)2N(R15)-C,-C6-alkylene-N(R15a)R15b;
-C(O)N(R16)-Ci-C6-alkylene-C(O)OR16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)-
C(=N(R' 7b)(R' 7a))(NR' 7cR' 7d); -N(R18)C(O)-C , -C6-alkylene-
N(R18b)C(O)R' 8a; -C(O)N(R19)-C , -C6-alkylene-C(O)R' 9a; -N(R22)C(O)-C , -C6-alkylene-
N(R22b)-N(R22c)(R22a); -C0-C6-alkylene-N(R23)-C , .C6-alkylene-N(R23b)R23a; or -NR24C(O)-C i.C6-alkylene-OR24a; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; each R3 (when R3 is present) is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R7)C(O)-C i -C6-alkylene-
N(R7a)(R7b); -C(O)NR8R83; -NR9C(O)R93; -C(O)N(R10)-C,-C6-alkylene- N(R1Oa)RIOb; -NR1 1C(O)NR1 13R1 lb where Rl la; -C(O)R12; -NR13C(O)OR l3a;
-C(O)N(R14)N(RI4a)(R14b); -S(O)2N(R15)-C,-C6-alkylene-N(R15a)R15b;
-C(O)N(R16)-Cι-C6-alkylene-C(O)ORl6a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R17)-
C(=N(R17b)(R17a))(NR17cR17d); -N(R18)C(O)-Ci-C6-alkylene-
N(R18b)C(O)R' 8a; -C(O)N(R ' 9)-C , -C6-alkylene-C(O)R' 9a; -N(R22)C(O)-C , -C6-alkylene-
N(R22b)-N(R22c)(R22a); -C0-C6-alkylene-N(R23)-C,.C6-alkylene-N(R23b)R23a; or -NR24C(O)-C i.C6-alkylene-OR24a; where each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; provided that when R50 and R52 are hydrogen, R51 is hydrogen or methyl, R53 is hydrogen or methoxy, and R54 is hydrogen or methoxy, then B is not 2,3-dihydro-l,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R3 where R3 is halo.
[00222] Another embodiment (W) of the invention is a Compound of Formula I where R5 , R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C,-C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl. [00223] Another embodiment (X) of the invention is a Compound of Formula I where R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl.
Representative Compounds
[00224] Representative compounds of Formula I and/or II are depicted below. The examples are merely illustrative and do not limit the scope of the invention in any way. Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS). Names in Table 1 were generated using ACD/Labs naming software 8.00 release, product version 8.08 with the exception of Compound 374 which was named using ChemDraw v. 9.0.1. Table 1 Representative PI3K-alpha Inhibitors
[00225] The Compounds in Table 1 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 1 can be used to practice the invention. In particular, the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 1 which salt(s) are formed with one or two acids independently selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid. In particular, the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 1 which salt(s) are formed with one or two bases independently selected from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, and N-methylglucamine. Any individual compound (and any optional salt, optional solvate, and optional hydrate thereof) in Table 1 can be used in combination with any of the above embodiments.
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
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Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
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Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
1 -
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
,4-
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
1 -
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
1 -
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
,4-
1 -
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
-3-
Figure imgf000203_0001
Figure imgf000204_0001
Table 2a. Representative AKT Inhibitors
[00226] The Compounds in Table 2a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 2a can be used to practice the invention.
Figure imgf000204_0002
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Table 2b. Additional Representative AKT Inhibitors
[00227] The Compounds in Table 2b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 2b can be used to practice the invention.
Figure imgf000220_0002
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Table 3a. Representative c-MET and/or Flt-3 Inhibitors
[00228] The Compounds in Table 3a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3a can be used to practice the invention.
Figure imgf000224_0002
Figure imgf000225_0001
Table 3b. Additional Representative c-MET, c-KIT, and/or Flt-3 Inhibitors
[00229] The Compounds in Table 3b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3b can be used to practice the invention.
Figure imgf000225_0002
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Table 3c. Additional Representative c-MET, c-KIT, and/or FIt-3 Inhibitors
[00230] The Compounds in Table 3c can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3c can be used to practice the invention.
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Table 4. Representative EGFR, ErbB2, and/or VEGFR Inhibitors
[00231] The Compounds in Table 4 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 4 can be used to practice the invention. In particular, the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 4 which salt(s) are formed with one or two acids independently selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid.
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Table 5a. Representative IGF-IR Inhibitor
[00232] The Compounds in Table 5a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 5a can be used to practice the invention.
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Table 5b. Additional Representative IGFlR Inhibitors
[00233] The Compounds in Table 5b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 5b can be used to practice the invention.
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Table 6.
Representative Raf Inhibitors
[00234] The Compounds in Table 6 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 6 can be used to practice the invention.
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Table 7. Representative EGFR and/or VEGFR Inhibitors
[00235] The Compounds in Table 7 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 7 can be used to practice the invention.
Figure imgf000341_0002
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Table 8. c-KIT Inhibitors
[00236] The Compounds in Table 8 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 8 can be used to practice the invention.
Figure imgf000346_0002
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Table 9. c-KIT and/or Flt-3 Inhibitors
[00237] The Compounds in Table 9 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 9 can be used to practice the invention.
Entry Name
4-((£)-2- {3-[6-(4-methylpiperazin- 1 -yl)- lH-benzimidazol-2-yl]- lH-pyrazol-5- yl}ethenyl)phenol
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
General Administration
[00238] In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of PI3K according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other specific embodiments, administration may specifically be by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages. When treating brain cancers, including glioblastomas, the administration may specifically be by placing a gliadel, a dissolvable material that contains the chemotherapy drug (in particular BCNU), directly into brain tumors during an operation. [00239] The compositions will include a compound of Formula I or II as the/an active agent and can include a conventional pharmaceutical carrier or excipient and in addition may include other medicinal agents and pharmaceutical agents that are generally administered to a patient being treated for cancer.
[00240] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. [00241] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc. [00242] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. [00243] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
[00244] One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[00245] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
[00246] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[00247] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt or solvate thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension. [00248] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[00249] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[00250] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. [00251] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. [00252] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt or solvate thereof, and 99% to 1 % by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt or solvate thereof, with the rest being suitable pharmaceutical excipients.
[00253] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for treatment of a disease-state in accordance with the teachings of this invention. [00254] The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art. [00255] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate. [00256] Representative pharmaceutical formulations containing a compound of Formula I or II are described below in the Pharmaceutical Composition Examples.
UTILITY [00257] Certain compounds of Formula I have been tested using the assay described in
Biological Example 1 and have been determined to be PI3K inhibitors. As such compounds of Formula I are useful for treating diseases, particularly cancer in which PBKactivity contributes to the pathology and/or symptomatology of the disease. For example, cancer in which PDK activity contributes to its pathology and/or symptomatology include breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric carcinoma, glioblastoma, hepatocellular carcinoma, small cell lung cancer, non- small cell lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and thyroid carcinoma, and the like.
Suitable in vitro assays for measuring PBK activity and the inhibition thereof by compounds are known. Typically, the assay will measure PI3K-induced ATP consumption. For further details of an in vitro assay for measuring PI3K activity see Biological Examples, Example 1 infra. Cellular activity can be determined using assays as described in Biological Examples 2, 3, and 4 infra. Suitable in vivo models of cancer are known to those of ordinary skill in the art. For further details of in vivo assays see Biological Examples 5-10, infra. Examples describing the administration of a Compound of Formula I in combination with anticancer agents are described in Biological Examples 1 1-14, infra. Following the examples disclosed herein, as well as that disclosed in the art, a person of ordinary skill in the art can determine what ombinations of a Compound of Formula I and anti-cancer agents would be effective for treating cancer.
PREPARATIONS OF THE INTERMEDIATES AND COMPOUNDS OF THE INVENTION [00258] Compounds of this invention can be made by the synthetic procedures described in WO 2007/044729, the disclsoure of which is incorporated by reference herein. [00259] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. [00260] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 0C to about 1500C, in another embodiment from about O0C. to about 1250C and most specifically at about room (or ambient) temperature, e.g., about 2O0C. Unless otherwise stated (as in the case of a hydrogenation), all reactions are performed under an atmosphere of nitrogen. [00261] Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes. [00262] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of Formula I that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention. Some of the compounds of the invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.
[00263] In particular, in this application B can be 2-hydroxy-pyridinyl, also described as its structure:
Figure imgf000368_0001
14.
Both 2-hydroxy-pyridinyl and the above structure 14 include, and are equivalent to, pyridin-2(lH)-one and its structure 15:
Figure imgf000368_0002
15.
Regardless of which structure or which terminology is used, each tautomer is included within the scope of the Invention.
[00264] The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group" or "protective group". A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
[00265] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specifϊc reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization. [00266] In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. [00267] In Compounds of Formula I
Figure imgf000370_0001
the hydrogen on the -NHS(O)2- group is highly acidic. Thus, intermediates leading to Compounds of Formula I, as well as Compounds of Formula I themselves, can be recovered as uncharged or zwitterionic molecules, or cationic salts such a sodium or potassium, depending on the substitutions on the B ring and on reaction conditions. In the examples that follow, unless otherwise specified, the final form of the compound was assumed to be the uncharged molecule in the absence of analytical techniques that would have determined otherwise.
[00268] Compounds of Formula I can be prepared using methods known to one of ordinary skill in the art. In another embodiment, fusion of appropriate reagents at 180 0C in the presence of a base such as K2CO3 and metallic copper is known to provide intermediates of formula 1 (see S. H. Dandegaonker and C. K. Mesta, J. Med. Chem. 1965, 8, 884).
[00269] Alternatively, the intermediate of formula 3 can be prepared according to the scheme below where each LG1 is a leaving group (in one embodiment halo, in another embodiment chloro) and all other groups are as defined in the Detailed Description of the Invention.
Scheme 1
Figure imgf000371_0001
[00270] In scheme 1 , an intermediate of formula 3 can be prepared by briefly heating commercially available 2,3-dichloroquinoxaline and an intermediate of formula 2 (which are commercially available or can be prepared by one of ordinary skill in the art), a base such as K2CO3, in a solvent, such as DMF or DMSO. Upon completion (about 2 hours), the reaction mixture is then poured into water and followed by 2 N HCl. The product is then extracted into a solvent such as ethyl acetate and washed with water and brine. The organic layers are combined and dried over a drying agent such as sodium sulfate, filtered, and concentrated under vacuum.
[00271] The intermediate of formula 3 is then treated with an intermediate of formula
4 in a solvent such as DMF or p-xylene at reflux temperature. Upon completion of the reaction (about 16 hours or less), the reaction is allowed to cool, extracted into DCM, washed with 2 N HCl and brine, dried over a drying agent such as sodium sulfate or magnesium sulfate, filtered, and concentrated to give a compound of Formula I.
[00272] Alternatively, other methods to prepare quinoxaline derivatives are known to one skilled in the art and include, but are not limited to S. V. Litvinenko, V. I. Savich, D.
D. Bobrovnik, Chem. Heterocycl. Compd. (Engl. Transl), 1994, 30, 340 and W. C.
Lumma, R. D. Hartman, J. Med. Chem. 1981, 24, 93.
[00273] The following compounds were prepared in a manner similar to that described above.
Example 1: N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3- nitrobenzenesulfonamide.
Example 2: N-(3-{[2,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-4- chlorobenzenesulfonamide.
Example 3: N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide. Example 4: 4-chloro-yV-(3-chloroquinoxalin-2-yl)benzenesulfonamide. Example 5: 4-chloro-./V-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO-J6) δ 9.18 (s, IH), 8.78 (s, IH), 8.40-8.60 (m, 3H), 7.98 (t, 2H), 7.62 (d, IH), 7.41 (m, 2H), 6.98 (d, IH), 6.59 (d, IH), 3.78 (s, 3H), 3.76 (s, 3H); MS (EI) m/z for C22H19TV5O6S: 482.1 (MH+). Example 6: /V-(3-(2,5-dimethoxyphenyIamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 12.68 ( br s, IH ), 9.18 (s, IH), 8.55 (s, IH), 8.08 (d, 2H), 7.98 (d, IH), 7.78 (d, 2H), 7.62 (dd, IH), 7.40 (m, 2H), 7.00 (d, IH), 6.60 (dd, IH), 3.78 (s, 6H) ; MS (EI) m/z for C22H19CW4O4S: 471.1 (MH+). Example 7: iV-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-4-methylphenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz, DMSO-J6) δ 12.0 (br s, 1 H), 10.6 (s, 1 H), 10.0 (br s, 1 H), 9.52 (s, 1 H), 8.91 (d, 1 H), 8.25 (d, 1 H), 7.69 (dd, IH), 7.47 (m, 1 H), 7.39 (d, 1 H), 7.16 (m, 3 H), 6.01 (dd, 1 H); MS (EI) m/z for C26H27CW6O4S: 555 (MH+).
[00274] Compounds of Formula I where B is phenyl substituted with R3a where R3a is alkylamino or dialkylamino or B is heteroaryl substituted with R3 where R3 is amino, alkylamino, or dialkylamino, and all other groups are as defined in the Summary of the Invention can be prepared according to Scheme 2. Scheme 2
Figure imgf000372_0001
5 l(c)
LG is a leaving group such as chloro. 5 is reacted with NHRaRb or HO-Ci-C6-alkylene- NHRaRb where Ra and Rb are independently hydrogen or alkyl. The reaction is carried out in the presence of a base, such as KHCO3, in a solvent such as DMF. [00275] Compounds of Formula I where B is phenyl substituted with R3a where R3a is aminoalkyloxy, alkylaminoalkyloxy, or dialkylaminoalkyloxy or B is heteroaryl substituted with R3 where R3 is aminoalkyloxy, alkylaminoalkyloxy, or dialkylaminoalkyloxy, and all other groups are as defined in the Summary of the Invention can be prepared according to Scheme 3. Scheme 3
Figure imgf000373_0001
l(c)
The reaction is carried out in the presence of a base such as NaH in a solvent such as
DMF.
[00276] Compounds of Formula I where B is phenyl substituted with R3a or B is heteroaryl substituted with R3 where R3a and R3 are i. -N(R7)C(O)-C,-C6-alkylene-N(R7a)(R7b) where R7, R7a, and R7b are as defined in the Summary of the Invention; ii. -NR9C(O)R9a where R9 is as defined in the Summary of the Invention; iii. -NR1 1C(O)NR1 laR" lb where R1 la, R1 la, and R1 lb are as defined in the Summary of the Invention; iv. -NR13C(O)OR133 where R13 and R13a are as defined in the Summary of the
Invention; v. -N(R18)C(O)-Ci-C6-alkylene-N(R18b)C(O)Rl8a where R18, R18a, and R18b are as defined in the Summary of the Invention; vi. -N(R20)C(O)-C i -C6-alkylene-C(O)R20a where R20 and R20a as defined in the
Summary of the Invention; vii. -NR21S(O)2-C, -C6-alkylene-N(R21b)R21a where R21, R21a, and R21b are as defined in the Summary of the Invention; viii. -N(R22)C(O)-C0-C6-alkylene-N(R22b)-N(R22c)(R22a), where R22, R22a and R22b are as defined in the Summary of the Invention; ix. -NR24C(O)-C,-C6-alkylene-OR24a where R24 and R24a are as defined in the
Summary of the Invention; and where the alkylene in R3 and R3a are independently optionally substituted as described in the Summary of the Invention can be prepared according to Scheme 4 by reacting with an intermediate of formula 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), or 9(g):
9(a) HOC(O)-C i -C6-alkylene-N(R7a)(R7b) where Ra is R7a or a N-protecting group, such as Boc or Fmoc; 9(b) HOC(O)R93;
9(c) HOC(O)NR1 13R1 lb; 9(d) HOC(O)OR13a; 9(e) HOC(O)-C i -C6-alkylene-N(R' 8b)C(0)R' 8a; 9(f) HOC(O)-C i -C6-alkylene-C(O)R20a; 9(g) LG-S(O)2-Ci.C6-alkylene-N(R2lb)Ra where Ra is R21a or a N-protecting group, such as Boc or Fmoc.
Scheme 4
Figure imgf000374_0001
l(e)
R , 1i0υ0υ in Scheme 4 is -C(O)R9a, -C(O)NR1 13R1 lb, -C(0)0R13a, -C(O)-C, -C6-alkylene- N(R18b)C(O)R18a, -C(O)-C ,-C6-alkylene-C(O)R20a, or -S(O)2-C, .C6-alkylene-N(R21b)Ra. The reaction is carried out under standard amide coupling conditions known to one of ordinary skill in the art. In particular, the reaction is carried out in the presence of a coupling agent such as HATU, a base such as DIEA, and in a solvent such as DMF. Where applicable, the N-protecting group is then removed using procedures known to one of ordinary skill in the art, such as treating with acid where PG is Boc. [00277] Proceeding as described for Scheme 4, compounds of the invention where B is phenyl substituted with R3a or B is heteroaryl substituted with R3 where R3a and R3 are a) -C(O)NR8R83; b) -C(O)N(R1 °)-C , -C6-alkylene-N(R' Oa)R1Ob; c) -C(O)R12 where R12 is an N-substituted heterocycloalkyl; d) -C(O)N(R14)N(R14a)(R14b); e) -C(O)N(R16)-C,-C6-alkylene-C(O)OR16a; or f) -C(O)N(R19)-Ci-C6-alkylene-C(O)R19a; or can be prepared by exchanging the starting materials as necessary. In particular, the intermediate of formula 11 :
11 is used instead of 8.
[00278] Compounds of Formula I where B is phenyl substituted with R3a or B is heteroaryl substituted with R3 where R3a and R3 are -NHC(O)CH2NR7aR7b where R7a and
R7b are as defined in the Summary of the Invention can be prepared according to Scheme
5.
Scheme 5
Figure imgf000376_0001
12 l(f)
LG is a leaving group such as bromo or chloro. 12 is reacted with NH(R7b)R7a in the presence of a base, such as DIEA, in a solvent such as ACN. [00279] Compounds of Formula I can be prepared according to Scheme 6. Scheme 6
Figure imgf000376_0002
l(h)
LG in Scheme 6 is a leaving group such as chloro. The reaction can be carried out by irradiating in a solvent such as DMA. Alternatively, the reaction can be carried out in the presence of acetic acid in a solvent such as DMA and by heating.
Example 8 6-chloro-N-(3-(3,5-dimethoxyphenyIamino)quinoxalin-2-yl)pyridine-3-sulfonamide
Figure imgf000377_0001
[00280] ό-chloropyridine-S-sulfonamide. 6-chloropyridine-3-sulfonyl chloride (4.1 g, 19.3 mmol) was stirred in ammonium hydroxide (30 mL) at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (150 mL) and any insoluble material filtered. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous phase was further extracted with EtOAc (1 x 15 mL). The combined EtOAc extractions were washed with H2O (1 x 50 mL) and saturated NaCl (1 x 50 mL), dried over Na2SO4, and concentrated in vacuo to give 6-chloropyridine-3-sulfonamide (2.58 g, 69%). MS (EI) m/z for C5H5Cl2N2O2S: 190.9 (MHO.
[00281] 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide.
2,3-dichloroquinoxaline (1.09 g, 5.48 mmol), 6-chloropyridine-3 -sulfonamide (1.05 g, 5.45 mmol), K2CO3 (753 mg, 5.45 mmol) and dry DMSO (30 mL) were combined and heated to 150 0C with vigorous stirring for 3-4 hr. The reaction mixture was allowed to cool to room temperature, then poured into 1% AcOH in ice water (300 mL) with vigorous stirring. The resulting solids were filtered, washed with H2O and dried under high vacuum to give 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (1.87g, 96%). MS (EI) m/z for C3H8Cl2N4O2S: 354.99 (MH+).
[00282| 6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3- sulfonamide. 6 -Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2 mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) were combined and heated to 125 0C with stirring overnight. The reaction was allowed to cool to room temperature and diluted with Et2O with vigorous stirring. The resulting solids were filtered, washed with Et2O and dried to give 6-chloro-N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (920 mg, 89%). 1H NMR (400 MHz, DMSO-J6) δ 12.20 (br s, IH), 9.12 (d, IH), 9.01 (br s, IH), 8.53 (dd, IH), 7.91 (br d, IH), 7.77 (d, IH), 7.60 (dd, IH), 7.40 (m, 4H), 6.26 (m, IH), 3.78 (s, 6H). MS (EI) m/z for C2IHi8CW5O4S: 472.0 (MH+).
Example 9 yV-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yI)-6-(2-(dimethylamino)- ethylamino)pyridine-3-sulfonamide
Figure imgf000378_0001
[00283] 6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-pyridine-3- sulfonamide (100 mg, 0.21 mmol), prepared using procedures similar to those used in Example 8, KHCO3 (40 mg, 0.40 mmol), N'/Z-dimethylethane-l^-diamine (225 μL, 2.0 mmol) and dry DMF (1.0 mL) were combined and heated to 130 0C with stirring overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxy-phenylamino)-quinoxalin-2-yl)-6-(2- (dimethylamino)ethylamino)pyridine-3-sulfonamide (21.0 mg, 19%). 1H NMR (400 MHz, DMSO-J6) δ 8.76 (br s, IH), 8.63 (d, IH), 8.07 (dd, IH), 7.40 (m, IH), 7.34 (m, IH), 7.28 (d, 2H), 7.14 (m, 4H), 6.47 (d, IH), 6.12 (m, IH), 3.75 (s, 6H), 3.35 (m, 2H), 3.14 (m, 2H), 2.74 (s, 6H). MS (EI) m/z for C25H29N7O4S: 524.1 (MH+).
[00284] Example 10: /V-(3-(3,5-dimethoxyphenylamino)quinoxaIin-2-yl)-6- (dimethylamino)pyridine-3-sulfonamide was prepared using procedures similar to those used in Example 9. 1H NMR (400 MHz, DMSO-J6) δ 12.00 (br s, IH), 8.92 (br s, IH), 8.74 (d, IH), 8.10 (dd, IH), 7.38 (br s, IH), 7.54 (m, IH), 7.33 (m, 4H), 6.70 (d, IH), 6.22 (s, IH), 3.77 (s, 6H), 3.08 (s, 6H). MS (EI) m/z for C23H24N6O4S: 481.1 (MH+).
Example 11
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)- ethoxy)pyridine-3-sulfonamide
Figure imgf000379_0001
[00285] N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (100 mg, 0.21 mmol), prepared using procedures similar to those described above in Example 1, 2-(dimethylamino)ethanol (50 μL, 0.50 mmol) and dry DMF were combined and 60% NaH in oil (80 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2- (dimethylamino)ethoxy)pyridine-3-sulfonamide (23 mg, 21%). 1H ΝMR (400 MHz, DMSO-J6) δ 8.78 (d, IH), 8.73 (s, IH), 8.38 (dd, IH), 7.40 (dd, IH), 7.31 (m, 3H), 7.14 (m, 2H), 6.85 (d, IH), 6.12 (m, IH), 4.56 (m, 2H), 3.76 (s, 6H), 3.43 (m, 2H), 2.77 (s, 6H). MS (EI) m/z for C25H28N6O5S: 525.1 (MH+).
Example 12
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo-l,6-dihydropyridine-
3-sulfonamide
Figure imgf000379_0002
[00286] N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (220 mg, 0.47 mmol), prepared using procedures similar to those described above in Example 8, DMSO (5 mL), and 3N NaOH (5 mL) are combined and heated to 100 0C overnight with stirring. Upon cooling to room temperature, the reaction mixture was diluted with H2O and the pH was adjusted to 7.0 with IN HCl. The resulting solid was filtered, washed with H2O, and air-dried. The solid was then sonicated in EtOAc, filtered, washed with EtOAc, and dried under high vacuum to give N-(2>-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo- 1 ,6-dihydropyridine-3-sulfonamide ( 190 mg, 90%). 1H NMR (400 MHz, DMSO-J6) δ 12.23 (br s, IH), 12.10 (br s, IH), 8.97 (s, IH), 8.23 (s, IH), 7.95 (m, 2H), 7.59 (m, IH), 7.37 (m, 4H), 6.43 (d, IH), 6.25 (s, IH), 3.77 (s, 6H). MS (EI) m/z for C2iH,9N5O5S: 454.0 (MH+).
[0185] Example 13: yV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-6- oxo-l,6-dihydropyridine-3-sulfonamide. The title compound was prepared according to the above Example 12. 1H NMR (400 MHz, DMSO-J6) δ 12.22 (br s, IH), 12.10 (br s, IH), 9.16 (s, IH), 8.60 (s, IH), 8.14 (d, IH), 7.94 (m, IH), 7.85 (dd, IH), 7.62 (m, IH), 7.40 (m, 3H) 6.69 (dd, IH), 6.43 (d, IH), 3.81 (s, 3H). MS (EI) m/z for C20Hi6ClN5O4S: 456.0 (MH").
Example 14 3-amino-7V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide.
Figure imgf000380_0001
Figure imgf000380_0002
[00287| W-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. A flask was charged with N-(3-chloroquinoxalin-2-yl)-3- nitrobenzenesulfonamide (5 g, 13.7 mmol), prepared using procedures similar to those in Example 1, 3,5-dimethoxyaniline (4.2 g, 27.4 mmol), and 80 mL of xylene. The reaction mixture was stirred under an N2 atmosphere at 150 0C for 3 hours, after which time, solvent was removed on a rotary evaporator, and 10 mL of Dichloromethane and 50 mL of methanol were added. The slurry was heated to reflux and filtered while hot, resulting in 4.6 g (69.7 %) of N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide MS (EI) m/z for C22Hi9N5O6S: 482.2 (MH+).
Example 153-amino-7V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)benzenesulfonamide
Figure imgf000381_0001
[00288] A flask was charged with N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)- 3-nitro-benzenesulfonamide (3.4g, 7.06 mmol), prepared using procedures similar to those in Example 14, tin chloride solvate (6.4 g, 28.2 mmol), and 30 mL of DMA. A few drops of water were added and the reaction mixture was stirred at 80 0C for 3 hours, after which time, solvent was removed on a rotary evaporator, and 50 mL of water and 10 mL of Methanol were added. The slurry was filtered, and the filtrate was washed with MeOH, water, and diethyl ether (20 mL of each), resulting in 3.25 g 3-amino-N-(3-(3,5- dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 12.2 (br s, IH), 8.85 (s, IH), 7.90 (br s, IH), 7.50-7.60 (m, IH), 7.3-7.4 (m, 4H), 7.2 (m, 3H), 6.74 (m, IH), 6.24 (m, IH), 5.56 (br s, 2H), 3.76 (s, 6H). MS (EI) m/z for C22H21N5O4S: 452.0 (MH+). [00289] The following compounds were made using procedures similar to those used in Example 15.
Example 16: Proceeding as above, 3-amino-/V-(3-(2,5-dimethoxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide was prepared. 1H NMR (400 MHz, DMSO) δ 12.4 (br s, IH), 9.20 (s, IH), 8.56 (d, IH), 7.95 (d, IH), 7.62 (m, IH), 7.38 (m, 2H), 7.24 (q, 2H), 7.14 (d, IH), 6.98 (d, IH), 6.8 (m, IH), 6.60 (m, IH), 5.6 (br s, 2H), 3.78 (d, 6H). MS (EI) m/z for C22H21N5O4S: 452.3 (MH+).
Example 17: Proceeding as above, 3-amino-/V-(3-(2-chloro-5-hydroxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide was prepared. MS (EI) m/z for C20H16ClN5O3S 1.0 x C2H1O2F3: 442.2, 444.2 (MH+).
Example 18: Proceeding as above, 3-amino-./V-(3-(6-methoxyquinolin-8- yIamino)quinoxalin-2-yl)benzenesulfonamide was prepared. MS (EI) m/z for C24H20N6O3S: 473.0 (MH+).
Example 19: 3-amino-/V-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C21H18FN5O3S: 439.99 (MH+).
Example 20: 3-amino-/V-(3-(2-chIoro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C2iH18ClN5O3S: 457.02 (MH+).
Example 21 : 3-amino-/V-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C22H21N5O3S: 436.32 (MH+).
Example 22a and Example 22b
3-amino-iV-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)benzenesulfonamide and 3-amino-/V-(3-(3-amino-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide
Figure imgf000382_0001
[00290] To a mixture of N-(3-{[3-(methyloxy)-5-nitrophenyl]amino}quinoxalin-2-yl)- 3-nitrobenzenesulfonamide (400 mg), THF (2 mL) and EtOH (2 niL) was added formic acid (938 μL), potassium formate (203 mg). After the mixture was flushed with N2, 10%wt PdVC (50 mg) was added. The resulting mixture was heated at 60 0C with stirring. LC/MS analysis indicated that the reaction mixture contained the complete reduced di- amino compound as the major product and the partially reduced mono-amino compound as a minor product. A portion of the crude mixture was purified by HPLC to give the two products. Product A: 3-amino-N-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2- yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 12.2 (br s, IH), 9.51 (s, IH), 8.77 (s, IH), 8.21 (s, IH), 7.92 (s, IH), 7.48 (m, IH), 7.43-7.38 (m, 3H), 7.24-7.16 (m, 3H), 6.75 (d, IH), 5.57 (br s, 2H), 3.90 (s, 3H). MS (EI) for C2iHi8N6O5S: 467.00 (MH+). Product B: 3-amino-N-(3-(3-amino-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 12.0 (br. s, IH), 8.53 (s, IH), 7.84 (s, IH), 7.56 (d, IH), 7.37-7.30 (m, 2H), 7.21-7.17 (m, 3H), 6.87 (s, IH), 6.81 (s, IH), 6.74 (br s, 2H), 5.91 (s, IH), 5.56 (br s, 3H), 3.69 (s, 3H). MS (EI) for C2IH20N6O3S: 437.2 (MH+).
Example 23a and Example 23b
7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3-(hydroxyamino)- benzenesulfonamide and 3-amino-N-(3-{[3,5-(dimethoxy)phenyl]amino}quinoxalin-
2-yl)benzenesulfonamide
Figure imgf000383_0001
[00291] To a solution jV-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)- 3-nitrobenzenesulfonamide (1.3g) in 20 mL of THF and 10 mL of MeOH was added 10%wt Pd/C (100 mg). The mixture was stirred under a H2 balloon overnight. A portion of the reaction mixture was taken out and filtered, then purified by HPLC to afford two products. Product A: N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3- (hydroxyamino)benzenesulfonamide. MS (EI) for C22H2|N5O5S: 468.1 (MH+). Product B: 3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 12.2 (br s, IH), 8.85 (s, IH), 7.90 (br s, IH), 7.50-7.60 (m, IH), 7.3-7.4 (m, 4H), 7.2 (m, 3H), 6.74 (m, IH), 6.24 (m, IH), 5.56 (br s, 2H), 3.76 (s, 6H). MS (EI) for C22H2,N5O4S: 452.0 (MH+).
Example 24
(S)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)propanamide hydrochloride.
Figure imgf000384_0001
[00292] (5)-fe/-/-butyl l-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yI)sulfamoyl)phenylamino)-l-oxopropan-2-ylcarbamate. 3-amino-N-(3-(3,5- dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide (1.1 mmol, 500 mg), prepared using procedures similar to those described above in Example 15, (L)-Boc-Ala- OH (1.5 mmol, 284 mg), dichloromethane (15 mL), DMF (10 mL), DIEA (2 mmol, 330 μL), and HATU (2 mmol, 760 mg) stirred at room temperature over night. The crude mixture was column purified using 1/1 ethyl acetate/hexanes on silica to gave 160 mg. [00293] (5)-2-amino-7V-(3-(7V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)propanamide hydrochloride. 4 N HCl is dioxane (10 mL) was added to a solution of (S)-tert-buty\ l-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin- 2-yl)sulfamoyl)phenylamino)-l-oxopropan-2-ylcarbamate (160 mg) and DCM (15 mL). The mixture was stirred at room temperature for 3 hours. The solvent decanted and ether added to the solid, ether decanted to gave 80 mg product as HCl salt. 1H NMR (400 MHz, CD3OD) δ 8.50-8.49 (t, IH), 7.89-7.87 (m, IH), 7.74-7.72 (m, IH), 7.61-7.5 (m, 3H), 7.40-7.36 (m, 2H), 7.21-7.20 (d, 2H), 6.23-6.21 (t, IH), 4.09-4.03 (q, IH), 3.78 (s, 6H), 1.60-1.58 (d, 3H); MS (EI) m/z for C25H26N6O5S-HCl: 523.1 (MH+). [00294] The following compounds were prepared as the free amine and/or HCl salt using procedures similar to those in Example 24. Where the deprotection step is not necessary, Step B in the above scheme was not preformed.
Example25: vV-(2-chloro-5-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyI)-2-(methyIamino)acetamide. The title compound was prepared according to the Examples above. 1H NMR (400 MHz, DMSO-J6) δ 10.50 (s, IH), 9.14 (s, IH), 9.03 (m, 2H), 8.63 (d, IH), 8.44 (d, IH), 7.98 (m, IH), 7.91 (dd, IH), 7.80 (d, IH), 7.67 (m, IH), 7.44 (m, 3H), 6.71 (dd, IH), 4.06 (m, 2H), 3.83 (s, 3H), 2.64 (t, 3H). MS (EI) m/z for C24H22Cl2N6O4S: 561.0 (MH+).
Example 26: (5)-2-amino-iV-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin- 2-yl)sulfamoyl)phenyl)propanamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 8.72-8.71 (d, IH), 8.48-8.46 (t, IH), 7.86-7.84 (m, IH), 7.80-7.78 (m, IH), 7.63-7.59 (m, 2H), 7.58-7.55 (t, IH), 7.41-7.38 (m, 2H), 7.24-7.22 (d, IH), 6.60-6.58 (dd, IH), 4.10-4.04 (q, IH), 3.83 (s, 3H), 1.61-1.60 (d, 3H); MS (EI) m/z for C24H23ClN6O4S-HCl: 527.2 (MH+).
Example 27: (S)-2-amino-/V-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin- 2-yl)sulfamoyl)phenyl)butanamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 8.74-8.73 (d, IH), 8.80-8.47 (t, IH), 7.87-7.85 (m, IH), 7.80-7.78 (m, IH), 7.67-7.61 (m, 2H), 7.59-7.55 (t, IH), 7.42-7.39 (m, 2H), 7.26-7.24 (d, IH), 6.62-6.59 (dd, IH), 3.96-3.93 (t, IH), 3.84 (s, 3H), 2.02-1.94 (m, 2H, 1.09-1.06 (t, 3H); MS (EI) m/z for C25H25ClN6O4S-HCl: 541.3 (MH+). Example 28: (5)-N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 8.78-8.77 (d, IH), 8.47-8.46 (t, IH), 7.87-7.85 (m, IH), 7.80-7.75 (m, IH), 7.69-7.65 (m, 2H), 7.59-7.55 (t, IH), 7.45-7.41 (m, 2H), 7.31-7.28 (d, IH), 6.65-6.63 (dd, IH), 4.42-4.38 (m, IH), 3.86 (s, 3H), 3.48-3.42 (m, 2H), 2.55-2.49 (m, IH), 2.18-2.08 (m, 3H); MS (EI) m/z for C26H25ClN6O4S-HCl: 553.3 (MH+). Exmaple 29: (S)-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 10.62 (br s, IH), 8.50-8.49 (t, IH), 7.90-7.87 (m, IH), 7.76-7.73 (m, IH), 7.63-7.58 (m, 3H), 7.43-7.35 (m, 2H), 7.14 (s, 2H), 6.27-6.26 (t, IH), 4.43-4.38 (m, IH), 3.78 (s, 6H), 3.48-3.41 (m, IH), 3.40-3.36 (m, 1H(, 2.54-2.48 (m, IH), 2.19-2.05 (m, 3H); MS (EI) m/z for C27H28N6O5S-HCl: 549.3 (MH+).
Example 30: (R)-2-amino-7V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-hydroxypropanamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 8.49-8.48 (t, IH), 7.89-7.87 (m, IH), 7.75-7.72 (m, IH), 7.65-7.62 (m, 2H), 7.62-7.55 (t, IH), 7.44-7.38 (m, 2H), 7.23-7.22 (d, 2H), 6.27-6.26 (t, IH), 4.07-4.05 (m, IH), 3.99-3.93 (m, 2H), 3.80 (s, 6H); MS (EI) m/z for C25H26N6O6S HCl: 539.1 (MH+). Example 31: /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)piperidine-3-carboxamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 8.79-8.78 (d, IH), 8.45 (m, IH), 7.83-7.81 (d, IH), 7.76-7.74 (m, IH), 7.636 (m, 2H), 7.54-7.50 (t, IH), 7.41 (m, 2H), 7.30-7.28 (d, IH), 6.65-6.62 (dd, IH), 3.86 (s, 3H), 3.40-3.32 (m, 2H), 3.20-3.13 (m, 3H), 2.93 (m, IH), 2.15-2.11 (m, IH), 1.98-1.93 (m, 2H), 1.83 (m, IH); MS (EI) m/z for C27H27ClN6O4S HCl: 567.3 (MH+). Example32: (5)-2-amino-/V-(3-(/V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)butanamide hydrochloride. MS (EI) m/z for C26H28N6O5S HCl: 537.1 (MH+).
Example 33: (R)-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamide hydrochloride. MS (EI) m/z for C27H28N6O5S-HCl: 549.1 (MH+). Example 34: (R)-N-(3-(iV-(3-(2-chloro-5-methoxy-phenyIamino)quinoxalin-2- yl)suIfamoyl)phenyI)pyrrolidine-2-carboxamide hydrochloride. MS (EI) m/z for C26H25ClN6O4S-HCl: 553 (MH+).
Example 35: (R)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)propanamide. 1H NMR (400 MHz, DMSO-J6) δ 10.2 (br s, 1 H), 8.82 (s, 1 H), 8.27 (m, 1 H), 7.75 (m, 2 H), 7.33 (m, 5 H), 7.13 (m, 2 H), 6.14 (t, 1 H), 3.77 (s, 6 H), 1.39 (d, 3 H); MS (EI) m/z for C25H26N6O5S: 523 (MH+). Example 36:/V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide. 1H NMR (400 MHz, DMSO-J6) δ 10.6 (s, 1 H), 9.48 (s, 1 H), 8.95 (br s, 1 H), 8.75 (br s, 1 H), 8.19 (br s, 1 H), 7.77 (dd, 1 H), 7.69 (dd, 1 H), 7.41 (m, 4 H), 7.17 (m, 2 H), 6.60 (dd, 1 H), 3.91 (s, 2 H), 3.82 (s, 6 H), 2.62 (s, 3 H); MS (EI) m/z for C24H23ClN6O4S: 527 (MH+).
Example 37: (/?)-2-amino-7V-(3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin- 2-yl)sulfamoyI)phenyl)propanamide. 1H NMR (400 MHz, DMSO-J6) δ 10.5 (s, 1 H), 9.47 (s, 1 H), 8.95 (d, 1 H), 8.22 (d, 2 H), 8.14 (br s, 2 H), 7.76 (m, 2 H), 7.40 (m, 4 H), 7.17 (m, 2 H), 6.60 (m, 1 H), 3.97 (q, 1 H), 3.96 (s, 3 H), 1.45 (d, 3 H); MS (EI) m/z for C24H23ClN6O4S: 527 (MH+).
Example 38: 2-amino-7V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylpropanamide. 1H NMR (400 MHz, DMSO-J6) δ 10.1 (s, 1 H), 9.46 (s, 1 H), 8.95 (d, 1 H), 8.50 (br s, 1 H), 8.27 (m, 1 H), 7.81 (m, 2 H), 7.47 (m, 1 H), 7.37 (m, 3 H), 7.17 (m, 2 H), 6.61 (dd, 1 H), 3.83 (s, 3 H), 1.60 (s, 6 H); MS (EI) m/z for C25H25ClN6O4S: 541 (MH+).
Example 39: 2-amino-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylpropanamide. 1H NMR (400 MHz, DMSO-J6) δ 10.33 (s, 1 H), 8.89 (s, 1 H), 8.32 (br s, 4 H), 7.92 (m, 3 H), 7.59 (m, 2 H), 7.37 (m, 4 H), 6.24 (s, 1 H), 3.76 (s, 6 H), 1.61 (s, 6 H); MS (EI) m/z for C26H28N6O5S: 537 (MH+). Example 40: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2-yl)sulfamoyl)-4- methylphenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz, DMSO-J6) δ 10.58 (s, 1 H), 9.80 (br s, 1 H), 8.85 (s, 1 H), 8.25 (s, 1 H), 7.67 (dd, 1 H), 7.30 (m, 7 H), 6.16 (m, 1 H), 4.02 (br s, 2 H), 3.77 (s, 6 H), 2.81 (s, 6 H), 2.54 (s, 3 H); MS (EI) m/z for C27H30N6O5S: 551 (MH+). Example 41 : 7V-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-((2-(dimethylamino)ethyl)(methyl)amino)acetamide. 1H
NMR (400 MHz, DMSO-J6) δ 10.0 (s, 1 H), 9.48 (s, 1 H), 8.96 (d, 1 H), 8.16 (m, 1 H),
7.76 (m, 2 H), 7.39 (m, 4 H), 7.17 (m, 2 H), 6.61 (dd, 1 H), 3.82 (s, 3 H), 3.40 (br s, 2 H),
2.94 (br s, 2 H), 2.71 (br t, 2 H), 2.60 (s, 6 H), 2.33 (s, 3 H); MS (EI) m/z for
C28H32CW7O4S: 598 (MH+).
Example 42: 2-amino-iV-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. 1H NMR (400 MHz, DMSO-J6) δ 10.5 (s, 1 H), 9.48
(s, 1 H), 8.94 (s, 1 H), 8.15 (s, 1 H), 8.06 (br s, 3 H), 7.74 (m, 2 H), 7.39 (m, 4 H), 7.18
(m, 2 H), 6.61 (dd, 1 H), 3.83 (s, 3 H), 3.77 (s, 2 H); MS (EI) m/z for C23H2 ,ClN6O4S:
513 (MH+).
Example 43 : yV-(3-(/V-(3-(2-acetyl-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz, DMSO-J6) δ 12.4 (s, 1 H), 10.5 (s, 1 H), 9.27 (s, 1 H), 8.25 (s, 1 H), 8.01 (d, 1 H), 7.82 (d, 1 H), 7.71
(d, 1 H), 7.42 (m, 3 H), 7.21 (m, 2 H), 6.63 (dd, 1H),3.91 (m, 5 H), 2.75 (s, 6 H), 2.61 (s,
3 H); MS (EI) m/z for C27H28N6O5S: 549 (MH+).
Example 44: N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)formamide. 1H NMR (400 MHz, DMSO-J6) δ 12.6 (s, 1 H), 10.5
(s, 1 H), 9.16 (s, 1 H), 8.53 (br s, 1 H), 8.35 (m, 2 H), 8.02 (s, 1 H), 7.56 (m, 7 H), 6.70
(dd, 1 H), 3.83 (s, 3 H); MS (EI) m/z for C22H18CUV5O4S: 484 (MH+).
Example 45: 2-amino-N-(5-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-2-methyIphenyl)acetamide. 1H NMR (400 MHz, DMSO-J6) δ 12.4 (s, 1
H), 10.1 (br s, 1 H), 8.82 (s, 1 H), 8.20 (m, 3 H), 7.82 (m, 1 H), 7.30 (m, 6 H), 6.20 (s, 1
H), 3.85 (s, 2 H), 3.77 (s, 6 H), 2.26 (s, 3 H); MS (EI) m/z for C25H26N6O5S: 523 (MH+).
Example 46: N-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methyl-2-(methylamino)propanamide. 1H NMR (400 MHz,
DMSO-J6) δ 10.09 (s, 1 H), 9.46 (s, 1 H), 8.95 (m, 3 H), 8.28 (s, 1 H), 7.81 (m, 2 H),
7.41 (m, 4 H), 7.17 (m, 2 H), 6.60 (dd, 1 H), 3.82 (s, 3 H), 2.53 (s, 3 H), 1.60 (s, 6 H);
MS (EI) m/z for C26H27ClN6O4S: 555 (MH+).
Example 47: (S)-/V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)propanamide. 1H NMR (400 MHz, DMSO-J6) δ 10.61 (s, 1 H), 9.47 (s, 1 H), 8.95 (s, 1 H), 8.82 (br s, 2 H), 8.27 (m, 1 H), 7.74 (m, 2
H), 7.42 (m, 4 H), 7.17 (m, 2 H), 6.60 (dd, 1 H), 3.90 (m, 1 H), 3.82 (s, 3 H), 2.59 (s, 3
H), 1.49 (d, 3 H); MS (EI) m/z for C25H25ClN6O4S: 541 (MH+).
Example 48: 3-amino-iV-(5-(7V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-2-methylphenyl)propanamide. 1H NMR (400 MHz, DMSO-^6) δ 12.25
(s, 1 H), 9.77 (s, 1 H), 8.82 (s, 1 H), 7.84 (m, 5 H), 7.50 (d, 1 H), 7.37 (m, 5 H), 6.22 (m,
1 H), 3.74 (s, 6 H), 3.08 (m, 2 H), 2.77 (m, 2 H), 2.27 (s, 3 H); MS (EI) m/z for
C26H28N6O5S: 537 (MH+).
Example 49: l-amino-iV-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-^6) δ 9.54 (br s, 1 H), 9.42 (s, 1 H), 8.91 (s, 1 H), 8.21 (s, 1 H), 8.20 (br s, 2 H), 7.81 (m, 2
H), 7.48 (m, 4 H), 7.22 (m, 2 H), 6.61 (dd, 1 H), 3.82 (s, 3 H), 1.63 (m, 2 H), 1.26 (m, 2
H); MS (EI) m/z for C25H23ClN6O4S: 539 (MH+).
Example 50: (_S)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-
2-yl)sulfamoyl)phenyl)-6-(dimethylamino)hexanamide. 1H NMR (400 MHz, DMSO- d6) δ 9.47 (br s, 1 H), 8.95 (d, 1 H), 8.26 (m, 1 H), 7.73 (m, 2 H), 7.30 (m, 4 H), 7.26 (m,
4 H), 7.16 (m, 2 H), 6.59 (dd, 1 H), 3.82 (s, 3 H), 3.34 (m, 1 H), 2.20 (m, 2 H), 2.09 (s, 6
H), 1.50 (m, 6 H); MS (EI) m/z for C29H34ClN7O4S: 610 (MH+).
Example 51 : l-amino-iV-(3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopentanecarboxamide. 1H ΝMR (400 MHz, DMSO-^6) δ 10.12 (br s, 1 H), 9.46 (s, 1 H), 8.95 (d, 1 H), 8.26 (m, 1 H), 8.16 (m, 3 H), 7.84 (m, 2
H), 7.35 (m, 6 H), 6.60 (dd, 1 H), 3.82 (s, 3 H), 2.34 (m, 2 H), 1.91 (m, 6 H); MS (EI) m/z for C27H27ClN6O4S: 567 (MH+).
Example 52: /V-(5-(7V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyI)-2-methylphenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz,
DMSO-^6) δ 12.0 (br s, 1 H), 9.98 (s, 1 H), 9.43 (s, 1 H), 8.91 (m, 1 H), 8.08 (s, 1 H),
7.84 (dd, 1 H), 7.32 (m, 6 H), 6.61 (dd, 1 H), 4.07 (s, 2 H), 3.82 (s, 3 H), 2.82 (s, 6 H),
2.21 (s, 3 H); MS (EI) m/z for C26H27ClN6O4S: 555 (MH+).
Example 53: l-amino-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclobutanecarboxamide. 1H NMR (400 MHz, DMSO-(Z6) δ 10.34 (br s, 1 H), 8.81 (s, 1 H), 8.49 (br s, 3 H), 8.34 (s, 1 H), 7.83 (m, 2 H), 7.43 (m, 3 H), 7.31 (m, 2 H), 7.16 (m, 2 H), 6.16 (s, 1 H), 3.77 (s, 6 H), 2.83 (m, 2 H), 2.25 (m, 3 H), 2.05 (m, 1 H); MS (EI) m/z for C27H28N6O5S: 549 (MH+). Example 54: /V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(3-(2- (dimethylamino)ethyl)ureido)benzenesulfonamide. 1H NMR (400 MHz, DMSO-J6) δ 8.91 (br s, 1 H), 8.81 (s, 1 H), 8.08 (s, 1 H), 7.60 (s, 1 H), 7.38 (m, 9 H), 6.28 (m, 1 H),
6.15 (s, 1 H), 3.78 (s, 6 H), 3.40 (m, 2 H), 3.08 (m, 2 H), 2.74 (s, 6 H); MS (EI) m/z for C27H3 IN7O5S: 566 (MH+).
Example 55: l-amino-7V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopentanecarboxamide. 1H NMR (400 MHz, DMSO-J6) δ 12.40 (br s, 1 H), 10.58 (s, 1 H), 8.46 (m, 4 H), 7.80 (m, 3 H), 7.59 (m, 2 H), 7.34 (m, 4
H), 6.25 (m, 1 H), 3.76 (s, 6 H), 2.35 (m, 2 H), 1.90 (m, 8 H); MS (EI) m/z for
C28H30N6O5S: 563 (MH+).
Example 56: l-amino-./V-(3-(./V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-J6) δ 9.54 (br s, 1 H), 8.84 (s, 1 H), 8.29 (s, 1 H), 7.75 (m, 2 H), 7.39 (m, 6 H), 7.17 (m, 2 H),
6.16 (m, 1 H), 3.78 (s, 6 H), 1.52 (m, 2 H), 1.17 (m, 2 H); MS (EI) m/z for C26H26N6O5S: 535 (MH+).
Example 57: 2-(dimethylamino)ethyl 3-(N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenylcarbamate. 1H NMR (400 MHz, DMSO-J6) δ 9.78 (br s, 1 H), 8.79 (s, 1 H), 8.19 (s, 1 H), 7.66 (d, 1 H), 7.31 (m, 9 H), 6.14 (m, 1 H), 4.17 (t, 2 H), 3.78 (s, 6 H), 2.54 (t, 2 H), 2.21 (s, 6 H): MS (EI) m/z for C27H30N6O6S: 567 (MH+).
Example 58: 4-amino-/V-(3-(Λr-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)tetrahydro-2H-pyran-4-carboxamide. 1H NMR (400 MHz, DMSO-J6) δ 12.2 (br s, 1 H), 10.6 (s, 1 H), 8.74 (m, 5 H), 7.93 (m, 2 H), 7.47 (m, 6 H), 6.24 (m, 1 H), 3.77 (m, 10 H), 2.45 (m, 2 H), 1.81 (m, 2 H); MS (EI) m/z for C28H30N6O6S: 579 (MH+).
Example 59: Λf-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-Λ3-(2- (dimethylamino)ethyl)benzene-l,3-disulfonamide. 1H NMR (400 MHz, DMSO-J6) δ 9.35 (m, 2 H), 8.92 (m, 1 H), 8.64 (s, 1 H), 8.30 (m, 1 H), 8.1 1 (s, 1 H), 7.86 (m, 1 H), 7.68 (m, 1 H), 7.49 (s, 1 H), 7.42 (m, 2 H), 7.21 (m, 2 H), 6.61 (m, 1 H), 3.82 (s, 3 H),
3.05 (m, 4 H), 2.74 (s, 6 H); MS (EI) m/z for C25H27ClN6O5S2: 591 (MH+).
Example 60: ΛH3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-/V3-(3-
(dimethylamino)propyl)benzene-l,3-disulfonamide. 1H NMR (400 MHz, DMSO-^6) δ 9.38 (m, 2 H), 8.90 (m, 1 H), 8.60 (s, 1 H), 8.32 (m, 1 H), 8.12 (s, 1 H), 7.88 (m, 1 H),
7.72 (m, 1 H), 7.59 (s, 1 H), 7.40 (m, 2 H), 7.20 (m, 2 H), 6.67 (m, 1 H), 3.82 (s, 3 H),
2.97 (m, 2 H), 2.78 (m, 2 H), 2.71 (s, 6 H), 1.70 (m, 2 H); MS (EI) m/z for
C26H29ClN6O5S2: 605 (MH+).
Example 61 : 7V-(3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-4-methylphenyl)-2-(methylamino)acetamide. MS (EI) m/z for C25H25
ClN6O4S: 541.0 (MH+).
Example 62: (S)-2-amino-/V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-
2-yl)suIfamoyl)-4-methylphenyl)propanamide. MS (EI) m/z for C25H25 ClN6O4S:
541.2 (MH+).
Example 63 : (R)-2-amino-/V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-
2-yl)sulfamoyl)-4-methyIphenyl)propanamide. MS (EI) m/z for C25H25 ClN6O4S:
541.0 (MH+).
Example 64: (S)--/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)propanamide. MS (EI) m/z for C26H28N6O5S:
537.1 (MH+).
Example 65: (R)-jV-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)phenyl)-2-(methylamino)propanamide. MS (EI) m/z for C25H25
ClN6O4S: 541.1(MH+).
Example 66: (/?)-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)propanamide. MS (EI) m/z for C26H28N6O5S:
537.3 (MH+).
Example 67: /V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)piperidine-2-carboxamide. MS (EI) m/z for C28H30N6O5S: 563.1
(MH+). Example 68: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyI)phenyl)-2-(2-(dimethylamino)ethylamino)acetamide. MS (EI) m/z for
C28H33N7O5S: 580.1 (MH+).
Example 69: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-(methylamino)piperidin-l-yl)acetamide. MS (EI) m/z for
C30H35N7O6S: 606.1 (MH+).
Example 70: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-(dimethylamino)piperidin-l-yl)acetamide. MS (EI) m/z for
C31H37N7O5S: 620.1 (MH+).
Example 71: /V-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz, DMSO) δ
12.4 (br s, IH), 10.9 (s, IH), 9.8 (s, IH), 8.9 (s, IH), 8.3 (br s, IH), 7.9 (d, 2H), 7.8 (d,
IH), 7.6 (t, 2H), 7.4 (q, 2H), 7.3 (s, IH), 6.25 (s, IH), 4.15 (s, 2H), 3.8 (s, 6H), 2.9 (s,
6H). MS (EI) m/z for C26H28N6O5S 2.0 x C2HiO2F3: 537.1 (MH+).
Example 72 : /V-(3-(/V-(3-(2-chloro-5-methoxy-phenyIamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(ethylamino)acetamide. 1H NMR (400 MHz, DMSO) δ 10.8
(s, IH), 9.20 (s, IH), 8.84 (br s, 2H), 8.64 (br s, IH), 8.30 (s, IH), 7.9-8.0 (br s, IH), 7.80
(t, 2H), 7.55-7.68 (m, 2H), 7.4 (d, 3H), 6.70 (m, IH), 3.97 (br s, 2H), 3.83 (s, 3H), 3.04
(br s, 2H), 1.3 (t, 3H). MS (EI) m/z for C25H25ClN6O4S 2.0 x C2H1O2F3: 541.3, 543.2
(MH+).
Example 73: 2-(azetidin-l-yl)-/V-(3-(N-(3-(2-chloro-5- methoxyphenyIamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. 1H NMR (400
MHz, DMSO) δ 10.8 (s, IH), 10.2 (s, IH), 9.2 (s, IH), 8.7 (s, IH), 8.3 (s, IH), 7.9-8.0 (br s, IH), 7.80 (d, IH), 7.72 (d, IH), 7.65 (br s, IH), 7.56 (t, IH), 7.40 (d, 3H), 6.70 (m,
IH), 4.28 (s, 2H), 4.15 (m, 4H), 3.82 (s, 3H), 2.32 (br s, IH). MS (EI) m/z for
C26H25ClN6O4S 2.0 x C2H1O2F3: 553.3, 555.2 (MH+).
Example 74: N-(3-(N-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide. The title compound was prepared according to the Examples above. 1H NMR (400 MHz, DMSO) δ 10.6 (s, IH), 9.5 (s,
IH), 8.95 (d, IH), 8.18 (t, IH), 7.78 (m, IH), 7.70 (m, IH), 7.54 (d, IH), 7.46 (m, IH), 7.38 (t, IH), 7.32 (d, IH), 7.12-7.22 (m, 2H), 6.56 (m, IH), 3.90 (s, 2H), 3.82 (s, 3H), 2.62 (s, 3H). MS (EI) m/z for C24H23BrN6O4S: 572.77, 570.90 (MH+). Example 75: 2-(dimethylamino)-Λ'-(3-(ΛL(3-(6-methoxy-quinolin-8- ylamino)quinoxalin-2-yl)sulfamoyl)phenyI)acetamide. The title compound was prepared according to the Examples above. 1H NMR (400 MHz, DMSO) δ 10.9 (s, IH), 10.6 (s, IH), 9.13 (s, IH), 8.80 (d, IH), 8.26-8.30 (m, 2H), 7.85 (d, IH), 7.70 (d, IH), 7.60 (q, IH), 7.54 (m, IH), 7.44 (t, 2H), 7.20 (t, 2H), 6.80 (d, IH), 4.00 (s, 2H), 3.94 (s, 3H), 2.78 (s, 6H). MS (EI) m/z for C28H27N7O4S: 558.3 (MH+). Example 76: 7V-(3-(7V-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz, DMSO) δ 10.6 (s, IH), 9.4 (s, IH), 8.9 (s, IH), 8.25 (s, IH), 7.78 (d, IH), 7.70 (d, IH), 7.54 (d, IH), 7.48 (d, IH), 7.40 (t, 2H), 6.56 (d, IH), 4.02 (s, 2H), 3.82 (s, 3H), 2.80 (s, 6H). MS (EI) m/z for C25H25BrN6O4S: 586.79, 584.91 (MH+).
Example 77: /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-nuoroethylamino)acetamide. 1H NMR (400 MHz, DMSO) δ 10.6 (s, IH), 9.4 (s, IH), 8.9 (d, IH), 8.20 (s, IH), 7.78 (d, IH), 7.70 (d, IH), 7.48 (m, IH), 7.36-7.44 (m, 3H), 7.20 (q, 3H), 6.6 (m, IH), 4.78 (t, IH), 4.66 (t, IH), 3.94 (s, 2H), 3.82 (s, 3H), 3.4 (t, IH), 3.3 (t, IH). MS (EI) m/z for C25H24ClFN6O4S: 559.2, 561.2 (MH+).
Example 78: iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)formamide. 1H NMR (400 MHz, DMSO) δ 12.4 (br s, IH), 10.5 (s, IH), 8.90 (s, IH), 8.3 (s, IH), 7.9 (br s, IH), 7.85 (d, IH), 7.75 (d, IH), 7.5-7.6 (m, 2H), 7.3-7.4 (m, 4H), 6.2 (s, IH), 3.8 (s, 3H). MS (EI) m/z for C23H21N5O5S: 480.1 (MH+).
Example 79: /V-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-(dimethyIamino)azetidin-l-yl)acetamide. 1H NMR (400 MHz, DMSO) δ 10.2 (br s, IH), 9.5 (s, IH), 8.95 (d, IH), 8.2 (s, IH), 7.75 (d, IH), 7.65 (d, IH), 7.45 (d, IH), 7.40 (d, IH), 7.30-7.35 (t, IH), 7.1-7.2 (q, 2H), 6.60 (m, IH), 3.82 (s, 3H). MS (EI) m/z for C28H30ClN7O4S: 480.1 (MH+). Example 80: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2-(pyrrolidin-l-yl)acetamide. MS (EI) m/z for C28H30NOO5S:
563.18 (MH+).
Example 81 : N-(3-(jV-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyI)phenyl)-2-(ethyl(methyI)amino)acetamide. 1H NMR (400 MHz,
DMSO) δ 12.0 (s, IH), 10.6 (s, IH), 9.65 (s, IH), 9.5 (s, IH), 8.95 (s, IH), 8.25 (s, IH),
7.8 (d, IH), 7.70 (d, IH), 7.45-7.50 (d, IH), 7.3-7.4 (m, 3H), 7.2 (t, 2H), 6.60 (d, IH),
4.02 (br s, 2H), 3.82 (s, 3H), 3.14 (br s, 2H), 2.80 (s, 3H) 1.2 (t, 3H). MS (EI) m/z for
C26H27ClN6O4S: 555.2, 557.3 (MH+).
Example 82: 7V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2-(3-(piperidin-l-yl)azetidin-l-yl)acetamide. MS (EI) m/z for
C3IH34ClN7O4S 2.0 x C2H1O2F3: 636.3, 638.3 (MH+).
Example 83: /V-(3-(/V-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide. MS (EI) m/z for C24H23FN6O4S:
511.04 (MH+).
Example 84: iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-methylpiperidine-4-carboxamide. MS (EI) m/z for
C29H32N6O5S 1.0 x C2H4O2: 577.2 (MH+).
Example 85: /V-(3-(/V-(3-(3-methoxyphenylamino)quiiioxalin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide. 1H NMR (400 MHz, DMSO) δ
10.6 (s, IH), 8.82 (s, IH), 8.22 (t, IH), 7.86 (t, IH), 7.76 (m, IH), 7.66 (m, IH), 7.46 (m,
IH), 7.41 (m, IH), 7.38 (t, IH), 7.28 (m IH), 7.24 (t, IH), 7.12 (m, 2H), 6.56 (d, IH),
3.88 (s, 2H), 3.80 (s, 3H), 2.60 (s, 3H). MS (EI) m/z for C24H24N6O4S: 492.99 (MH+).
Example 86: /V-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2,2,2-trifluoroethylamino)acetamide. 1H NMR (400 MHz,
DMSO) δ 10.4 (s, IH), 9.2 (s, IH), 8.65 (s, IH), 8.4 (s, IH), 8.00 (m, IH), 7.80 (d, IH),
7.75 (d, IH), 7.65 (q, IH), 7.55 (t, IH), 7.40-7.5 (m, 3H), 6.7 (m, IH), 3.82 (s, 3H), 3.62
(br s, 2H), 3.55 (br d, 2H). MS (EI) m/z for C25H22ClF3N6O4S 1.0 x C2HiO2F3: 595.0,
597.0 (MH+). Example 87: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-(piperidin-l-yI)propanamide. MS (EI) m/z for C30H34NeOsS:
591.2 (MH+).
Example 88: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-(dimethylamino)butanamide. MS (EI) m/z for C28H32N6O5S
1.0 x C2H4O2: 565.2 (MH+).
Example 89: 2-(dimethylamino)-/V-(3-(iV-(3-(3-fluoro-5-methoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. 1H NMR (400 MHz,
DMSO) δ 10.9 (s, IH), 9.8 (br s, IH), 9.1 (s, IH), 8.34 (s, IH), 7.90 (d, IH), 7.76 (d, IH),
7.52-7.68 (m, 4H), 7.40 (m, 2H), 6.54 (m, IH), 4.16 (s, 2H), 3.82 (s, 3H), 2.86 (s, 6H).
MS (EI) m/z for C25H25FN6O4S: 525.05 (MH+).
Example 90: /V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(piperidin-l-yl)acetamide. MS (EI) m/z for C^H32N6O5S:
577.37 (MH+).
Example 91 : 2-(dimethylamino)-/V-(3-(7V-(3-(3-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. 1H NMR (400 MHz, DMSO) δ 10.5 (s, IH), 8.8 (s,
IH), 8.25 (s, IH), 7.83 (t, IH), 7.76 (d, IH), 7.64 (d, IH), 7.3-7.48 (m, 4H), 7.22 (t, IH),
7.12 (t, 2H), 6.56 (m, IH), 3.96 (s, 2H), 3.78 (s, 3H), 2.76 (s, 6H). MS (EI) m/z for
C25H26N6O4S: 507.1 (MH+).
Example 92 : /V-(3-(N-(3-(2-chloro-5-hydroxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide. 1H NMR (400 MHz, DMSO) δ
10.8 (s, IH), 9.9 (s, IH), 9.8 (s, IH), 9.1 (s, IH), 8.55 (s, IH), 8.34 (s, IH), 7.9-8.0 (br s,
IH), 7.82 (d, IH), 7.76 (d, IH), 7.52-7.66 (m, 2H), 7.42 (t, IH), 7.26 (d, IH), 6.50 (m,
IH), 4.16 (s, 2H), 2.86 (s, 6H). MS (EI) m/z for C24H23ClN6O4S: 527.1, 529.0 (MH+).
Example 93: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-morpholinoacetamide. MS (EI) m/z for C28H3oN606S: 579.1
(MH+).
Example 94: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z for C24H23N5O5S: 494.0 (MH+). Example 97: 2-amino-7V-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-4-methylphenyl)-2-methylpropanamide. MS (EI) m/z for
C26H27ClN6O4S: 556.12 (MH+).
Example 98: N-(3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(dimethylamino)acetamide. MS (EI) m/z for C25H25ClN6O4S:
542.05 (MH+).
Example 99: 2-amino-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxal-n-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z for C24H24N6O5S: 509.59 (MH+).
Example 100 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)benzoic acid
Figure imgf000396_0001
[00295] To a solution of N-(3-{[2-chloro-5-(methoxy)-phenyl]amino}quinoxalin-2- yl)-3-cyanobenzenesulfonamide (6.02 g, 12.95 mmol), prepared using procedures similar to those in Example 115 or Example 423, in methanol (20 mL) and 1,4-dioxane (20 mL) was added 6.0 N aqueous sodium hydroxide (40 mL) at room temperature. The solution was stirred at 90 0C for 3.5 h. The reaction was cooled to room temperature and neutralized slowly by adding 2.0 N hydrochloric acid until the pH of the solution became in the 2-3 range at 0° C. The solution was diluted with ethyl acetate (300 mL). The organic layer was washed with saturated aqueous sodium chloride (50 mL) and dried over magnesium sulfate. Filtration and concentration at reduced pressure afforded 3-{[(3-{[2-chloro-5-(methoxy)-phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoic acid (5.921 g, 94%). MS (EI) m/z for C22H17 ClN4O5S: 485.0 (MH+). [00296] The following compounds were preapred using procedures ismilar to those used in Example 100. Example 101: Proceeding as above, 3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-
2-yl)sulfamoyl)benzoic acid was prepared. MS (EI) m/z for C23H20N4O6S: 481.0
(MH+).
Example 102: 3-(/V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-methyI-l-(piperidin-l-yl)propan-2-yl)benzamide. MS (EI) m/z for C31H35ClN6O4S: 623.06 (MH+).
Example 103: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-methyl-l-oxo-l-(piperidin-l-yl)propan-2-yl)benzamide. MS (EI) m/z for C31H33ClN6O5S: 637.65 (MH+).
Example 104
3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-iV-[2-
(dimethy lam ino)ethy 1 ] benzamide
Figure imgf000397_0001
[00297] To a solution of 3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}benzoic acid (0.20 g, 0.42 mmol), prepared using procedures similar to Example 100, in dimethyl formamide (4 mL) were added 2-(7-aza-lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate ( ΗATU, 0.32 g, 0.83 mmol) and iV-ethyldiisopropylamine (DIEA, 0.13 g, 1.04 mmol) at room temperature. The reaction was stirred for 15 min before N, iV-dimethylethane- 1 ,2-diamine (73 mg, 0.83 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL), 1.0 N aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford 3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]benzamide (0.20 g, 87%) as yellow solid. MS (EI) m/z for C26H27
ClN6O4S: 555.1 (MH+).
[00298] The following compounds were prepared using procedures similar to those in
Example 104.
Example 105: 5-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-2-methoxybenzamide. 1H NMR (400 MHz,
DMSO-J6) δ 9.45 (s, IH), 8.95 (d, IH), 8.57 (d, IH), 8.28 (t, IH), 8.14 (dd, IH), 7.46
(dd, IH), 7.39 (m, 2H), 7.17 (m, 4H), 6.60 (dd, IH), 3.89 (s, 3H), 3.82 (s, 3H), 3.38 (m,
2H), 2.43 (m, 2H), 2.21 (s, 6H). MS (EI) m/z for C27H29ClN6O5S: 585.3 (MH+).
Example 106: 5-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-N-(2-(dimethylamino)ethyl)-2-fluorobenzamide. 1H NMR (400 MHz,
DMSO-J6) δ 9.40 (br s, IH), 9.16 (s, IH), 8.73 (m, IH), 8.67 (d, IH), 8.36 (dd, IH), 8.26
(m, IH), 7.94 (br s, IH), 7.66 (m, IH), 7.59 (t, IH), 7.43 (m, 3H), 6.71 (dd, IH), 3.83 (s,
3H), 3.62 (m, 2H), 3.27 (m, 2H), 2.85 (d, 6H). MS (EI) m/z for C26H26ClFN6O4S: 573.1
(MH+).
Example 107: 3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-
(dimethylamino)ethyl)benzamide. MS (EI) m/z for C27H30N6O5S: 551.1 (MH+).
Example 108: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-/V-methylbenzamide. MS (EI) m/z for
C27H29 ClN6O4S: 569.1 (MH+).
Example 109: 3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-
(dimethylamino)ethyl)-/V-methyIbenzamide. MS (EI) m/z for C28H32N6O5S: 565.1
(MH+).
Example 110: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)benzamide. MS (EI) m/z for C22H18 ClN5O4S: 484.0 (MH+).
Example 111: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-morpholinoethyl)benzamide. MS (EI) m/z for C28H29 ClN6O5S:
597.0 (MH+).
Example 112: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-/V-methyIbenzamide. MS (EI) m/z for C23H20 ClN5O4S: 498.0 (MH+). Example 113: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)-iV-morpholinobenzamide. MS (EI) m/z for C26H25 ClN6O5S: 569.0 (MH+).
Example 114
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-{5- [(dimethylamino)methyl]-l,3,4-oxadiazol-2-yl}benzenesulfonamide
Figure imgf000399_0001
[00299] To a solution of 3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin- 2-yl)amino]sulfonyl}benzoic acid (0.25 g, 0.52 mmol), prepared as described above in Example 100, in dimethylformamide (2.6 mL) were added 2-(7-aza-lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.25 g, 0.67 mmol) and N-ethyldiisopropylamine (DIEA, 0.11 g, 0.88 mmol) at room temperature. The reaction was stirred for 15 min before 2-(dimethylamino)acetohydrazide (78 mg, 0.67 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (30 mL), saturated aqueous sodium bicarbonate (30 mL), 1.0 N aqueous hydrochloric acid (20 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford 180 mg of a coupled intermediate which was then heated in phosphorus oxychloride (5 mL) at 100 OC for 4h. The reaction was cooled to room temperature and treated with ice water (50 mL) and extracted with dichloromethane (3 X 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a crude product which was subjected to reverse phase ΗPLC to afford vV-(3-{[2-chloro-5-(methoxy)- phenyl]amino}quinoxalin-2-yl)-3-{5-[(dimethylamino)methyl]- l,3,4-oxadiazol-2-yl}- benzenesulfonamide (16 mg, 5 %) as yellow solid. MS (EI) m/z for C26H24 ClN7O4S: 566.0 (MH+).
Example 115 N-(3-(3-methoxy-5-nitro-phenylamino)-quinoxalin-2-yI)-3-nitrobenzenesulfonamide
Figure imgf000400_0001
[00300] 7V-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide.
2,3-Dichloroquinoxaline (26.1 g, 131.1 mmol), m-Nitrobenzene sulfonamide (26.5 g, 131.1 mmol) and potassium carbonate (18.1 g, 131.1) were dissolved in anhydrous DMSO (500 mL). The reaction was heated to 150 °C for 2 h. The reaction mixture was poured into water (400 mL), followed by addition of 2M HCl (60 mL). The product was extracted with EtOAc (3 x 500 mL). The organic layers were combined and washed water (2 x 500 mL) and brine (2 x 500 mL). The product was then dried with sodium sulfate to give N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide. MS (EI) m/z for Ci4H9ClN4O4S: 364.94, 366.97 (MH+)
[00301] iV-(3-(3-methoxy-5-nitrophenylainino)quinoxalin-2-yl)-3-nitro- benzenesulfonamide. N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (700 mg, 1.92 mmol), 3-methoxy-5-nitroaniline (645 mg, 3.84 mmol) and p-xylene (7 mL) were combined and heated to 140°C, then stirred for 16 hours at 130 °C. The reaction was allowed to cool, placed in a sep. funnel, diluted with DCM, and washed with 2M HCl and brine and concentrated in vacuo. The resulting solid was washed with Et2O to give N-(3- (3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide (400 mg, 42%). MS (EI) m/z for C2IH16N6O7S: 496.94 (MH+).
[00302] The following compounds were prepared using procedures similar to those in Example 115. Example 116: jV-(3-(2-chIoro-5-methoxyphenylamino)quinoxalin-2-yl)-3- cyanobenzenesulfonamide. MS (EI) m/z for C22Hi6 ClN5O3S: 465.9 (MH+). Example 117: 3-cyano-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C23Hi9N5O4S: 462.3 (MH+). Example 118: /V-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- fluorobenzenesulfonamide. MS (EI) m/z for C22H19 FN4O4S: 456.0 (MH+). Example 119: 3-bromo-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C22H19 BrN4O4S: 516.9 (MH+). Example 120: 3-bromo-N-(3-(2,5-dimethoxy-phenylamino)quinoxaIin-2- yl)benzenesulfonamide. MS (EI) m/z for C22Hi9 BrN4O4S: 516.9 (MH+). Example 121: 7V-(3-(3-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide. MS (EI) m/z for C21H18N4O3S: 407.0 (MH+).
Example 122: iV-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C2,H,7FN4O3S: 425.0 (MH+). Example 123: 7V-(3-(2,5-dimethoxy-phenylamino)quinoxaIin-2-yl)-4- methoxybenzenesulfonamide. MS (EI) m/z for C23H22N4O5S: 467.0 (MH+). Example 124: 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yI)-4- methoxybenzenesulfonamide. MS (EI) m/z for C23H22N4O5S: 467.0 (MH+). Example 125: /V-(3-(4-chloro-3-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C2iH17ClN4O3S: 440.9 (MH+). Example 126: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)thiophene-2- sulfonamide. MS (EI) m/z for C20H18N4O4S2: 443.0 (MH+). Example 127: /V-(3-(6-methoxyquinolin-8-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C24H18N6O5S: 502.95 (MH+). Example 128: 3-nitro-ZV-(3-(pyridin-4-ylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for Ci9H14N6O4S: 423.2 (MH+). Example 129: /V-(3-(2-chloropyridin-4-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonam.de. MS (EI) m/z for Ci9H13ClN6O4S: 456.93, 458.90 (MH+). Example 130: /V-(3-(4,6-dimethoxypyrimidin-2-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C20H17N7O6S: 484.03 (MH+). Example 131: 7V-(3-(4-hydroxy-6-methoxypyrimidin-2-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for Ci9Hi5N7O6S: 469.97 (MH+). Example 132: 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2- fluorobenzenesulfonamide. MS (EI) m/z for C22Hi9FN4O4S: 455.3 (MH+). Example 133 : 7V-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C2 ,H16BrN5O5 S: 531.82, 532.84 (MH+). Example 134: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- methylbenzenesulfonam.de. MS (EI) m/z for C23H22N4O4S: 451.0 (MH+). Example 136: /V-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- methylbenzenesulfonamide. MS (EI) m/z for C23H22N4O4S: 451.0 (MH+). Example 137: /V-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C2iHi6FN5O5S: 470.0 (MH+). Example 138: 4-bromo-/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)benzenesulfonamide. MS (EI) m/z for C22Hi9BrN4O4S: 516.9, 514.9 (MH+). Example 139: /V-(3-(3-methoxyphenylamino)quinoxalin-2-yl)-3-nitro- benzenesulfonamide. MS (EI) m/z for C2,Hi7N5O5S: 451.93 (MH+). Example 140: N-(3-(2-chIoro-5-hydroxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C20Hi4ClN5O5S: 472.15, 474.13 (MH+). Example 141 : 3-acetyl-jV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C23H19ClN4O4S: 483.08 (MH+). Example 142: 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin- 2-yl)benzenesulfonamide. MS (EI) m/z for C22H20N4O4S: 437.49 (MH+). Example 143: /V-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C22H20N4O3S: 421.46 (MH+). Example 144: /V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C21Hi7ClN4O3S: 440.59 (MH+). Example 145: N-(3-(2,5-dimethoxy-phenylamino)quinoxalin- 2-yl)benzenesulfonamide. MS (EI) m/z for C22H20N4O4S: 437.53 (MH+). Example 146: 4-chloro-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C22Hi9ClN4O4S: 470.54 (MH+). Example 147: /V-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C22Hi9N5O5S: 466.32 (MH+). Example 148: /V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide. MS (EI) m/z for C2 iH I6ClN5O5S: 485.86 (MH+). Example 149: 7V-(3-(4-chloro-2,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C22Hi9ClN4O4S: 470.99 (MH+).
Example 150
/V-(3-{[3,5-bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5- yl)benzenesulfonamide
Figure imgf000403_0001
[00303] To a stirred solution of 3-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin- 2-yl)benzenesulfonamide (0.20 g, 0.44 mmol), prepared using procedures similar to those described in Example 115, in dimethylformamide (1.2 rnL) at 500C were added sodium azide (0.11 g, 1.76 mmol) and ammonium chloride (94 mg, 1.76 mmol). The crude mixture was heated at 100 0C overnight. The reaction was cooled to room temperature treated with ice water (20 mL) followed by concentrated hydrochloric acid (10 mL). The solid obtained was filtered under reduced pressure and washed with hexane (20 mL), diethyl ether (20 mL), and ethyl acetate (5 mL) to afford N-(S- {[3,5- bis(methoxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide (55 mg, 25%) as light yellow solid. MS (EI) m/z for C23H20N8O4S: 505.0 (MH+). Example 151 N-(3-(2,6-dichloropyridin-4-ylamino)quinoxaIin-2-yl)-3-nitrobenzenesulfonamide.
[00304] A mixture of N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (1 g), 2,6-dichloropyridin-4-amine (760 mg) and p-xylene (10 mL) was heated at 135 0C with stirring overnight. Upon cooling to room temperature, the mixture was dissolved in dichloromethane, washed with 2 N HCl (2 x) and brine, concentrated in vacuo to give a crude product of N- {3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3- nitrobenzenesulfonamide. A small portion of this crude product was purified by HPLC to give N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitro- benzenesulfonamide. 1H ΝMR (400 MHz, DMSO) δ 9.71 (s, IH), 8.90 (s, IH), 8.50 (d, 2H), 8.8.41 (d, IH), 8.30 (s, 2H), 7.88-7.78 (m, 27.65 (d, IH), 7.47-7.37 (m, 2H); MS (EI) m/z for C19H12Cl2N6O4S: 491.1, 493.1 (MH+).
Example 152
7V-(3-(2-chloro-6-methoxypyridin-4-ylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide
[00305] To a crude product of N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide (1.24 g) prepared using procedures similar to those for Example 151, was added anhydrous DMSO (10 mL), followed by sodium methoxide (273 mg). The resulting mixture was heated at 100 0C for 3 days. The mixture was diluted with EtOAc and water, and the pH was adjusted to about 4 by adding acetic acid. The product was extracted with EtOAc (3 x). The combined extracts were washed with brine to give the crude product. A portion of the crude product was purified by prep HPLC to give N-(3-{[2-chloro-6-(methyloxy)pyridin-4-yl]amino}quinoxalin-2-yl)-3- nitrobenzenesulfonamide. IH ΝMR (400 MHz, DMSO) δ 9.44 (s, IH), 8.90 (s, IH), 8.50 (d, IH), 8.42 (d, IH), 7.88-7.84 (m, 2H), 7.77 (s, IH), 7.74 (s, IH), 7.64 (d, IH), 7.45- 7.38 (m, 2H), 3.82 (s, 3H); MS (EI) m/z for C20H15ClN6O5S: 496.94 (MH+). Example 153
2-(dimethylamino)-N-(3-(yV-(3-(3-(2-(dimethylamino)acetainido)-5-methoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide
Figure imgf000405_0001
[00306] 3-amino-iV-(3-(3-amino-5-methoxyphenylamino)quinoxalin- 2-yI)benzenesulfonamide. N-(3-(3-Methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3- nitrobenzenesulfonamide (400 mg, 0.81 mmol), prepared as described above in Example 115, was dissolved in 1: 1 THF:EtOH (4 mL), to which was added formic acid (938 μl, 2.42 mmol) and potassium formate (203 mg, 2.42 mmol). The system was flushed with nitrogen, and then 10%wt Pd/C (50 mg) was added. The reaction was then heated to 600C. Once the reaction was determined complete by LC-MS, it was allowed to cool, and DMF was added for solubility. The solution was then filtered through a nylon frit to remove the catalyst. The filtrate was diluted water and the pH adjusted to 7 and extracted with DCM (2x) and EtOAc (2x). All organic layers were combined and evaporated to dryness to give 3-amino-/V-(3-(3-amino-5-methoxyphenylamino)quinoxalin-2- yl)benzenesulfonamide (330 mg, 93%). MS (EI) m/z for C2iH20N6O3S: 437.06 (MH+) [00307] 2-(dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)-acetamido)-5- methoxyphenylamino)quinoxalin-2-yl)-sulfamoyI)phenyl)acetamide. 3-Amino-jV-(3- (3-amino-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide (330 mg, 0.76 mmol), DMF (4 mL), /V~,N,-Dimethylglycine (312 mg, 3.02 mmol), HATU (1.15 g, 3.02 mmol), and 1.29(mL) (7.56 mmol) DIEA (1.29 mL, 7,56 mmol) were combined and heated to 90°C, followed by heating at 5O0C for over 16 hours. The reaction was allowed to cool, placed into a sep. funnel diluted with water and aqueous LiCl and extracted with EtOAc. The final compound was then purified by prep. HPLC to give 2- (dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)acetamido)-5-methoxy- phenylamino)-quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. 1H NMR (400 MHz,
CD3OD) δ 8.45 (t, IH), 7.93 (t, IH), 7.85-7.88 (m, IH), 7.70-7.74 (m, IH), 7.65-7.68 (m,
IH), 7.58-7.62 (m, IH), 7.58 (t, IH), 7.34-7.42 (m, 3H), 7.0 (t, IH), 4.05 (d, 2H), 3.8 (s,
3H), 2.9-3.0 (d, 12H). MS (EI) m/z for C29H34N8O5S: 607.2 (MH+).
[00308] The following title compounds were prepared using procedures similar to those in Example 153.
Example 154: yV-(3-(2,5-dimethoxyphenylamino)-7-methylquiπoxalin-2- yl)benzenesulfonamide. MS (EI) m/z for C23H22N4O4S: 451.0 (MH+).
Example 155a and Example 155b
N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3-
(methylamino)benzenesulfonamide and 7V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)-3-(dimethylamino)benzenesulfonamide.
Figure imgf000406_0001
[00309] To a solution of 3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide (414 mg) in DMF (4.5 niL) was added iodomethane (114 μL). The reaction mixture was heated at 35-50 0C until the formation of both mono- methylated and di-methylated products was detected by LC/MS. The mixture was diluted with EtOAc, washed with water, 10% LiCl (2 x) and brine. After removal of solvent in vacuo, the crude mixture was purified by flash silica column chromatography eluting with 15% EtOAc in hexanes, affording the mono-methylated and di-methylated products. Product A: jV-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3- (methylamino)-benzenesulfonamide (35 mg). 1H NMR (400 MHz, DMSO) δ 12.2 (s, IH), 8.93 (s, IH), 7.85 (d, IH), 7.58 (d, IH), 7.40-7.20 (m, 7H), 6.76 (m, IH), 6.24 (m, IH), 6.16 (br s, IH), 3.77 (s, 6H), 2.71 (s, 3H). MS (EI) for C23H23N5O4S: 466.05 (MH+). Product B: N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3- (dimethylamino)benzenesulfonamide (33 mg). 1H NMR (400 MHz, DMSO) δ 1220 (s, IH), 8.98 (s, IH), 7.98 (d, IH), 7.56 (d, IH), 7.42-7.32 (m, 7H), 6.74 (m, IH), 6.24 (m, IH), 3.77 (s, 6H), 2.97 (s, 6H). MS (EI) for C24H25N5O4S: 480.04 (MH+).
Example 156
7V-(3-{[(2-{[3,5-bis(methoxy)phenyl]amino}pyrido[2,3-b]pyrazin- 3-yl)amino]sulfonyI}phenyl)-7V-2-[2-(dimethylamino)ethyl]-7V-2-methyIglycinamide
Figure imgf000407_0001
[00310] To a THF suspension (1.3 mL) of 3-amino-N-(3-{[3,5-(dimethoxy)- phenyl] amino }-quinoxalin-2-yl)benzenesulfonamide (126 mg, 0.28 mmol), prepared using procedures similar to those described for Example 15, was added 0.143 mL of 2M aqeuos Na2CO3. To this yellow suspension is added dropwise 33 μL (0.42 mmol) of chlororacetyl chloride. The reaction mixture turns clear after a few minutes and is allowed to stir at 230C for Ih. To the reaction is added a DMSO (1 mL) solution containing 180 μL (1.4 mmol) of N,N\N' trimethylethelyenediamine. The reaction is then warmed to 6O0C and stirred for 18h. The product is isolated by preparative RP- HPLC (NH4O Ac/ ACN) gradient, the appropriate fractions were pooled and lyophilize to give a solid yellow as the acetic acid salt: 59 mg (51%). 1H-NMR (400 MHz, CDCL3): δ 10.1 (br s, IH), 8.37 (br s, 2H), 8.18 (d, IH), 7.97 (d, IH), 7.60 (br d, IH), 7.27 (s, 2H), 7.20 (br s, 3H), 6.15 (s, IH), 3.82 (m, 2H), 3.65 (s, 6H), 3.20 (br m, 2H), 2.82 (br s, 8H), 2.42 (s, 3H), 2.02 (s, 3H). MS (EI) m/z for C28H34N8O5S: 595.84 (MH+).
[00311] The following title compounds were prepared using similar procedures to those in Example 156.
Example 157: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-((3-(diniethylamino)propyl)(methyl)amino)acetamide. MS
(EI) m/z for C30H37N7O5S: 608.1 (MH+). Example 158: 2-(l,4'-bipiperidin-l'-yl)-N-(3-(yV-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z for
C34H4|N7O5S: 660.1 (MH+).
Example 159: tert-butyl 2-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenylcarbamoyl)piperidine-l-carboxylate. MS (EI) m/z for
C33H38N6O7S: 663.1 (MH+).
Example 160: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(l-(dimethylamino)propan-2-yl)benzamide. MS (EI) m/z for C27H29
ClN6O4S: 569.0 (MH+).
Example 161 : /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- ureidobenzenesulfonamide. MS (EI) m/z for C23H22N6O5S: 495.40 (MH+).
Example 162: 2-(dimethylamino)-7V-(3-(jV-(3-(5-methoxy-
2-methylphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z for
C26H28N6O4S: 521.69 (MH+).
Example 163: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-methyIpiperazin-l-yl)acetamide. MS (EI) m/z for
C29H33N7O5S: 592.61 (MH+).
Example 164: 2-acetamido-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z for C26H26N6O6S: 550.59 (MH+).
Example 165: tert-butyl 2-(3-(ZV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenylamino)-2-oxoethylcarbamate. MS (EI) m/z for C^H32N6O7S:
609.32 (MH+).
Example 166
/V-(2-(3,5-dimethoxy-phenyIamino)pyrido[2,3-b]pyrazin-3-yl)-3- nitrobenzenesulfonamide
Figure imgf000408_0001
[00312] To a xylene suspension (15 mL) of N-(2-chloropyrido[2,3-b]pyrazin-3-yl)- 3-nitrobenzenesulfonamide (1 g, 2.7 mmol) (prepared using procedures similar to those in Asier, et al J. Org Chem 2005, 70(7), 2878 and Leeson, et al J. Med.Chem 1991, 34, 1243) was added 420 mg (2.7 mmol) of 3,5 dimethoxyaniline. After refluxing the reaction for Ih, the reaction is cooled , the precipitate is collected by filtration and dried under vacumn to give 830 mg of the product as a ~6:1 mixture of isomers with the major being N-(2-(3,5-dimethoxy-phenylamino)pyrido[2,3-b]pyrazin-3-yl)-3- nitrobenzenesulfonamide which was assigned by known chemical reactivity. Analytical HPLC, ret. time = 3.3 min (14%), 3.05 min (86%), (conditions: Phenomenex Gemini C18 50x4.6 column, gradient 5% to 95% MeCN/H2O, in the presence of 0.1% TFA, 5 min run at 3.5 ml/min flow rate, λ =254 nm). 1H-NMR (400 MHz, DMSO-d6): major isomer δ 9.14 (br s, IH), 8.69 (dd, IH), 8.60 (dd, IH), 8.33 (dt, 2H), 7.77 (t, IH), 7.49 (dd, IH), 7.37 d, 2H), 7.05 (s, IH), 6.26 (t, IH), 3.77 (s, 6H); MS (EI) m/z for C21H18N6O6S: 483.08 (MH+).
Example 167
3-amino-N-(2-(3,5-dimethoxy-phenylamino)pyrido[2,3-b]pyrazin-3- yl)benzenesulfonamide.
[00313] To a 1: 1 THF/EtOH suspension (1 mL) of N-(3-(3,5-dimethoxyphenylamino)- pyrido[3,2-b]pyrazin-2-yl)-3-nitrobenzenesulfonamide (190 mg, 0.21 mmol) (prepared using procedures similar to those in Examples 166) was added 47 μL (1.26 mmol) of formic acid plus 99 mg (1.17 mmol) of potassium formate and 50 mg of 10% palladium on charcoal. After refluxing the reaction for Ih, hot filtration through celite (washing with a small portion of DMF), dilution with 30 mL of water, the pH was adjusted to 5.5 with 5% NaHCO3, the product is isolated as a precipitate 140 mg (80%) of white powder. Analytical HPLC, ret. time = 2.6 min (90%), 3.05 min (10%), 100% pure (conditions: YMC C18 5x4.6 column, gradient 10% to 90% MeCN/H2O, in the presence of 0.1% TFA, 9 min run at 1 ml/min flow rate, λ =254 nm). 1H-NMR (400 MHz, CDCL3): δ 8.48 (br s, IH), 8.34 (dd, IH), 7.92 (dd, IH), 7.41 (dd, IH), 7.15 (m, 3H), 7.13 (d, 2H), 6.86 (dd, IH), 6. 28 (t, IH), 3.83 (s, 6H); MS (EI) m/z for C2IH20N6O4S: 453.03 (MH+). Example 168
3-amino-jV-(3-{[3,5-bis(methoxy)phenyl]amino}pyrido[2,3-b]pyrazin-
2-yl)benzenesulfonamide
Figure imgf000410_0001
[00314] To a 1 :1 THF/EtOH suspension (1 mL) of 3-nitro-N-(3-{[3,5-bis(methoxy)- phenyl]amino}pyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide (100 mg, 0.21 mmol) (prepared using procedures similar to those used in Example 166) was added 46 μL (0.63 mmol) of formic acid plus lOOmg (0.63 mmol) of potassium formate and 100 mg of 10% palladium on charcoal. After refluxing the reaction for Ih, hot filtration through celite, and concentration, the product is isolated by preparative RP-HPLC (NH4OAdACN) gradient. The appropriate fractions were pooled and lyophilize to give solid yellow product: 3.2 mg (4%). 1H-NMR (400 MHz, CDCl3): δ 8.62 (d, IH), 8.52 (s, IH), 7.62 (d, IH), 7.3 (m, 4H), 7.18 (d, 2H), 6.88 (d, IH), 6.27 (t, IH), 3.96 (br s, 2H), 3.83 (s, 6H). MS (EI) m/z for C2iH20N6O4S: 453.22 (MH+).
Example 169
N-(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)-3-(l-{[2- (dimethylamino)-ethyl]amino}ethyl)benzenesulfonamide trifluoracetic acid salt
Figure imgf000410_0002
[00315] To a dichloroethane solution (0.6 mL) of 3-acetyl-N-(3-{[2-chloro-5- (methoxy)-phenyl]amino}quinoxalin-2-yl)benzenesulfonamide (150 mg, 0.31 mmol), prepared using procedures similar to those in Example 1 15, and 51 μL (0.37 mmol) of /V,N-dimethylethylenediamine was added 19 μL of acetic acid followed by 132 mg (0.62 mmol) of sodium cyanoborohydride. The reaction mixture was refluxed for 18h under a nitrogen atmosphere. After concentration (in vacuo), the product is isolated by preparative RP-HPLC (0.1 % TFA/ACN) gradient, followed by lyophilization of appropriate fractions to give solid yellow solid: 189 mg (90%). 1H-NMR (400 MHz, J3- MeOD): δ 8.74 (s, IH), 8.18 (s, IH), 8.12 (d, IH), 7.71 (m, 3H), 7.48 (m, 4H), 7.28 (d, IH), 6.63 (d, IH), 4.38 (q, IH), 3.80 (s, 3H), 3.30 (m, 3H), 3.12 (m, IH), 2.84 (s, 3H), 1.60 (d, 3H). MS (EI) m/z for C27H3 ,ClN6O3 S: 555.56 (MH+).
Example 170
N*N-{ [(3-{ [(3-{ [2-chloro-5-(methoxy)phenyl] amino}quinoxalin-2-yl)amino] sulfonyl}- 4-methylphenyl)amino](dimeth\iamino)methylidene}-7V-methylmethanaminium
Figure imgf000411_0001
[00316] To a dimethylformamide solution (1 mL) of 3-amino-./v"-(3-{[2-chloro-5- (methoxy)-phenyl] amino }quinoxalin-2-yl)2-methylbenzenesulfonamide (200 mg, 0.40 mmol), prepared using procedures similar to those described in Example 1 15, is added 312 μL (1.8 mmol) of DIEA and 122 mg (0.6 mmol) of HATU. After stirring for 18h at 60 0C, the product was precipitated from a 1 : 1 mixture of hexane/ethyl acetate, filtered and dried to afford 60 mg (26%). 1H NMR (400 MHz, DMSO-J6): δ 9.26 (b rs, IH), 8.96 (br s, IH), 7.80 (s, IH), 7.51 (br s, IH), 7.45 (d, IH), 7.18 (brm, 4H), 6.91 (br s, IH), 6.60 (br d, IH), 3.82 (s, 3H), 3.36 (s, 3H), 2.85 (s, 6H), 2.58 (s, 3H). MS (EI) m/z for C27H31ClN7O3S+: 569.32 (MH+). Example 171
2-Bromo-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide
Figure imgf000412_0001
[00317] In a 50 mL round-bottom flask was added 2-bromoacetic acid (1.87 g, 13.5 mmol), N,N-diisopropylcarbodiimide (860 mg, 6.8 mmol) and 10 mL DCM. To this mixture was added 3-amino-N-(3-(3,5-dimethoxyphenylamino) quinoxalin-2-yl) benzenesulfonamide (2.03 g, 4.5 mmol), prepared using procedures similar to those in Example 168. The reaction was stirred overnight at room temperature. Complete consumption of the starting aniline was confirmed by LCMS. The solvent was evaporated off to yield the crude product (2-bromo-Ν-(3-(Ν-(3-(3,5- dimethoxyphenylamino) quinoxalin-2-yl)sulfamoyl) phenyl) acetamide). This was used directly in the next step without purther purification.
General Alkylation Procedure 1
Figure imgf000412_0002
[00318] Into a 2-dram vial was placed 2-bromo-vV-(3-(N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl) sulfamoyl) phenyl) acetamide (86 mg, 0.15 mmol), prepared using procedures similar to those in Example 171, along with 2 mL of acetonitrile. Eight equivalents (1.2 mmol) of the desired amine, aniline, hydrazine or alkoxyamine were added followed by the addition of Hunig's Base (41 μL, 0.25 mmol). The reaction then was stirred at 50 0C for one hour (overnight for aniline reagents). Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture. A Waters Fractionlynx preparative reverse-phase HPLC - equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile - was used to carry out the purification.
[0186] The following title compounds were prepared according to General Library Alkylation Procedure 1.
Example 172: /V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-2-(methylamino)acetamide. 1H-NMR (400MHz, d6-DMSO): 8.81 (s, IH), 8.23 (t, IH), 7.75 (d, IH), 7.66 (d, IH), 7.41-7.38 (m, IH), 7.35 (m, IH), 7.32 (d, 2H), 7.29-7.27 (m, IH), 7.14-7.11 (m, 2H), 6.14 (t, IH), 3.80 (s, IH), 3.78 (s, 6H), 2.58 (s, 3H), 1.91 (s, 2H); MS (EI) m/z C25H26N6O5S: 523.6 (MH+). Example 173: 2-(cyclopropylmethylamino)-iV-(3-(iV-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)suIfamoyl)phenyl)acetamide. 1H-NMR (400MHz, de-DMSO): 10.58 (s, IH), 8.81 (s, IH), 8.20 (t, IH), 7.76 (d, IH), 7.67 (d, IH), 7.42-7.36 (m, 2H), 7.32 (d, 2H), 7.27 (s, IH), 7.14-7.12 (m, 2H), 6.15 (t, IH), 3.93 (s, 2H), 3.78 (s, 6H), 2.89 (s, IH), 2.88 (s, IH), 1.05-1.00 (m, IH), 0.59 (d, IH), 0.57 (d, IH), 0.35 (d, IH), 0.34 (d, IH); MS (EI) m/z C28H30N6O5S: 563.6 (MH+). Example 174: /V-(3-(jV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(2-hydroxy-propylamino)acetamide. 1H-NMR (400MHz, d6- DMSO): 10.49 ppm (s, IH), 8.81 ppm (s, IH), 8.23 ppm (t, IH), 8.13 ppm (s, IH), 7.76 ppm (d, IH), 7.765-7.763 (dd, IH), 7.41-7.37 ppm (m, 2H), 7.33-7.32 ppm (d, IH), 7.30- 7.28 ppm (m, IH), 7.16-7.09 ppm (m, 2H), 6.55 ppm (s, IH), 6.14 ppm (t, IH), 5.49 ppm (d, 2H), 5.25 ppm (s, IH), 3.85 ppm (s, IH), 3.78 ppm (s, 6H) 3.67-3.59 ppm (m, IH), 3.00-2.89 ppm (dd, IH), 2.79-2.76 ppm ( m, IH), 1.10 ppm (d, IH), 1.01-0.99 ppm (d, IH); MS (EI) m/z C27H30N6O6S: 566.6 (MH+).
Example 175: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-fluorobenzylamino)acetamide. 1H-NMR (400MHz, d6- DMSO): 10.42 ppm (s, IH), 8.82 ppm (s, IH), 8.23 ppm (s, IH), 8.14 ppm (s, IH), 7.75 ppm (d, IH), 7.65 ppm (d, IH), 7.49-7.32 ppm (m, 6H), 7.25-7.20 ppm (m, IH), 7.14- 7.12 ppm (m, 2H), 6.55 ppm (s, IH), 6.15 ppm (t, IH), 4.14 ppm (s, 2H), 3.78 ppm (s,
6H), 3.74 ppm (s, 2H); MS (EI) m/z C31H29FN6O5S: 616.7 (MH+).
Example 176: 2-(benzylamino)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-
2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z C3iH30N6O5S: 599 (MH+).
Example 177: 2-(diethylamino)-N-(3-(/V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C28H32N6O5S: 565 (MH+).
Example 178: 2-(4-(3,4-dichlorophenyl)piperazin-l-yl)-7V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C34H33Cl2N7O5S: 722 (MH+).
Example 179: /V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2,2-dimethylhydrazinyl)acetamide. MS (EI) m/z
C26H29N7O5S: 552 (MH+).
Example 180: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(p-toIylamino)acetamide. MS (EI) m/z C3|H30N6O5S: 599
(MH+).
Example 181: 2-(benzyloxyamino)-iV-(3-(7V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyI)acetamide. MS (EI) m/z
C31H30N6O6S: 615 (MH+).
Example 182: 2-(2-chlorophenylamino)-N-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H27ClN6O5S: 619 (MH+).
Example 183: /V-(3-(7V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(isopropylamino)acetamide. MS (EI) m/z C27H30N6O5S: 551
(MH+).
Example 184: 2-(4-cyclopentylpiperazin-l-yl)-/V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxaIin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C33H39N7O5S: 646 (MH+).
Example 185: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-propylpiperidin-l-yl)acetamide. MS (EI) m/z
C32H38N6O5S: 619 (MH+). Example 186: /V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(isobutoxyamino)acetamide. MS (EI) m/z C28H32N6O6S: 581
(MH+).
Example 187: 2-(3-tert-butylphenylamino)-./V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C34H36N6O5S: 641 (MH+).
Example 188: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-phenylpropan-2-ylamino)acetamide. MS (EI) m/z
C33H34N6O5S: 627 (MH+).
Example 189: N-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-fluoro-4-hydroxyphenylamino)acetamide. MS (EI) m/z
C30H27FN6O6S: 619 (MH+).
Example 190: 7V-(3-(./V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-(methylthio)benzylamino)acetamide. MS (EI) m/z
C32H32N6O5S2: 645 (MH+).
Example 191 : N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(5-fluoro-2-methylbenzylamino)acetamide. MS (EI) m/z
C32H31FN6O5S: 631 (MH+).
Examplel92: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(2-phenylpyrrolidin-l-yl)acetamide. MS (EI) m/z
C34H34N6O5S: 639 (MH+).
Example 193: 2-(2-benzylpyrrolidin-l-yl)-7V-(3-(iV-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C35H36N6O5S: 653 (MH+).
Example 194 : yV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-phenylmorpholino)acetamide. MS (EI) m/z C34H34N6O6S:
655 (MH+).
Example 195: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-(pyridin-4-yl)piperidin-l-yl)acetamide. MS (EI) m/z
C34H35N7O5S: 654 (MH+). Example 196: jY-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(o-tolylamino)acetamide. MS (EI) m/z C3iH30N6O5S: 599
(MH+).
Example 197: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-2-(2,4-dimethylbenzylamino)acetamide. MS (EI) m/z
C33H34N6O5S: 627 (MH+).
Example 198: 7V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(methyl(pyridin-3-ylmethyl)amino)acetamide. MS (EI) m/z
C3iH3iN7O5S: 614 (MH+).
Example 199: 2-(3-chloro-4-methylbenzylamino)-ZV-(3-(JV-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyI)acetamide. MS (EI) m/z
C32H31ClN6O5S: 647 (MH+).
Example 200: /V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyI)phenyl)-2-((2-(dimethylamino)-ethyl)(methyl)amino)acetamide. MS
(EI) m/z C29H35N7O5S: 594 (MH+).
Example 201: 2-(4-acetylpiperazin-l-yl)-/V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H33N7O6S: 620 (MH+).
Example 202: iY-(3-(7V-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2-(methyl(l-methylpyrrolidin-3-yl)amino)acetamide. MS (EI) m/z C30H35N7O5S: 606 (MH+).
Example 203: N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-methyl-l,4-diazepan-l-yl)acetamide. MS (EI) m/z
C30H35N7O5S: 606 (MH+).
Example 204: 2-(4-allylpiperazin-l-yl)-./V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyI)phenyl)acetamide. MS (EI) m/z
C31H35N7O5S: 618 (MH+).
Example 205: /V-^-ζΛ'-β-QjS-dimethoxyphenylamiiK^qiiinoxalin^- yl)sulfamoyl)phenyl)-2-(4-isopropylpiperazin-l-yl)acetamide MS (EI) m/z
C31H37N7O5S: 620 (MH+). Example 206: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-(dimethyIamino)pyrrolidin-l-yl)acetamide. MS (EI) m/z
C30H35N7O5S: 606 (MH+).
Example 207: N-(3-(jV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-(dimethylamino)azetidin-l-yl)acetamide. MS (EI) m/z
C29H33N7O5S: 592 (MH+).
Example 208: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-oxopiperidin-l-yl)acetamide. MS (EI) m/z C29H30N6O6S:
591 (MH+).
Example 209: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-((2-methoxyethyl)(methyl)amino)acetamide. MS (EI) m/z
C28H32N6O6S: 581 (MH+).
Example 210: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-methylbenzyloxyamino)acetamide. MS (EI) m/z
C32H32N6O6S: 629 (MH+).
Example 211: N-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yI)suIfamoyI)phenyl)-2-(2-methoxybenzyloxyamino)acetamide. MS (EI) m/z
C32H32N6O7S: 645 (MH+).
Example 212: /V-(3-(yV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(propylamino)acetamide. MS (EI) m/z C27H30N6O5S: 551
(MH+).
Example 213: /V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(ethyl(methyl)amino)acetamide. MS (EI) m/z C27H3oN605S:
551 (MH+).
Example 214: 2-(allyl(methyl)amino)-/V-(3-(/V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)suIfamoyl)phenyl)acetamide. MS (EI) m/z
C28H30N6O5S: 563 (MH+).
Example 215: 2-(terf-butylamino)-vV-(3-0V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C28H32N6O5S: 565 (MH+). Example 216: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(isobutylamino)acetamide. MS (EI) m/z C28H32N6O5S: 565
(MH+).
Example 217: 2-(butylamino)-yV-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-
2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z C28H32N6O5S: 565 (MH+).
Example 218: /V-(3-(iV-(3-(3,5-dimethoxy-phenylainino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(isopropyl(methyl)amino)acetamide. MS (EI) m/z
C28H32N6O5S: 565 (MH+).
Example 219: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-formylpiperazin-l-yl)acetamide. MS (EI) m/z
C29H31N7O6S: 606 (MH+).
Example 220: /V-(3-(jV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-ethylpiperazin-l-yl)acetamide. MS (EI) m/z C30H35N7O5S:
606 (MH+).
Example 221: jV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2-(4-formyl-l,4-diazepan-l-yl)acetamide. MS (EI) m/z
C30H33N7O6S: 620 (MH+).
Example 222: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(ethyl(2-hydroxyethyl)amino)acetamide. MS (EI) m/z
C28H32N6O6S: 581 (MH+).
Example 223: (iS)-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-hydroxypyrrolidin-l-yl)acetamide. MS (EI) m/z
C28H30N6O6S: 579 (MH+).
Example 224: N-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2,6-dimethylmorpholino)acetamide. MS (EI) m/z
C30H34N6O6S: 607 (MH+).
Example 225: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-2-(2-methylbenzylamino)acetamide. MS (EI) m/z C32H32N6O5S:
613 (MH+). Example 226: yV-(3-(jV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-methoxy-ethylamino)acetamide. MS (EI) m/z
C27H30N6O6S: 567 (MH+).
Example 227: N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(thiazolidin-3-yl)acetamide. MS (EI) m/z C27H28N6O5S2: 581
(MH+).
Example 228: N-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-(hydroxymethyl)piperidin-l-yl)acetamide. MS (EI) m/z
C30H34N6O6S: 607 (MH+).
Example 229: 7V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(2-phenylpropyIamino)acetamide. MS (EI) m/z C33H34N6O5S:
627 (MH+).
Example 230: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(isobutyl(methyl)amino)acetamide. MS (EI) m/z
C29H34N6O5S: 579 (MH+).
Example 231: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(phenylamino)acetamide. MS (EI) m/z C3oH28N605S: 585
(MH+).
Example 232: iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-propylphenylamino)acetamide. MS (EI) m/z C33H34N6O5S:
627 (MH+).
Example 233: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-isopropylphenylamino)acetamide. MS (EI) m/z
C33H34N6O5S: 627 (MH+).
Example 234: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-fluoro-4-methylphenylamino)acetamide. MS (EI) m/z
C31H29FN6O5S: 617 (MH+).
Example 235: 2-(4-chlorophenylamino)-/V-(3-(N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H27ClN6O5S: 619 (MH+). Example 236: 7V-(3-(N-(3-(3,5-dimethoxy-phenylainino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-methoxyphenylamino)acetamide. MS (EI) m/z
C3 IH30N6O6S: 615 (MH+).
Example 237: 2-(3-chlorophenylamino)-yV-(3-(yV-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H27ClN6O5S: 619 (MH+).
Example 238: /V-(3-(yV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2,3-dimethyIphenylamino)acetamide. MS (EI) m/z
C32H32N6O5S: 613 (MH+).
Example 239: /V-(3-(yV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-fluorophenylamino)acetamide. MS (EI) m/z
C30H27FN6O5S: 603 (MH+).
Example 240: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(3-fluorophenyIamino)acetamide. MS (EI) m/z
C30H27FN6O5S: 603 (MH+).
Example 241: /V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(thiophen-2-ylmethylamino)acetamide. MS (EI) m/z
C29H28N6O5S2: 605 (MH+).
Example 242: 2-(cyclohexyI(ethyl)amino)-N-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyI)acetamide. MS (EI) m/z
C32H38N6O5S: 619 (MH+).
Example 243: 2-((cyclopropylmethyl)(propyl)amino)-N-(3-(7V-(3-(3,5- dimethoxyphenylamino)quinoxaIin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C31H36N6O5S: 605 (MH+).
Example 244: 2-(allyl(cyclopentyl)amino)-/V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C32H36N6O5S: 617 (MH+).
Example 245: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)qiiinoxalin-2- yl)sulfamoyl)phenyI)-2-(ethyl(isopropyl)amino)acetamide. MS (EI) m/z
C29H34N6O5S: 579 (MH+). Example 246: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(ethyl(phenyl)amino)acetamide. MS (EI) m/z C32H32N6OsS:
613 (MH+).
Example 247: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(2-methylpyrrolidin-l-yl)acetamide. MS (EI) m/z
C29H32N6O5S: 577 (MH+).
Example 248: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-2-(2-methylpiperidin-l-yl)acetamide. MS (EI) m/z
C30H34N6O5S: 591 (MH+).
Example 249: 7V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(pyridin-2-ylmethylamino)acetamide. MS (EI) m/z
C30H29N7O5S: 600 (MH+).
Example 250: 2-(benzyl(methyl)amino)-/V-(3-(7V-(3-(3,5-dimethoxy- phenyIamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C32H32N6O5S: 613 (MH+).
Example 251 : 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(l-phenyIethylamino)acetamide. MS (EI) m/z C32H32N6OsS:
613 (MH+).
Example 252: 7V-(3-(Λr-(3-(3,5-dimethoxy-phenylamino)quiπoxalin-2- yl)sulfamoyl)phenyl)-2-(3-methylpiperidin-l-yl)acetamide. MS (EI) m/z
C30H34N6O5S: 591 (MH+).
Example 253: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-methylpiperidin-l-yl)acetamide. MS (EI) m/z
C30H34N6O5S: 591 (MH+).
Example 254: 2-(3,4-dihydroisoquinolin-2(lH)-yl)-/V-(3-(/V-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyI)phenyl)acetamide. MS (EI) m/z
C33H32N6O5S: 625 (MH+).
Example 255: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2,6-dimethylpiperidin-l-yl)acetamide. MS (EI) m/z
C31H36N6O5S: 605 (MH+). Example 256: jY-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-hydroxybenzylamino)acetamide. MS (EI) m/z C3IH30N6O6S: 615 (MH+).
General Library Acylation Procedure 1
Figure imgf000422_0001
[00319] Into a 2-dram vial were added 3-amino-N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide (54 mg, 0.12 mmol), prepared using procedures similar to those described in Example 15, DMA (2 mL) and the desired carboxylic acid (0.17 mmol). DIEA (70 μL, 0.4 mmol) followed by HATU (53 mg,0.14 mmol) were added to the vial and the reaction mixture stirred at 50 0C overnight. Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.
[00320] The following title compounds were prepared according to General Library
Acylation Procedure 1.
Example 257: N-(3-(yV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyI)morpholine-4-carboxamide: MS (EI) m/z for C26H25ClN6O5S:
567 (MH").
Example 258: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide. MS (EI) m/z for C26H28N6O5S:
535.1 (MH").
Example 259: N-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)propionamide. 1H-NMR (400MHz, d6-DMSO): 12.37 (s,lH), 10.20 (s, IH), 8.88 (s, IH), 8.37 (s, IH), 7.93 (s, IH), 7.77 (t, 2H), 7.59 (t, IH), 7.51 (t, IH), 7.41-7.34 (m, 4H), 6.24 (t, IH), 3.76 (s, 6H), 2.36-2.31 (dd, 2H), 1.10 (s, IH), 1.08 (s, IH), 1.06 (s, IH); MS (EI) m/z C25H25N5O5S: 508.6 (MH+).
Example 260: N-(3-(ΛH3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)pyridazine-4-carboxamide. 1H-NMR (400MHz, d6-DMSO):
1 1.01 (s, IH), 9.66 (dd, IH), 9.52 (dd, IH), 8.90 (s, IH), 8.55 (s, IH), 8.13 (dd, IH), 7.99
(d, IH), 7.93 (d, IH), 7.65-7.58 (m, 2H), 7.42-7.35 (m, 4H), 6.24 (t, IH), 3.75 (s, 6H);
MS (EI) m/z C27H23N7O5S: 558.6 (MH+).
Example 261 : iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylnicotinamide. 1H-NMR (400MHz, d6-DMSO): 10.78 ppm (s, IH), 8.90 ppm (s, IH), 8.58-8.57 ppm (dd, 2H), 7.90-7.86 (m, 4H), 7.60-7.56 ppm (m, 2H), 7.42-7.34 (m, 5H), 6.23 ppm (t, IH), 3.74 ppm (s, 6H), 2.57 ppm (s, 3H);
MS (EI) m/z C29H26N5O5S: 570.6 (MH+).
Example 262: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(o-tolyloxy)acetamide. 1H-NMR (400MHz, d6-DMSO): 12.37 ppm (s, IH), 10.41 ppm (s, IH), 8.90 ppm (s, IH), 8.41 ppm (s, IH), 7.93 ppm (s, IH),
7.90-7.8 (m, 2H), 7.59-7.53 ppm (m, 2H), 7.42-7.33 ppm (m, 4H), 7.17-7.12 ppm (m,
2H), 6.89-6.85 ppm (m, 2H), 6.24 ppm (t, IH), 4.74 ppm (s, 2H), 3.76 ppm (s, 6H), 2.33 ppm (s, 2H); MS (EI) m/z C31H29N5O6S: 599.7 (MH+).
Example 263: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaHn-2- yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide. MS (EI) m/z C31H29N5O6S: 600
(MH+).
Example 264: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide. MS (EI) m/z C28H24N6O5S: 557
(MH+).
Example 265: iV-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)thiazole-4-carboxamide. MS (EI) m/z C26H22N6O5S2: 563 (MH+).
Example 266: 2-bromo-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)thiophene-3-carboxamide. MS (EI) m/z C27H22BrN5O5S2 640
(MH+). Example 267: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pivalamide. MS (EI) m/z C27H29N5O5S: 536 (MH+).
Example 268: 7V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pent-4-enamide. MS (EI) m/z C27H27N5O5S: 534 (MH+).
Example 269: yV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H25N5O5S: 556 (MH+).
Example 270: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)butyramide. MS (EI) m/z C26H27N5O5S: 522 (MH+).
Example 271 : N-(3-(vV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methoxyacetamide. MS (EI) m/z C25H25N5O6S: 524 (MH+).
Example 272 : /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)cyclobutanecarboxamide. MS (EI) m/z C27H27N5O5S: 534
(MH+).
Example 273: N-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- y^sulfamoyOphenyO^-methylcydopropanecarboxamide. MS (EI) m/z C27H27N5O5S:
534 (MH+).
Example 274: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yOsulfamoyOphenyO-l-methylcyclopropanecarboxamide. MS (EI) m/z C27H27N5O5S:
534 (MH+).
Example 275: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methylbutanamide. MS (EI) m/z C27H29N5O5S: 536 (MH+).
Example 276: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-ethoxyacetamide. MS (EI) m/z C26H27N5O6S: 538 (MH+).
Example 277: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methoxypropanamide. MS (EI) m/z C26H27N5O6S: 538
(MH+).
Example 278: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-hydroxyacetamide. MS (EI) m/z C24H23N5O6S: 510 (MH+).
Example279: yV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)isobutyramide. MS (EI) m/z C26H27N5O5S: 522 (MH+). Example 280: jV-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-hydroxycyclopropanecarboxamide. MS (EI) m/z
C26H25N5O6S: 536 (MH+).
Example 281 : 7V-(3-(/V-(3-(3,5-dimethoxy-phenylainino)quinoxalin-2- yl)sulfamoyl)phenyl)furan-3-carboxamide. MS (EI) m/z C27H23N5O6S: 546 (MH+).
Example 282: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)tetrahydrofuran-3-carboxamide. MS (EI) m/z C27H27N5O6S:
550 (MH+).
Example 283: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)tetrahydrofuran-2-carboxamide. MS (EI) m/z C27H27N5O6S:
550 (MH+).
Example 284 : N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)furan-2-carboxamide. MS (EI) m/z C27H23N5O6S: 546 (MH+).
Example 285: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)isonicotinamide. MS (EI) m/z C28H24N6O5S: 557 (MH+).
Example 286: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-lH-pyrrole-2-carboxamide. MS (EI) m/z C27H24N6O5S: 545
(MH+).
Example 287: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)phenyl)pyrazine-2-carboxamide. MS (EI) m/z C27H23N7O5S: 558 (MH ).
Example 288: N-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-methyl-lH-pyrrole-2-carboxamide. MS (EI) m/z
C28H26N6O5S: 559 (MH+).
Example 289: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-5-methylisoxazole-3-carboxamide. MS (EI) m/z C27H24N6O6S:
561 (MH+).
Example 290: 7V-(3-(jY-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)thiophene-2-carboxamide. MS (EI) m/z C27H23N5O5S2: 562
(MH+). Example 291 : (S)-Λ'-(3-(Λ'-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-methylpyrrolidine-2-carboxamide. MS (EI) m/z C28H30N6O5S: 563 (MH+).
Example 292 : /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylbenzamide. MS (EI) m/z C30H27N5O5S: 570 (MH+). Example 293 : N-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-phenylacetamide. MS (EI) m/z C30H27N5O5S: 570 (MH+). Example 294: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methylpicolinamide. MS (EI) m/z C29H26N6O5S: 571 (MH+). Example 295: 7V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(pyridin-3-yl)acetamide. MS (EI) m/z C29H26N6O5S: 571 (MH+).
Example 296: iV-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-6-hydroxypicolinamide. MS (EI) m/z C28H24N6O6S: 573 (MH+). Example 297: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-fluorobenzamide MS (EI) m/z C29H24FN5O5S: 574 (MH+). Example 298: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-4-fluorobenzamide. MS (EI) m/z C29H24FN5O5S: 574 (MH+). Example 299: N-(3-(Λ'-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-fluorobenzamide. MS (EI) m/z C29H24FN5O5S: 574 (MH+). Example 300: 2-cyclohexyl-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z C30H33N5O5S: 576 (MH+). Example 301 : /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-oxocyclopentyl)acetamide. MS (EI) m/z C29H29N5O6S: 576 (MH+).
Example 302: 4-cyclopropyl-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-oxobutanamide. MS (EI) m/z C29H29N5O6S: 576 (MH+). Example 303: /V-(3-(A'-(3-(3,5-dimethoxy-phenylam-no)quinoxalin-2- yl)suIfamoyl)phenyl)-3-oxocyclohexanecarboxamide. MS (EI) m/z C29H29N5O6S: 576 (MH+). Example 304: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-(pyridiπ-3-yl)propanamide. MS (EI) m/z C3OH28NOOSS: 585
(MH+).
Example 305: 7V-(3-(Λ'-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methoxybenzamide. MS (EI) m/z C30H27N5O6S: 586 (MH+).
Example 306: N-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methoxybenzamide. MS (EI) m/z C30H27N5O6S: 586 (MH+).
Example 307: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-phenoxyacetamide. MS (EI) m/z C30H27N5O6S: 586 (MH+).
Example 308: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-methoxybenzamide. MS (EI) m/z C30H27N5O6S: 586 (MH+).
Example 309: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-fluorophenyl)acetamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 310: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-fluorophenyl)acetamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 311 : /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-fluorophenyl)acetamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 312: 2-chloro-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H24ClN5O5S: 590 (MH+).
Example 313: 4-chloro-A^3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H24ClN5O5S: 590 (MH+).
Example 314: 3-chloro-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H24ClN5O5S: 590 (MH+).
Example 315: (lR,2R)-N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-phenylcyclopropanecarboxamide. MS (EI) m/z C32H29N5O5S:
596 (MH+). Example 316: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yOsuIfamoyOphenyO-l-phenylcyclopropanecarboxamide. MS (EI) m/z C32H29Ns05S:
596 (MH+).
Example 317: Λ'-β^Λ'-P-^S-dimethoxy-phenylaminoJquinoxalin^- yI)sulfamoyl)phenyl)-2-(lH-imidazol-4-yl)acetamide. MS (EI) m/z C27H25N7O5S: 560
(MH+).
Example 318: jV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-4-methoxy-2-methylbenzamide. MS (EI) m/z C31H29N5O6S: 600
(MH+).
Example 319: iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-fluorophenoxy)acetamide. MS (EI) m/z C30H26FN5O6S:
604 (MH+).
Example 320: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-5-fluoro-2-methoxybenzamide. MS (EI) m/z C30H26FN5O6S:
604 (MH+).
Example 321: 2-(4-chIorophenyl)-/V-(3-(/V-(3-(3,5-dimethoxy- phenyIamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H26ClN5O5S: 604 (MH+).
Example 322: 2-(2-chlorophenyl)-/V-(3-(N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H26ClN5O5S: 604 (MH+).
Example 323: 2-(3-chlorophenyl)-/V-(3-(/V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z
C30H26ClN5O5S: 604 (MH+).
Example 324: l-acetyl-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)piperidine-4-carboxamide. MS (EI) m/z C30H32N6O6S: 605
(MH+).
Example 325: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(pyridin-4-yl)acetamide. MS (EI) m/z C29H26N6O5S: 571
(MH+). Example 326: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(pyridin-2-yl)acetamide. MS (EI) m/z C29H26N6O5S: 571 (MH+).
Example 327: 2,4-dichloro-7V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H23Cl2N5O5S: 624 (MH+). Example 328: 3,4-dichloro-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H23Cl2N5O5S: 624 (MH+). Example 329: 2,5-dichIoro-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H23Cl2N5O5S: 624 (MH+). Example 330: 3,5-dichloro-/V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H23Cl2N5O5S: 624 (MH+). Example 331 : 2,3-dichloro-Λ'-(3-(Λ'-(3-(3,5-dimethoxy-phenylamiπo)quinoxalin-2- yl)sulfamoyl)phenyl)benzamide. MS (EI) m/z C29H23Cl2N5O5S: 624 (MH+).
Example 332: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pentanamide. MS (EI) m/z C27H29N5O5S: 536 (MH+).
Example 333 : /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methylbutanamide. MS (EI) m/z C27H29N5O5S: 536 (MH+).
Example 334: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-lH-imidazole-2-carboxamide. MS (EI) m/z C26H23N7O5S: 546
(MH+).
Example 335: jV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-lH-imidazole-4-carboxamide. MS (EI) m/z C26H23N7O5S: 546
(MH+).
Example 336: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)isoxazole-5-carboxamide. MS (EI) m/z C26H22N6O6S: 547
(MH+).
Example 337: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3,3-dimethylbutanamide. MS (EI) m/z C28H3,N5O5S: 550
(MH+).
Example 338: /V-(3-(Λ'-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methyIpentanamide. MS (EI) m/z C28H3|N5O5S: 550 (MH+). Example 339: N-(3-(N-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yI)sulfamoyl)phenyl)-2,2-dimethylbutanamide. MS (EI) m/z C28H3 ,N5O5S: 550
(MH+).
Example 340: N-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-methylpentanamide. MS (EI) m/z C28H3iN5O5S: 550 (MH+).
Example 341 : iV-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)pyrimidine-5-carboxamide. MS (EI) m/z C27H23N7O5S: 558
(MH+).
Example 342: /V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methylfuran-2-carboxamide. MS (EI) m/z C28H2SNsO6S: 560
(MH+).
Example 343: 7V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)thiophene-3-carboxamide. MS (EI) m/z C27H23N5O5S2: 562
(MH+).
Example 344: /V-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-oxocyclopentanecarboxamide. MS (EI) m/z C28H27N5O6S:
562 (MH+).
Example 345: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-2-(2-methoxyethoxy)acetamide. MS (EI) m/z C27H29N5O7S: 568
(MH+).
Example 346: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-methylbenzamide. MS (EI) m/z C30H27N5O5S: 570 (MH+).
Example 347: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-methylisoxazol-4-yl)acetamide. MS (EI) m/z C28H26N6O6S:
575 (MH+).
Example 348: 3-cyclopentyl-/V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)propanamide. MS (EI) m/z C30H33N5O5S: 576 (MH+).
Example 349: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-o-tolylacetamide. MS (EI) m/z QnH29N5O5S: 584 (MH+).
Example 350: /V-(3-(/V-(3-(3»5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methoxynicotinamide. MS (EI) m/z C29H26N6O6S: 587 (MH+). Example 351 : /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-4-fluoro-3-methylbenzamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 352: jV-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-fluoro-2-methylbenzamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 353 : N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-fluoro-4-methylbenzamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 354: N-(3-(7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-fluoro-5-methylbenzamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 355: iV-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-5-fluoro-2-methylbenzamide. MS (EI) m/z C30H26FN5O5S: 588
(MH+).
Example 356: 6-chIoro-/V-(3-(/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2- yl)sulfamoyl)phenyl)nicotinamide. MS (EI) m/z C28H23ClN6O5S: 591 (MH+).
Example 357: 2-chloro-7V-(3-(/V-(3-(3,5-dimethoxy-phenylaniino)quinoxalin-2- yl)sulfamoyl)phenyl)nicotinamide. MS (EI) m/z C28H23ClN6O5S: 591 (MH+).
Example 358: 2-chloro-N-(3-(Λr-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)isonicotinamide. MS (EI) m/z C28H23ClN6O5S: 591 (MH+).
Example 359: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)phenyl)-4-(dimethylamino)benzamide. MS (EI) m/z C31H30N6O5S: 599
(MH+).
Example 360: /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-(dimethylamino)benzamide. MS (EI) m/z C3iH30N6O5S: 599
(MH+).
Example 361 : /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)benzo[d][l,3]dioxole-5-carboxamide. MS (EI) m/z C30H25N5O7S:
600 (MH+). Example 362: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(m-tolyloxy)acetamide. MS (EI) m/z C3)H29N5O6S: 600
(MH+).
Example 363: 7V-(3-(iV-(3-(3,5-dimethoxy-phenylamiπo)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(4-methoxyphenyl)acetamide. MS (EI) m/z C31H29N5O6S: 600
(MH+).
Example 364: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(2-methoxyphenyl)acetamide. MS (EI) m/z C3iH29N5O6S: 600
(MH+).
Example 365: iV-(3-(/V-(3-(3,5-dimethoxy-phenylainino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(3-methoxyphenyl)acetamide. MS (EI) m/z C3IH29NsO6S: 600
(MH+).
Example 366: /V-(3-(Λ'-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-methoxy-4-methylbenzamide. MS (EI) m/z C31H29N5O6S: 600
(MH+).
Example 367: /V-(3-(iY-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-3-fluoro-4-methoxybenzamide. MS (EI) m/z C30H26FN5O6S:
604 (MH+).
Example 368: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-fluoro-6-methoxybenzamide. MS (EI) m/z C30H2OFN5O6S:
604 (MH+).
Example 369: /V-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)phenyl)-3-(4-methoxyphenyl)propanamide. MS (EI) m/z C32H3IN5O6S:
614 (MH+).
Example 370: N-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)phenyl)-3-(2-methoxyphenyl)propanamide. MS (EI) m/z C32H3]N5O6S:
614 (MH+).
Example 371 : /V-(3-(/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)suIfamoyl)phenyl)-3-(3-methoxyphenyl)propanamide. MS (EI) m/z C32H3|N5O6S:
614 (MH+). Example 372
Λ'-(3-(Λ'-(3-(3,5-dimethoxy-phenylamino)qu-noxa--n-2- yl)sulfamoyl)phenyl)azetidine-3-carboxamide.
Figure imgf000433_0001
[00321] Into a 20 mL vial was added 3-amino-N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide (0.24 mmol, 1 equiv), prepared using procedures similar to those described in Example 15, DMA ( 5 mL) and \-{tert- butoxycarbonyl)azetidine-3-carboxylic acid (0.336 mmol, 1.4 equiv). Hunig's Base (0.792 mmol, 3.3 equiv) and HATU (0.288 mmol, 1.2 equiv) were added to the vial and the reaction mixture was then stirred at room temperature overnight. Completion of the reaction was indicated by LCMS. The solvent was removed by rotary evaporation. The crude mixture was carried forward without further purification. The residue was suspended in 5 mL ethyl acetate and chilled in an ice bath. A solution of 4 N HCl in dioxane ( 3 mL, 5 equiv) was added with stirring. The reaction mixture was then stirred at room temperature overnight. The solid materials were collected by filtration, washed with ethylacetate then purified further by preparative reverse-phase HPLC (ammonium acetate/ ACN). A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification. N-(3-(N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide was obtained (26 mg, 20%). 1H-NMR (400MHz, d6-DMSO): 10.26 (s, IH), 8.81 (s, IH), 8.25 (t, IH), 8.14 (s, IH), 7.74 (d, IH), 7.69 (d, IH), 7.41-7.39 (m, IH), 7.36 (d, IH), 7.32 (d, 2H), 7.30-7.28 (dd, IH), 7.14-7.1 1 (m, 2H), 6.14 (t, IH), 4.09 (d, 4H), 3.78 (s, 6H); MS (EI) m/z C26H26N6O5S: 535.6 (MH+). Example 373 /V-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide
Figure imgf000434_0001
[00322] A flask was charged with 2,3-dichloroquinoxaline (3.5 g, 18 mmol), 85 mL of dimethylsulfoxide, benzene sulfonamide (2.8 g, 18 mmol), and cesium carbonate (5.8 g, 18 mmol). The reaction mixture was stirred under an N2 atmosphere for 15 h at 150 0C, after which time, it was transferred to a separatory funnel and 100 mL of water were added. Concentrated HCl was then added in order to acidify the reaction mixture to pH<2. The aqueous layer was subsequently washed three times with 90 mL ethyl acetate. The ethyl acetate layers were then washed two times with 150 mL water, three times with 100 mL brine and then dried over sodium sulfate. The ethyl acetate was removed on a rotary-evaporator. A slurry was formed by adding ethyl acetate and dichloromethane to the dried crude product, filtration yielded N-(3-chloroquinoxalin-2-yl)- benzenesulfonamide which was used without further purification. MS (EI) m/z C14H10ClN3O2S: 319.9 (MH+).
[00323] A CEM microwave reaction vessel was charged with N-(3-chloroquinoxalin- 2-yl)benzenesulfonamide (52 mg, 0.16 mmol), prepared using procedures similar to those described in the above step, 4-fluoroaniline (36 mg, 0.32 mmol), and 0.8 mL of dimethylacetamide. The vessel was sealed and the reaction mixture was heated under microwave radiation for 25 m at 120 0C in a CEM Discover microwave instrument. Methanol ( 1 mL) was added to the reaction mixture and after 20 minutes the product precipitated out of the solution. Filtration yielded N-(3-(4- fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide (39 mg, 62 %). 1H-NMR (400MHz, de-DMSO): δ 12.30 (s, IH), 9.1 1 (s, IH), 8.16-8.10 (d, 2H), 8.02-7.90 (m, 3H), 7.68-7.58 (m, 3H), 7.55-7.51 (m, IH), 7.41-7.32 (m, 2H), 7.25-7.16 (m, 2H); MS (EI) m/z C20Hi5FN4O2S: 395.0 (MH+).
Example 374 yV-(3-(yV-(3-chIoroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide
Scheme A
Figure imgf000435_0001
Scheme B
Figure imgf000435_0002
Scheme A
[00324] A flask was charged with 3-aminobenzene sulfonamide (3.3 g, 19 mmol), and 20 niL of 1 : 1 acetone:H2θ. The solution was stirred at room temperature until the aminobenzene sulfonamide had dissolved. The flask was then cooled in an ice bath and dimethylamino-acetyl chloride HCl (4.6 g, 29 mmol) was added. To the resulting slurry sodium bicarbonate (4.8 g, 57 mmol) was added over a 15 m period. After 30 min the reaction was removed from the ice bath and allowed to stir at room temperature for 15 h. The reaction mixture was then filtered and washed with methanol and acetonitrile. The filtrate was dried on a rotary evaporator to yield 2-(dimethylamino)-Λf-(3-sulfamoyl- phenyl)acetamide, which was submitted to the next step without further purification. MS (EO mZz C10H15N3O3S: 258.0 (MH+). Scheme B
[00325] A flask was charged with dichloroquinozaline (1.0 g, 5.8 mmol), 10 mL of dimethylacetamide, 2-(dimetyhlamino)-N-(3-sulfamoylphenyl)acetamide (0.70 g, 2.7 mmol), and cesium carbonate (1.8 g, 5.5 mmol). The reaction mixture was stirred for 3 h at 140 0C and then filtered. The solvent was evaporated from the filtrate on a rotary- evaporator to yield (N-(3-(N-(3-chloroquinoxalin-2-yl)sulfamoyl)phenyl)- 2-(dimethylamino)acetamide) which was submitted to the next step without further purification. MS (EI) m/z Ci8H18ClN5O3S: 420.0 (MH+).
General Amination Procedure Ia
Figure imgf000436_0001
[00326] A CEM microwave reaction vessel was charged with N-(3-(N-(3- chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide (30 mg, 0.071 mmol), prepared using procedures similar to those described in Example 374, the desired aniline (16 mg, 0.14 mmol, 2 eq), and 0.5 mL of dimethylacetamide. The vessel was sealed and the reaction mixture was heated under microwave radiation for 70 min at 140 0C in a CEM Discover microwave instrument. The solvent was then removed by rotary- evaporation. Purification of the final product was accomplished by preparatory reverse- phase HPLC with the eluents 25 mM aqueous NH4OAc/ACN to the desired product.
[00327] The following compounds were prepared according to the above General Amination Procedure Ia.
Example 375: 2-(dimethylamino)-iV-(3-(N-(3-(3-fluorophenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. 1H-NMR (400MHz, CDCl3): 9.40 ppm (s, IH), 8.43 ppm (s, IH), 8.22 ppm (s, IH), 8.07-8.02 ppm (d, IH), 7.97-7.93 ppm (d, IH), 7.76-7.71 (m, 2H), 7.53-7.48 ppm (t, IH), 7.45-7.36 ppm (m, 4H), 7.35-7.28 ppm (m, 2H), 6.84- 6.77 ppm (t, IH), 3.10 ppm (s, 2H), 2.38 ppm (s, 6H); MS (EI) m/z C24H23FN6O3S: 495
(MH+).
Example 376: 2-(dimethylamino)-/V-(3-(/V-(3-(4-fluorophenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z C24H23FN6O3S: 495 (MH+).
Example 377: /V-(3-(7V-(3-(4-chloro-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide. MS (EI) m/z C24H23ClN6O3S: 51 1
(MH+).
General Amination Procedure Ib
Figure imgf000437_0001
[00328] A CEM microwave reaction vessel was charged with N-(3-(N-(3- chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide (62 mg, 0.147 mmol), prepared using procedures similar to those in Example 374, the desired aniline (0.567 mmol, 4 eq), and 1.0 raL of toluene. The vessel was sealed and the reaction mixture was heated under microwave radiation for 60 min at 180 0C in a CEM Discover microwave instrument. The solvent was removed on a rotary-evaporator. Purification of the final product was done by preparatory HPLC with NH4OAc/ ACN as eluent to yield the desired product.
[00329] The following compounds were prepared according to the above General Amination Procedure Ib.
Example 378/V-(3-(N-(3-(3-chIoro-phenylamino)quinoxaIin-2-yl)sulfamoyl)phenyl)- 2-(dimethyIamino)acetamide. MS (EI) m/z C24H23ClN6O3S: 51 1 (MH+). Example 379: 2-(dimethylamino)-/V-(3-(/V-(3-(4-fluoro-3- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. 2- (dimethylamino)-/V-(3-(/V-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl). 1H-NMR (400MHz, CDCl3): δ 9.47 (s, IH), 8.36 (s, IH), 8.29 (s, IH), 7.91-7.87 (d, IH), 7.80-7.73 (m, 2H), 7.66-7.63 (d, IH), 7.53-7.47 (t, IH), 7.43-7.30 (m, 4H), 7.10-7.04 (t, IH), 6.55-5.95 (br s, IH), 3.96 (s, 3H), 3.12 (s, 2H), 2.39 (s, 6H), 2.08 (s,3H(AcOH); MS (EI) m/z C25H25FN6O4S: 525 (MH+).
Example 380
N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- isopropoxybenzenesulfonamide
Figure imgf000438_0001
[00330] 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4-isopropoxy- benzenesulfonamide. A solution of 2,3-dichloroquinoxaline (2.0 mL, 0.38 M) was combined with K2CO3 (105 mg, 0.76 mmol) in a glass vial. A solution of 4-isopropoxybenzene sulfonamide (1.75 mL, 0.43 M) was added and the solution was stirred overnight at 125 0C. After cooling, acetic acid (45 mL, 0.79 mmol) and 3,5-dimethoxyaniline (230 mg, 1.5 mmol) were added. The reaction mixture was stirred again at 125 0C overnight. Upon cooling, the reaction mixture was diluted with 8 mL of methanol and then 8 mL of water. The precipitate was collected by filtration and recrystallized from N,N-dimethylacetamide/water to give N-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)-4-isopropoxy-benzenesulfonamide (45 mg, 12%). 1H- ΝMR (400MHz, d6-DMSO): 12.16 (bs, IH), 8.93 (s, IH), 8.03 (d, 2H), 7.92 (bs, IH), 7.56 (d, IH), 7.36 (m, 4H), 7.07 (d, 2H), 6.24 (s, IH), 4.72 (m, IH), 3.76 (s, 6H), 1.27 (d, 6H); MS (EI) m/z C25H26N4O5S: 495 (MH+).
[0187] Examples 381-411 were synthesized proceeding as above in Example 423. In the cases where the product did not precipitate, the mixture was purified by reverse phase
HPLC.
Example 381 : 3-chloro-W-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- methylbenzenesulfonamide. 1H-NMR (400MHz, d6-DMSO): 12.31 (bs, IH), 8.96 (s,
IH), 8.18 (s, IH), 7.98 (d, IH), 7.92 (bs, IH), 7.58 (d, 2H), 7.43-7.33 (m, 4H), 6.24 (t,
IH), 3.76 (s, 6H), 2.39 (s, 3H); MS (EI) m/z C23H21ClN4O4S: 485 (MH+). Example 382: N-(3-(3,5-diinethoxy-phenylainino)quinoxalin-2-yl)naphthalene-l- sulfonamide. MS (EI) m/z C26H22N4O4S: 487 (MH+). Example 383 : /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- fluorobenzenesulfonamide. MS (EI) m/z C22Hi9FN4O4S: 455 (MH+). Example 384: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- fluorobenzenesulfonamide. MS (EI) m/z C22Hi9FN4O4S: 455 (MH+). Example 385: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- (trifluoromethyl)benzenesulfonamide. MS (EI) m/z C23Hi9F3N4O4S: 505 (MH+). Example 386: N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4- (trifluoromethyl)benzenesulfonamide. MS (EI) m/z C23Hi9F3N4O4S: 505 (MH+). Example 387: /V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2-yl)-4- (trifluoromethoxy)benzenesulfonamide. MS (EI) m/z C23Hi9F3N4O5S: 521 (MH+). Example 388: /V-(4-(yV-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)acetamide. MS (EI) m/z C24H23N5O5S: 494 (MH+). Example 389: /V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2-yl)-4-fluoro-2- methylbenzenesulfonam.de. MS (EI) m/z C23H2 ,FN4O4S: 469 (MH+). Example 390: 7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2- methylbenzenesulfonamide. MS (EI) m/z C23H22N4O4S: 451 (MH+). Example 391 : 2-chloro-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z C22H19ClN4O4S: 471 (MH+). Example 392 : N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3,5- difluorobenzenesulfonamide. MS (EI) m/z C22Hi8F2N4O4S: 473 (MH+). Example 393: 3,5-dichloro-7V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z C22Hi8Cl2N4O4S: 505 (MH+). Example 394 : /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3-fluoro-4- methylbenzenesulfonamide. MS (EI) m/z C23H2,FN4O4S: 469 (MH+). Example 395: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2- (trifluoromethyl)benzenesulfonamide. MS (EI) m/z C23Hi9F3N4O4S: 505 (MH+). Example 396: 4-cyano-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide. MS (EI) m/z C23Hi9N5O4S: 462 (MH+). Example 397: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-l- phenylmethanesulfonamide. MS (EI) m/z C23H22N4O4S: 451 (MH+). Example 398: 4,5-dichloro-7V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)thiophene-2-sulfonamide. MS (EI) m/z C20Hi6Cl2N4O4S2: 51 1 (MH+). Example 399: l-(3-chlorophenyl)-/V-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)methanesulfonamide. MS (EI) m/z C23H2 ,ClN4O4S: 485 (MH+). Example 400: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2,5- dimethylthiophene-3-sulfonamide. MS (EI) m/z C22H22N4O4S2: 471 (MH+). Example 401 : /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3,5- bis(trifluoromethyl)benzenesulfonamide. MS (EI) m/z C24Hi8F6N4O4S: 573 (MH+). Example 402: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4-fluoro-3- (trifluoromethyl)benzenesulfonamide. MS (EI) m/z C23Hi8F4N4O4S: 523 (MH+). Example 403: 5-chloro-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-l,3- dimethyl-lH-pyrazoIe-4-sulfonamide. MS (EI) m/z C2)H21ClN6O4S: 489 (MH+). Example 404: 5-chloro-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2- methoxybenzenesulfonamide. MS (EI) m/z C23H21ClN4O5 S: 501 (MH+). Example 405: 5-bromo-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2- methoxybenzenesulfonamide. MS (EI) m/z C23H2 ,BrN4O5S: 545 (MH+). Example 406: 2,5-dichloro-/V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)thiophene-3-sulfonamide. MS (EI) m/z C20Hi6Cl2N4O4S2: 51 1 (MH+). Example 407 : /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3,5- dimethylisoxazole-4-sulfonamide. MS (EI) m/z C2iH2iN5O5S: 456 (MH+). Example 408: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-2,5- dimethoxybenzenesulfonamide. MS (EI) m/z C24H24N4O6S: 497 (MH+). Example 409: 3-chloro-/V-(3-(3,5-dimethoxy-phenyIamino)quinoxalin-2-yl)-4- fluorobenzenesulfonam.de. MS (EI) m/z C22Hi8ClFN4O4S: 489 (MH+). Example 410: 4-(difIuoromethoxy)-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)benzenesulfonamide MS (EI) m/z C23H20F2N4O5S: 503 (MH+). Example 411: /V-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-3- (methylsulfonyl)benzenesulfonamide. MS (EI) m/z C23H22N4O6S2: 515 (MH+). General Acylation Procedure 2
Figure imgf000441_0001
[00331] jV-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)- sulfamoyl)phenyl)azetidine-3-carboxamide (125 mg, 0.23 mmol), prepared using procedures similar to those described in Example 372, was dissolved into 5 mL DCE in a 10 mL round-bottom flask. DIEA (1.17 mmol, 5.0 equiv.) was then added with stirring followed by acid chloride (0.47 mmol, 2.0 equiv.). The reaction was then stirred at room temperature for 1 hour or until complete as indicated by LCMS. The solvent was subsequently removed under reduced pressure on a rotary evaporator. The crude material was then redissolved in methanol. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous ΝH4OAC/CAΝ. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.
[00332] The following compounds were prepared according to General Acylation Procedure 2.
Example 412: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-propionyIazetidine-3-carboxamide. 1H-NMR (400MHz, d6- DMSO): 12.40 (s, IH), 10.45 (s, IH), 8.88 (s, IH), 8.40 (s, IH), 7.93 (s, IH), 7.82 (d, IH), 7.77 (d, IH), 7.60-7.45 (m, 2H), 7.41-7.30 (m, 4H), 6.24 (s, IH), 4.26 (t, IH), 4.22- 4.17 (m, IH), 3.99 (t, IH), 3.95-3.89 (m, IH), 3.76 (s, 6H), 3.59-3.45 (m, IH), 2.05 (dd, 2H), 0.95 (t, 3H); MS (EI) m/z C29H30N6O6S: 591 (MH+).
Example 413: l-acetyk/V-(3-{[(3-{[3,5-bis(methoxy)-phenyI]amino}quinoxalin-2- yl)amino[sulfonyl}phenyl)azetidine-3-carboxamide. MS (EI) m/z C28H28N6O6S: 577 (MH+). Example 414: l-(cyclopropanecarbonyl)-N-(3-(7V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide. MS (EI) m/z C30H30N6O6S: 603 (MH+).
General Reductive Amination Procedure 1
Figure imgf000442_0001
[00333] To a solution of N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)azetidine-3-carboxamide (1 10 mg, 0.19 mmol), prepared using procedures similar to those described in Example 372, in 3 mL of DCE and 200 μL of DMF, aldehyde (0.77 mmol, 4.0 eq.)was added slowly followed by tetramethylammonium triacetoxyborohydride (1.16 mmol, 6.0 eq). The reaction was stirred at room temperature overnight. LC/MS indicated the reaction was completed. The solvent was subsequently removed under reduced pressure on a rotary evaporator. The crude material was then redissolved in methanol. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NH4OAc/CAN. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.
[00334] The following title compounds were prepared according to General Reductive Amination Procedure 1.
Example 415: N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)phenyl)-l-ethylazetidine-3-carboxamide. 1H-NMR (400MHz, d6- DMSO): 10.29 (s, IH), 8.82 (s, IH), 8.25 (t, IH), 7.75-7.68 (m, 2H), 7.43-7.38 (m, IH), 7.375-7.340 (m, IH), 7.338-7.310 (d, 2H), 7.305-7.262 (m, IH), 7.15-7.08 (m, 2H), 6.56 (s, IH), 6.15 (t, IH), 4.15-4.08 (m, 2H), 4.06-3.95 (m, 2H), 3.78 (s, 6H), 3.65-3.56 (m,
IH), 3.12-3.04 (m, 2H), 1.03 (t, 3H); MS (EI) m/z C28H30N6O5S: 563 (MH+).
Example 416: l-(cyclopropylmethyl)-./V-(3-(/V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yI)sulfamoyl)phenyl)azetidine-3-carboxamide. MS (EI) m/z C30H32N6O5S: 589 (MH+).
Example 417: l-benzyl-7V-(3-(Λ'-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)azetidine-3-carboxamide. MS (EI) m/z C33H32N6O5S: 625
(MH+).
Example 418: /V-(3-(iV-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-l-(furan-2-ylmethyl)azetidine-3-carboxamide. MS (EI) m/z
C3,H30N6O6S: 615 (MH+).
Example 419: l-((lH-imidazol-5-yl)methyl)-/V-(3-(/V-(3-(3,5-dimethoxy- phenylamino)quinoxalin-2-yI)sulfamoyl)phenyl)azetidine-3-carboxamide. MS (EI) m/z C30H30N8O5S: 615 (MH+).
General Amide Formation Procedure Ia
Figure imgf000443_0001
[00335] Into a small 1 dram vial was added 3-(N-(3-(2-chloro-5-methoxy- phenylamino)-quinoxalin-2-yl)sulfamoyl)benzoic acid (61 mg, 0.13 mmol, 1.1 equiv), prepared using procedures described for Example 100. The acid was dissolved in DMA (1 mL) and DIEA (42 μL, 0.24 mmol, 2 equiv) was added then added to the solution. The amine reagent (1 mL of 0.12 M solution in DMA) was added to solution with stirring followed by HATU (64 mg, 0.17 mMol, 1.4 equiv). The reaction was stirred overnight at room temperature. Upon completion as indicated by LCMS analysis, 2 mL of methanol was added to the solution. Preparative reverse-phase HPLC was used to isolate the desired product. A Waters Fractionlynx preparative reverse-phase HPLC - equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile
- was used to carry out the purification.
[00336] The following compounds were prepared according to General Amide
Formation Procedure 1.
Example 420: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-7V-(3-(dimethylamino)propyl)benzamide. 3-(/V-(3-(2-chloro-5- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-
(dimethylamino)propyl)benzamide: 1H ΝMR (400 MHz, dό-DMSO): 9.44 (s, IH), 8.94
(s, IH), 8.79 (t, IH), 8.54 (s, IH), 8.24 (d, IH), 7.87 (d, IH), 7.48 (m, 3H), 7.33 (d, IH),
7.18 (m, 2H), 6.60 (dd, IH), 3.82 (IH), 3.04 (m, 3H), 2.51 (m, 5H), 1.91 (s, IH), 1.86 (m,
3H); MS (EI) m/z for C27H29ClN6O4S: 569 (MH+).
Example 421 : 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)-/V-(l-methylazetidin-3-yl)benzamide. 3-(N-(3-(2-chloro-5- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(l-methylazetidin-3-yl)benzamide:
1H ΝMR (400 MHz, dδ-DMSO): 9.43 (s, IH), 9.23 (d, IH), 8.94 (d, IH), 8.58 (s, IH),
8.29 (d, IH), 7.89 (d, IH), 7.56 (t, IH), 7.47 (d, IH), 7.44 (d, IH), 7.33 (d, IH), 7.18 (m,
2H), 6.60 (dd, IH), 4.81 (m, IH), 4.33 (m, 2H), 4.19 (m, 2H), 3.82 (s, IH), 2.51 (s, 3H);
MS (EI) m/z for C26H25ClN6O4S: 553 (MH+).
Example 422: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(pyridin-4-ylmethyl)benzamide. MS (EI) m/z C28H23ClN6O4S: 575
(MH+).
Example 423 : 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(3-(dimethylamino)propyl)benzamide. MS (EI) m/z C28H26ClN7O4S:
592 (MH+).
Example 424: N-(3-(2-chIoro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-(2,2- dimethylhydrazinecarbonyl)benzenesulfonamide. MS (EI) m/z C24H23ClN6O4S: 527
(MH+).
Example 425: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-methoxyethyl)benzamide. MS (EI) m/z C25H24ClN5O5S: 542
(MH+). Example 426: N-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2-yl)-3-(4- methylpiperazine-l-carbonyl)benzenesulfonamide. MS (EI) m/z C27H27ClN6O4S: 567
(MH+).
Example 427: 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-(pyrrolidin-l-yl)ethyl)benzamide. MS (EI) m/z C28H29ClN6O4S:
581 (MH+).
Example 428: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-(pyridin-4-yl)ethyl)benzamide. MS (EI) m/z C29H25ClN6O4S: 589
(MH+).
Example 429: /V-(2-(lH-imidazol-4-yl)ethyl)-3-(iV-(3-(2-chloro-5- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamide. MS (EI) m/z
C27H24ClN7O4S: 578 (MH+).
Example 430: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(piperidin-l-yl)benzamide. MS (EI) m/z C27H27ClN6O4S: 567 (MH+).
Example 431: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-N-(2-hydroxyethyl)benzamide. MS (EI) m/z C24H22ClN5O5S: 528
(MH+).
Example 432: 3-(/V-(3-(2-chIoro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(3-ethoxypropyl)benzamide. MS (EI) m/z C27H28ClN5O5S: 570
(MH+).
Example 433 : 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-7V-(3-(pyrrolidin-l-yl)propyl)benzamide. MS (EI) m/z C29H3 ,ClN6O4S:
595 (MH+).
Example 434: 3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(3-(diethylamino)propyl)benzamide. MS (EI) m/z C29H33ClN6O4S:
597 (MH+).
Example 435: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)-/V-(3-(2-oxopyrrolidin-l-yl)propyl)benzamide. MS (EI) m/z
C29H29ClN6O5S: 609 (MH+). Example 436: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)-N-(pyridin-2-ylmethyI)benzamide. MS (EI) m/z C28H23ClN6O4S: 575
(MH+).
Example 437: 3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)-jV-(2-cyanoethyI)-N-methylbenzamide. MS (EI) m/z C26H23ClN6O4S:
551 (MH+).
Example 438: 3-(/V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)-N-(2-cyanoethyl)-τV-ethylbenzamide. MS (EI) m/z C27H25ClN6O4S: 565
(MH+).
Example 439: 3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-(ethylthio)ethyl)benzamide. MS (EI) m/z C26H26ClN5O4S2: 572
(MH+).
Example 440: 3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2- yl)sulfamoyI)-/V-(3-propoxypropyl)benzamide. MS (EI) m/z C28H30ClN5O5S: 584
(MH+).
Example 441 : 3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(5-(diethylamino)pentan-2-yl)benzamide. MS (EI) m/z
C31H37ClN6O4S: 625 (MH+).
Example 442: 3-(jV-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)-7V-(3-methoxypropyl)benzamide. MS (EI) m/z C26H26ClN5O5S: 556
(MH+).
Example 443 : 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(3-morpholinopropyl)benzamide MS (EI) m/z C29H3 ,ClN6O5S: 611
(MH+).
Example 444: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(pyridin-3-ylmethyl)benzamide MS (EI) m/z C28H23ClN6O4S: 575
(MH+).
Example 445: 3-(/V-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoylHV-(2-cyanoethyl)benzamide. MS (EI) m/z C25H21ClN6O4S: 537 (MH+). Example 446: 3-(jV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-yV-(l-methoxypropan-2-yI)benzamide. MS (EI) m/z C26H26ClN5O5S:
556 (MH+).
Example 447: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-7V-(2-(methylthio)ethyl)benzamide. MS (EI) m/z C25H24ClN5O4S2: 558
(MH+).
Example 448: 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(3-(dimethylamino)propyl)-7V-methylbenzamide. MS (EI) m/z
C28H31ClN6O4S: 583 (MH+).
Example 449: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)-/V-(3-isopropoxypropyl)benzamide. MS (EI) m/z C28H30ClN5O5S: 584
(MH+).
Example 450: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-iV-(2-(dimethylamino)ethyl)-./V-ethylbenzamide. MS (EI) m/z
C28H31ClN6O4S: 583 (MH+).
Example 451: /V-(3-butoxypropyl)-3-(Λ'-(3-(2-chloro-5-methoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)benzamide. MS (EI) m/z C2C1H32ClN5O5S:
598 (MH+).
Example 452: 3-(/V-(3-(2-chloro-5-methoxy-phenyIamino)quinoxalin-2- yl)sulfamoyI)-N-(2-(diethylamino)ethyl)benzamide. MS (EI) m/z C28H31ClN6O4S: 583
(MH+).
Example 453: methyl 3-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)benzamido)propaπoate. MS (EI) m/z C26H24ClN5O6S: 570 (MH+).
Example 454: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-iV-methyl-./V-propylbenzamide. MS (EI) m/z C26H26ClN5O4S: 540
(MH+).
Example 455: ethyl 3-(3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxaIin-2- yl)sulfamoyl)benzamido)propanoate. MS (EI) m/z C27H26ClN5O6S: 584 (MH+).
Example 456: 3-(yV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-/V-(2-(piperidin-l-yl)ethyl)benzamide. MS (EI) m/z C29H3iClN6O4S:
595 (MH+). Example 457: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyI)-Λ'-((l-ethylpyrrolidin-2-yl)methyl)benzamide. MS (EI) m/z
C29H3IClN6O4S: 595 (MH+).
Example 458: N-(2-(bis(2-hydroxyethyl)amino)ethyl)-3-(N-(3-(2-chloro-5- methoxyphenylamino)quinoxalin-2-yl)sulfamoyI)benzamide. MS (EI) m/z
C28H31ClN6O6S: 615 (MH+).
Example 459: N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-(3-
(diethylamino)pyrrolidine-l-carbonyl)benzenesulfonamide. MS (EI) m/z
C30H33ClN6O4S: 609 (MH+).
Example 460: 3-(jV-(3-(2-chIoro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-jY-methyl-7V-(l-methylpyrrolidin-3-yl)benzamide. MS (EI) m/z
C28H29ClN6O4S: 581 (MH+).
Example 461 : 7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-(3-
(dimethylamino)pyrrolidine-l-carbonyl)benzenesulfonamide. MS (EI) m/z
C28H29ClN6O4S: 581 (MH+).
Example 462 : 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(2-methyl-l-morpholinopropan-2-yl)benzamide. MS (EI) m/z
C30H33ClN6O5S: 625 (MH+).
Example 463 : 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-N-(lH-pyrrol-l-yl)benzamide. MS (EI) m/z C26H21ClN6O4S: 549
(MH+).
Example 464: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-/V-(3-oxopyrazolidin-4-yl)benzamide. MS (EI) m/z C25H22ClN7O5S: 568
(MH+).
Example 465 : N-(3-(2-chloro-5-methoxy-phenylamlno)quinoxalin-2-yl)-3-(2-
((dimethylamino)methyl)piperidine-l-carbonyl)benzenesulfonamide. MS (EI) m/z
C30H33ClN6O4S: 609 (MH+).
Example 466: N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-(2-
(piperidin-l-ylmethyl)piperidine-l-carbonyl)benzenesulfonamide. MS (EI) m/z
C33H37ClN6O4S: 649 (MH+). Example 467: 3-(7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yI)sulfamoyl)-yV-(l-ethylpiperidin-3-yl)benzamide MS (EI) m/z C29H31ClN6O4S: 595 (MH+).
General Amide Formation Procedure Ib [00337] The procedure outlined in General Amide Formation Procedure Ia was used to incorporate a number of amines that contained a second amine group protected as the tert-butylcarbamate (i.e. where R', within NHR'R", contained a Boc-protected amine group). The deprotection was carried out after HPLC purification of the Boc-protected precursor.
[00338] Into a small 1 dram vial was added 3-(7V-(3-(2-chloro-5-methoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)benzoic acid (61 mg, 0.13 mmol, 1.1 equiv). The acid was dissolved in 1 mL of DMA and DIEA (42 μL, 0.24 mmol, 2 equiv) was added then added to the solution. The mono-Boc-protected diamine reagent (1 mL of 0.12 M solution in DMA, 1 equiv) was added to solution with stirring followed by HATU (64 mg, 0.17 mmol, 1.4 equiv). The reaction was stirred overnight at room temperature. Upon completion as indicated by LCMS analysis, 2 mL of methanol was added to the solution. Preparative reverse-phase HPLC was used to isolate the desired product directly from this crude reaction solution. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification. The product fractions were combined and concentrated to dryness under reduced pressure by rotary evaporation. A solution of 4 N HCl in dioxane (2 mL) was added. The solution was then stirred at room temperature until no starting material was detected. The deprotected product precipitated out of solution as an HCL salt and was collected by filtration, washed with ether and dried under vacuum.
[00339] The following compounds were prepared according to the above General Amide Formation Procedure Ib.
Example 468: 3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-iV-(piperidin-3-yl)benzamide. 3-(N-(3-(2-chloro- 5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-3-yl)benzamide: 1H
NMR (400 MHz, d6-DMSO): 12.82 (s, IH), 9.12 (s, IH), 9.04 (s, IH), 8.85 (d, IH), 8.65
(s, IH), 8.55 (s, IH), 8.18 (m, IH), 7.98 (s, IH), 7.69 (m, 2H), 7.43 (m, 2H), 6.69 (dd,
IH), 4.21 (s, IH), 3.83 (s, 3H), 3.69 (m, IH), 3.48 (m, IH), 3.18 (s, IH), 2.84 (q, 2H),
1.91 (s, 2H); MS (EI) m/z for C27H27ClN6O4S: 567 (MH+).
Example 469: 3-(iV-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)suIfamoyl)-./V-(piperidin-2-ylmethyl)benzamide. 3-(N-(3-(2-chloro-5- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-2-ylmethyl)benzamide:
NMR (400 MHz, d6-DMSO): 12.78 (s, IH), 9.16 (s, IH), 9.09 (s, IH), 8.79 (s, IH), 8.59
(d, 2H), 8.22 (t, 2H), 7.99 (s, IH), 7.74 (t, IH), 7.66 (s, IH), 7.42 (m, 2H), 6.69 (dd, IH),
3.82 (s, 3H), 3.69 (dd, IH), 3.57 (m, IH), 3.50 (m, 3H), 3.22 (s, 2H), 2.82 (d, IH), 1.68
(m, 5H); MS (EI) m/z for C28H29ClN6O4S: 581 (MH+).
Example 470: 3-(3-aminopyrrolidine-l-carbonyl)-N-(3-(2-chloro-5-methoxy- phenylamino)quinoxalin-2-yl)benzenesuIfonamide. MS (EI) m/z C26H25ClN6O4S:
553 (MH+).
Example 471 : 3-(3-aminoazetidine-l-carbonyl)-/V-(3-(2-chloro-5-methoxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide. MS (EI) m/z C25H23ClN6O4S:
539 (MH+).
Example 472: 3-(3-aminopiperidine-l-carbonyl)-/V-(3-(2-chloro-5-methoxy- phenylamino)quinoxalin-2-yl)benzenesulfonamide. MS (EI) m/z C27H27ClN6O4S:
567 (MH+).
Example 473: 3-(/V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2- yl)sulfamoyl)-yV-(pyrrolidin-3-yl)benzamide. MS (EI) m/z C26H25ClN6O4S: 553
(MH+).
Example 474: 7V-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-(3-
(methylamino)pyrrolidine-l-carbonyl)benzenesulfonamide. MS (EI) m/z
C27H27ClN6O4S: 567 (MH+).
Example 475: yV-(2-aminoethyl)-3-(W-(3-(2-chloro-5-methoxy- phenylamino)quinoxalin-2-yl)sulfamoyl)benzamide. MS (EI) m/z C24H23ClN6O4S:
527 (MH+). Example 476: 3-(4-amino-3-oxopyrazolidine-l-carbonyl)-Λ'-(3-(2-chloro-5- methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide. MS (EI) m/z C25H22ClN7O5S: 568 (MH+).
Example 477
3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-
7V-((l-methylpiperidin-2-yl)methyl)benzamide
[00340] 3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-./V- (piperidin-2-ylmethyl)benzamide (299 mg, 0.51 mmol, 1 equiv), prepared using procedures similar to those described for Example 514, was dissolved in 2.3 mL of DMA. Formic acid (388 μL, 10.28 mmol, 20 equiv) was added to solution with stirring followed by the addition of formaldehyde (508 μL of 37% aq. solution). The reaction was then stirred at room temperature overnight. Analysis of an aliquot of the reaction mixture by LCMS indicated the complete consumption of starting material. The reaction was diluted with methanol (2 mL). Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C 18, OCD 5 μM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.1H ΝMR (400 MHz, dό-DMSO): 9.44 (s, IH), 8.94 (s, IH), 8.79 (t, IH), 8.57 (s, IH), 8.27 (d, IH), 7.90 (d, IH) 7.54 (t, IH), 7.46 (d, IH), 7.39 (d, IH), 7.33 (d, IH), 7.18 (m, 2H), 6.60 (dd, IH), 3.82 (s, 3H), 3.59 (m, 2H), 3.00 (s, IH), 2.90 (s, 3H), 1.62 (m, 7H); MS (EI) m/z for C29H31ClN6O4S: 595 (MH+).
Example 478
3-(ΛL(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyI)-
/V-(l-methylpiperidin-3-yl)benzamide
[00341] The title compound was prepared using similar procedures to those used in Example 522. 1H NMR (400 MHz, d6-DMSO): 9.43 (s, IH), 8.93 (s, IH), 8.59 (s, IH), 8.24 (d, IH), 7.87 (d, IH), 7.47 (m, 2H), 7.40 (d, IH), 7.33 (d, IH), 7.19 (m, 2H), 6.60 (dd, IH), 4.21 (s, IH), 3.82 (s, IH), 2.76 (s, IH), 2.50 (m, 7H), 1.91 (m, 2H), 1.63 (m, 2H); MS (EI) m/z for C28H29ClN6O4S: 581 (MH+). Biological Examples Biological Example 1
PDKalpha Luciferase-Coupled Chemiluminescence Assay Protocol [003421 POKα activity is measured as the percent of ATP consumed following the kinase reaction using luciferase-luciferin-coupled chemiluminescence. Reactions were conducted in 384- well white, medium binding microti ter plates (Greiner). Kinase reactions were initiated by combining test compounds, ATP, substrate (PIP2), and kinase in a 20 μL volume in a buffer solution. The standard PDKalpha assay buffer is composed 50 mM Tris, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 1 mM DTT and 0.03% CHAPS. The standard assay concentrations for enzyme, ATP, and substrate are 0.5-1.1 nM, lμM, and 7.5 μM, respectively. The reaction mixture was incubated at ambient temperature for approximately 2 h. Following the kinase reaction, a 10 μL aliquot of luciferase-luciferin mix (Promega Kinase-Glo) was added and the chemiluminescence signal measured using a Victor2 plate reader (Perkin Elmer). Total ATP consumption was limited to 40-60% and IC50 values of control compounds correlate well with literature references.
[00343] Certain compounds of the invention demonstrated the ability to bind to PI3K when tested in this assay. The following embodiments are directed to the compounds themselves as well as their use in a method of treating. For example, in one embodiment of the invention, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 8 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 4 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 3 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 2 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 1.5 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 1 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.750 μM or less. In another embodiment, the PDK inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.5 μM or less. In another embodiment, the PBK inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.3 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.2 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.1 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.075 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.050 μM or less.
Biological Example 2
Phospho AKT assay
[00344] PC-3 cells were seeded on 6-well plates at 150,000 cells/well. Cells were cultured for 3 days, then treated with compounds in serum-free medium for 3 hr. EGF (100 ng/ml) was added for the last 10 min. Cells were lysed in TENN buffer. Phospho T308 Akt and total Akt were quantfied by ELISA performed according to the Biosource assay protocol. The readings of phospho Akt were normalized to total Akt readings.
Biological Example 3
Phospho S6 assay
[00345] PC-3 cells were seeded on 96-well plates at 8,000 cells/well. For each experiment, cells were seeded and treated in duplicated plates: one plate for phospho S6 CeIlELISA, and one plate for total S6 CeIlELISA. Cells were cultured on the plates for 3 days, then treated with compounds in serum-free medium for 3 hr in triplicate. Cells were fixed with 4% formaldehyde, quenched with 0.6% H2O2, blocked with 5% BSA, incubated with either phospho S6 antibody or total S6 antibody overnight, incubated with goat-anti-rabbit-IgG-HRP for 1 hr, and developed in chemiluminescent substrate. Biological Example 4
PIP3 assay
[00346] MCF-7 cells grown in 10-cm dishes were starved for 3 hours in DMEM, and then treated with compounds for 20 minutes. In the last 2 minutes of the incubation with the compounds, EGF (100 ng/ml) was added to stimulate the production of PIP3. The medium was aspirated and the cells were scraped with 10% trichloroacetic acid. The lipids were extracted from the pellet after the cell lysates were centrifuged. PIP3 in the cellular lipid extraction was quantified with the AlphaScreen [Registered TM of PerkinElmer] assay in which Grpl-PH is used as the PIP3 specific probe. The amount of cellular PIP3 was calculated from the standard curve of diC8 PI (3,4,5) P3.
Biological Example 5-10
In vivo models
[00347J Compound A is a Compound of Formula I. Compound B is N-(3,4-dichloro- 2-fluorophenyl)-7-({[(3ai?,5r,6a5)-2-methyloctahydrocyclopenta-[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.
[00348] Female and male athymic nude mice (NCr) 5-8 weeks of age and weighing approximately 20-25 g were used in the following model. Prior to initiation of a study, the animals were allowed to acclimate for a minimum of 48 h. During these studies, animals were provided food and water ad libitum and housed in a room conditioned at 70-75°F and 60% relative humidity. A 12 h light and 12 h dark cycle was maintained with automatic timers. All animals were examined daily for compound-induced or tumor-related deaths.
[00349] PC-3 human prostate adenocarcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 20% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization and 3x106 cells (passage 13, 99% viability) in 0.1 mL of ice-cold Hank's balanced salt solution were implanted subcutaneously into the hindflank of 5-8 week old male nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with Taxol and Compound A in combination with Rapamycin. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents. [00350] U-87 MG human glioblastoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 370C in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization and 2x106 cells (passage 5, 96% viability) in 0.1 mL of ice-cold Hank's balanced salt solution were implanted intradermally into the hindflank of 5-8 week old female nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent and the results are not included. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
[00351] A549 human lung carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37°C in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization and 10x106 cells (passage 12, 99% viability) in 0.1 mL of ice-cold Hank's balanced salt solution were implanted intradermally into the hindflank of 5-8 week old female nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with Compound B. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
[00352] MDA-MB-468 human breast adenocarcinoma cells, passage number <6, were maintained and propagated in log-phase growth in Dulbecco's Modification of Eagles's Medium (DMEM; Mediatech) containing L-Glutamine supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 0C in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 10 x 106 cells (passage 10, 98% viability) in 50% cold Hanks balanced salt solution/50% Matrigel (100 μL total volume per mouse) were implanted subcutaneously into the mammary fat pads of female nude mice. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with erlotinib. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
[00353] Calu-6 human lung anaplastic carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin- Streptomycin and non-essential amino acids at 37 0C in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 5x106 cells (passage #8, 96% viability) in 0.1 mL ice-cold Hank's balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with carboplatin. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
[00354] MCF7 human mammary adenocarcinoma cells were cultured in vitro in DMEM (Cellgro) supplemented with 10% Fetal Bovine Serum (Cellgro), Penicillin- Streptomycin and non-essential amino acids at 37 0C in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 5 x 106 cells (passage 10 and 95.4% viability for Study 1, passage 9 and 90% viability for Study 2) in 100 μL of a solution made of 50% cold Hanks balanced salt solution with 50% growth factor reduced matrigel (R&D Systems for Study 1 and Becton Dickinson for Study 2) implanted subcutaneously into the hindflank of female nude mice. [00355] For subcutaneous or intradermal tumors, the mean tumor weight of each animal in the respective control and treatment groups was determined twice weekly during the study. Tumor weight (TW) was determined by measuring perpendicular diameters with a caliper, using the following formula: tumor weight (mg) = [tumor volume = length (mm) x width2 (mm2)]/2 These data were recorded and plotted on a tumor weight vs. days post-implantation line graph and presented graphically as an indication of tumor growth rates. Percent inhibition of tumor growth (TGI) is determined with the following formula:
1 - ( Xf - X0 ) 100
( Yf - Xo )
where X0 = average TW of all tumors on group day
Xf = TW of treated group on Day f
Yf = TW of vehicle control group on Day f
If tumors regress below their starting sizes, then the percent tumor regression is determined with the following formula:
Figure imgf000457_0001
Tumor size is calculated individually for each tumor to obtain a mean ± SEM value for each experimental group. Statistical significance is determined using the 2-tailed Student's t-test (significance defined as PO.05).
Biological Examples 11-14
[00356] Compound A is a Compound of Formula I and is an inhibitor of class I PI3- kinases. Compound B is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine.
Prostate Cancer Xenograft Model - A Compound of Formula I in Combination with
Taxol
[00357] Compound A was tested alone and in combination with taxol in a prostate carcinoma tumor model. PC-3 is a human prostate carcinoma cell line that harbors a homozygous deletion mutation in PTEN, which results in constitutive activation of the PI3K pathway. In single-dose pharmacodynamic experiments, oral administration of Compound A results in a dose-dependent decrease in the phosphorylation of AKT, p70S6K, and S6 in PC-3 tumors grown ectopically in mice. Repeat-dose administration of a Compound A also inhibits the growth of these tumors, but does not induce regressions.
[00358] Oral administration of Compound A at 100mg/kg qd or 300 mg/kg biweekly (biw) resulted in substantial tumor growth inhibition in mice. See Figure 1. Comparable tumor growth inhibition was achieved with 7.5 mg/kg taxol administered i.v. twice weekly. While tumor growth was inhibited substantially with Compound A alone, the combination of either dose ofCompound A with taxol was superior to either agent alone and induced significant regression of the tumors. Body weight loss and dose skipping was minimal in all groups, and was not exacerbated in the combination group indicating that the combination was well tolerated. These results support the use of a Compound of Formula I in combination with taxol in tumors with constitutively activated PI3K signaling.
Prostate Cancer Xenograft Model - A Compound of Formula I in Combination with
Rapamycin
[00359] Compound A was tested alone and in combination with rapamycin in a prostate carcinoma tumor model (PC-3 cell line). Oral administration ofCompound A at 100mg/kg qd resulted in substantial tumor growth inhibition. See Figure 2. Comparable tumor growth inhibition was achieved with 5 mg/kg rapamycin administered i.p. daily. While tumor growth was inhibited substantially with Compound A alone, the combination of Compound A with rapamycin was superior to either agent alone and induced significant regression of the tumors. Body weight loss and dose skipping was minimal with each agent alone, but body weight loss was exacerbated in the combination group necessitating dose skipping. The fact that tumor regression was observed despite dose skipping suggests that using an intermittent dosing schedule would maintain efficacy and improve tolerability. These results support the use of a Compound of Formula I in combination with rapamycin in tumors with constitutively activated PI3K signaling. Non-Small Cell Lung Cancer Xenograft Model - A Compound of Formula I in
Combination with Carboplatin
[00360] Compound A was tested both as a single agent and in combination with carboplatin in a NSCLC tumor model.
[00361] Calu-6 is a human NSCLC cell line that harbors a heterozygous activating mutation in K-Ras (Q61K). Oral administration of a Compound A at 100mg/kg qd or 300 mg/kg every fourth day (q4d) to mice bearing Calu-6 tumors resulted in substantial tumor growth inhibition. See Figure 3. Both dose schedules resulted in similar inhibition of tumor growth. Significant tumor growth inhibition was also observed with 50 mg/kg carboplatin administered i.v. q4d, but was not as pronounced as with Compound A. While tumor growth was inhibited substantially with Compound A alone, the combination of the two agents was superior to either agent alone and resulted in almost complete inhibition of tumor growth. Body weight loss and dose skipping was minimal in all groups, and was not exacerbated in the combination group indicating that the combination was well tolerated. These results support the use of a Compound of Formula I both as a single agent and in combination with platins in tumors with activating mutations in K-Ras.
Non-small Cell Lung Cancer Xenograft Model - A Compound of Formula I in
Combination with Compound B
[00362] Compound A was tested both as a single agent and in combination with Compound B. The A549 human non-small cell lung carcinoma cell line harbors a homozygous stop mutation in the gene encoding LKBl, and an activating G12S mutation in K-Ras, promoting activation of both PI3K and mTOR. A549 cells also express wild- type EGFR.
[00363] As a single agent, Compound B, an inhibitor of EGFR, was orally administered once-daily at 30 mg/kg and Compound A was orally administered either at 30 mg/kg qd or 100 mg/kg q2d. Combination therapies consisted of Compound B with Compound A at 30 mg/kg or 100 mg/kg. Administration of each agent in the combination groups was separated by 6 h. Single agent administration of Compound B for 18 days caused a significant tumor growth inhibition of 80%. See Figure 4a. A significant tumor growth inhibition of 96% was observed with Compound A at 100 mg/kg q2d, whereas Compound A at 30 mg/kg qd lead to a lower but still significant TGI of 76%. The combination of Compound B 30 mg/kg qd with Compound A 30 mg/kg qd or with Compound A 100 mg/kg q2d resulted in significant efficacy associated with 15% and 39% regression, respectively, which was significantly higher than either of the single agent treatments alone.
[00364] As a single agent Compound B dosed at 30 mg/kg qd was generally well tolerated, with a body weight loss of 1.5-6.9% and no dose omission. Administration of Compound A dosed at 30 mg/kg qd was well tolerated with 4 doses skipped at the beginning of the study, which were not compound-related. Compound A dosed at 100 mg/kg q2d was also well tolerated with 1 dose skipped at the beginning of the study, which was not compound-related. The combination of Compound B at 30 mg/kg qd with Compound A at 30 mg/kg qd was fairly well tolerated with body weight loss of 1 to 8% and 2 doses skipped). However, the combination of Compound B at 30 mg/kg qd with Compound A at 100 mg/kg q2d was associated with body weight loss of 2 to 11% and 13 doses skipped within the first 10 days; however, body weights at the end of the study were not significantly different from the vehicle-treated control group. Single agent administration of Compound B and Compound A were well tolerated with minimal dose skipping. When administered in combination, minor body weight loss was observed that necessitated dose skipping primarily in the 100 mg/kg q2d group.
Breast Cancer Xenograft Model - A Compound of Formula I in Combination with
Compound B
[00365] Compound A was tested both as a single agent and in combination with Compound B, an EGFR inhibitor, in a breast tumor model. The MCF7 human breast carcinoma cell line harbors a heterozygous, activating mutation in PI3K (PI3KCA/E545K) and expresses wild-type EGFR.
[00366] Compound B was administered orally once-daily (qd) at 30 mg/kg, and Compound A was administered once-daily at 30 mg/kg or once every other day (q2d) at 100 mg/kg. Combination therapies consisted of Compound B together with Compound A at 30 mg/kg qd or 100 mg/kg q2d. Single agent administration of Compound B at 30 mg/kg qd for 14 days caused a tumor growth inhibition of 38%-61%. See Figures 4b-l and 4b-2. A significant tumor growth inhibition of 83%-91% was observed with Compound A at 100 mg/kg q2d, whereas Compound A at 30 mg/kg qd lead to a lower but still significant TGI of 57%. The combination of Compound B at 30 mg/kg qd with Compound A at 100 mg/kg q2d resulted in a significant efficacy associated with 16-22% regression, which was significantly higher than either of the single agent treatments alone. Combining Compound B at 30 mg/kg qd with Compound A at 30 mg/kg qd lead to a lower but still significant tumor growth inhibition of 66%, but did not add any benefit to the anti-tumor efficacy of the single treatments.
[00367] As a single agent Compound B dosed at 30 mg/kg qd was generally well tolerated, with a non significant final body weight loss of 4.5 to 6.1% and 7 to 13 dose omissions. Administration of Compound A at 30 mg/kg qd and 100 mg/kg q2d was well tolerated with minimal dose skipping and body weight loss. The combination of Compound B at 30 mg/kg qd with Compound A at 30 mg/kg qd lead to a body weight loss of 4 to 13% throughout the study and 14 doses skipped mostly within the first 9 days. The combination of Compound B at 30 mg/kg qd with Compound A at 100 mg/kg q2d was associated with a body weight loss of 3.7 to 13% throughout the study and 20 to 32 dose omissions.
Breast Cancer Xenograft Model - A Compound of Formula I in Combination with
Erlotinib
[00368] Compound A was tested both as a single agent and in combination with erlotinib, in an erolitinib-resistant tumor model with elevated PI3K signaling. [00369] MDA-MB-468 is a human breast carcinoma cell line that has an increase in the copy number of the EGFR gene and a homozygous deletion of PTEN. In vitro treatment of these cells with EGFR inhibitors such as erlotinib inhibits EGFR activity but fails to downregulate the PI3K pathway. Oral administration of erlotinib at 100 mg/kg qd to mice bearing MDA-MB-468 tumors resulted in significant but incomplete tumor growth inhibition. See Figure 5. Oral administration of Compound A at 100mg/kg qd resulted in a similar level of tumor growth inhibition. While tumor growth was inhibited substantially with Compound A alone, the combination of the two agents was superior to either agent alone and resulted in a regression of the tumors.
[00370J Mice administered Compound A at 100 mg/kg qd exhibited a modest (~3%) loss in body weight comparable to vehicle controls. Mice administered erlotinib exhibited an apparent decrease in their rate of body weight gain relative to vehicle controls. Coadministration with erlotinib resulted in a substantial loss in body weight in mice treated with Compound A (19% body weight loss from start of dosing). Consistent with these data, only minimal dose-skipping was required when Compound A was administered as monotherapy (1-3 doses skipped), but substantial dose-skipping was required for Compound A when erlotinib was coadministered. The fact that tumor regression was observed despite dose skipping suggests that use of an intermittent dosing schedule could maintain efficacy and improve tolerability. These results support the use of a Compound of Formula I in combination with erlotinib in tumors expressing EGF receptors and harboring PTEN deletions.
[00371] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

What is claimed is:
1. A method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula I:
Figure imgf000463_0001
I or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof; or administering a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula I and at least one of a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more of the hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation where the Compound of Formula I is that wherein:
W1, W2, W3, and W4 are -C(R1)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; and where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino; R51 is hydrogen or alkyl; R52 is hydrogen or halo;
R50, R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C , -C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R53 and R54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl; B is phenyl substituted with R3a and optionally further substituted with one, two, or three
R3; or
B is heteroaryl optionally substituted with one, two, or three R3; R3a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C i -C6-alkylene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R83 where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9a where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-C6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(R1 °)-C i -C6-alkylene-N(R10a)R10b where RIOa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R10 and R10b are independently hydrogen, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl; e) -NR1 1C(O)NR1 laR* lb where R1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R1 1 and Rl lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl; h) -C(O)N(R14)N(R14a)(R14b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-C,-C6-alkylene-N(R15a)R15b where R15, R15a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C,-C6-alkylene-C(O)OR16a where R16 is hydrogen, alkyl, or alkenyl and R16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; 1) -N(R17)-C(=N(R17b)(R17a))(NRl7cR17d) where R17, R17a, R17b, Rl 7c, and R17d are independently hydrogen, alkyl, or alkenyl; m) -N(Rl 8)C(O)-Ci-C6-alkylene-N(R18b)C(O)Rl8a where R18a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and R18b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(Rl9)-Ci-C6-alkylene-C(O)Rl9a where R19 is hydrogen, alkyl, or alkenyl and R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C i -C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and R20a is cycloalkyl or heterocycloalkyl; p) -NR21S(O)2-C i -C6-alkylene-N(R2lb)R21a where R21 is hydrogen, alkyl, or alkenyl and R2 la and R2 lb are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C i -C6-alkylene-N(R22b)-N(R22c)(R22a) where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-Ci-C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C i.C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and where each of the alkylene in R3a is independently optionally further substituted with 1,
2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and each R3 (when R3 is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo; alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or a) -N(R7)C(O)-C i -C6-alky lene-N(R7a)(R7b) where R7 is hydrogen, alkyl, or alkenyl and R7a and R7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R7a and R7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo); b) -C(O)NR8R8a where R8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H; c) -NR9C(O)R9a where R9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R9a is hydrogen, C2-C6-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl; d) -C(O)N(Rl0)-C|-C6-alkylene-N(R10a)Rl0b where RIOa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or hydroxyalkyl and R10 and R1Ob are independently hydrogen, alkyl, alkenyl, haloalkyl, or hydroxyalkyl; e) -NR1 1C(O)NR1 13R1 lb where R1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R1 ' and R1 lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminooalkyl, dialkylaminoalkyl; f) -C(O)R12 where R12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl; g) -NR13C(O)OR133 where R13 is hydrogen, alkyl, or alkenyl and R13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl); h) -C(O)N(Rl4)N(R14a)(Rl4b) where R14, R14a, and R14b are independently hydrogen, alkyl, or alkenyl; i) -S(O)2N(R15)-Ci-C6-alkylene-N(R15a)R15b where R15, R15a, and R15b are independently hydrogen, alkyl, or alkenyl; j) -C(O)N(R16)-C,-C6-alkylene-C(O)ORl6a where R16 is hydrogen, alkyl, or alkenyl and Rl6a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; 1) -N(Rl7)-C(=N(R17b)(R17a))(NR17cRl7d) where R17, RI7a, Rl7b, R17c, and Rl7d are independently hydrogen, alkyl, or alkenyl; m) -N(Rl8)C(O)-C,-C6-alkylene-N(R18b)C(O)R18a where R18a is hydrogen, alkyl, alkenyl, or alkoxy and R18 and R18b are independently hydrogen, alkyl, or alkenyl; n) -C(O)N(R19)-Ci-C6-alkylene-C(O)R19a where R19 is hydrogen, alkyl, or alkenyl and R19a is amino, alkylamino, dialkylamino, or heterocycloalkyl; o) -N(R20)C(O)-C i -C6-alkylene-C(O)R20a where R20 is hydrogen, alkyl, or alkenyl and R20a is cycloalkyl or heterocycloalkyl; p) -NR21S(O)2-Ci-C6-alkylene-N(R2lb)R21a where R21 is hydrogen, alkyl, or alkenyl and R21a and R21b are independently hydrogen, alkyl, or alkenyl; q) -N(R22)C(O)-C,-C6-alkylene-N(R22b)-N(R22c)(R22a), where R22, R22a and R22b are independently hydrogen, alkyl, or alkenyl; r) -C0-C6-alkylene-N(R23)-C , .C6-alkylene-N(R23b)R23a where R23, R23a and R23b are independently hydrogen, alkyl, or alkenyl; or s) -NR24C(O)-C i .C6-alkylene-OR24a where R24 is hydrogen, alkyl, or alkenyl and
R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; wherein each of the alkylene in R3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and provided that when R50 and R52 are hydrogen, R51 is hydrogen or methyl, R53 is hydrogen or methoxy, and R54 is hydrogen or methoxy, then B is not 2,3-dihydro-l,4- benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R3 where R3 is halo.
2. The method of Claim 1 where the cancer is selected from breast cancer, colon cancer, rectal cancer, endometrial cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, glioblastoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, and thyroid carcinoma.
3. The method of Claim 1 or 2 where the treatment is one or two chemotherapeutic agents.
4. The method of Claims 1 or 2 where the treatment is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
5. The method of Claim 4 where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, paclitaxel, carboplatin, lapatinib, erlotinib, and N-(3,4-dichloro-2-fiuorophenyl)-7-({[(3afl,5r,6a5>2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
6. The method of Claim 3 where the treatment is one chemotherapeutic agent and the chemotherapeutic agent is an EGFR inhibitor.
7. The method of Claim 3 where the treatment is one chemotherapeutic agent and the chemotherapeutic agent is a platin.
8. The method of Claim 3 where the treatment is one chemotherapeutic agent and the chemotherapeutic agent is a taxane.
9. The method of Claim 3 where the treatment is one chemotherapeutic agent and the chemotherapeutic agent is rapamycin or a rapamycin analogue.
10. The method of Claim 3 where the treatment is one chemotherapeutic agent and the chemotherapeutic agent is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3a/?,5r,6a5)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2- fluorophenyl)-7-({[(3a/?,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, or N-(4-bromo-3-chloro-2- fluorophenyl)-7-({[(3a/?,5s,6a5)-2-methyloctahydrocyclo-penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine; optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
1 1. The method of Claim 1 where the cancer is prostate cancer and the treatment is one or two chemotherapeutic agents selected from rapamycin, paclitaxel, and docetaxel.
12. The method of Claim 1 where the cancer is breast cancer and the treatment is one chemotherapeutic agent and the chemotherapeutic agent is lapatinib.
13. The method of Claim 1 where the cancer is breast cancer and the treatment is one chemotherapeutic agent and the chemotherapeutic agent is erlotinib.
14. The method of Claim 1 where the cancer is breast cancer and the treatment is one chemotherapeutic agent and the chemotherapeutic agent is N-(3,4-dichloro-2- fluorophenyl)-7-({[(3aΛ,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
15. The method of Claim 1 where the cancer is non-small cell lung cancer and the treatment is one chemotherapeutic agent where the chemotherapeutic agent is carboplatin.
16. The method of Claim 1 where the cancer is non-small cell lung cancer and the treatment is one chemotherapeutic agent where the chemotherapeutic agent is N-(3,4- dichloro-2-fluorophenyl)-7-({[(3a/?,5r,6a1S)-2-methyloctahydrocyclopenta-[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
17. The method of Claim 1 where the Compound of Formula I is according to Formula I(a)
Figure imgf000471_0001
I(a) where
W1, W2, W3, and W4 are -C(R1)=; or one or two of W1, W2, W3, and W4 are independently -N= and the remaining are -C(R1)=; and where each R1 is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino;
R51 is hydrogen or alkyl;
R52 is hydrogen or halo;
R50, R53, and R54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R55)C(O)-C , -C6-alkylene-N(R55a)R55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxy carbonyl, cyano, alkylthio, -S(O)2NR55R55a, or alkylcarbonylamino and where R55 and R55b are indepedently hydrogen, alkyl, or alkenyl and R55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R ,5"3 and R >5D4 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl; R3 is not present or R3 is alkyl; and R3a is -N(R7)C(O)-Ci-C6-alkylene-N(R7a)(R7b), -C(O)NR8R83 , -NR9C(O)R93, or -C(O)N(R10)-Cι-C6-alkylene-N(Rl0a)Rl0b; where each of the alkylene in R3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
18. The method of Claim 1 or 2 where the Compound of Formula I is selected from:
7V-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-l ,6-dihydropyridine-3- sulfonamide; iV-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-dimethylthiophene-3-sulfonamide;
Λ^-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-dichlorothiophene-3-sulfonamide;
M(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-l,6-dihydropyridine-3-sulfonamide;
Λ^-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-chloropyridine-3-sulfonamide; yV-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-dimethylisoxazole-4-sulfonamide; yV-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-5-chloro-l,3-dimethyl-l//-pyrazole-4- sulfonamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-/V-methyl-yV- propylbenzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylbutanamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- methylbutanamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pent-4-enamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)propanamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,2- dimethylpropanamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-[2-(dimethylamino)- 1 -methylethyl]benzamide;
Λ^-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)- yV2-methylglycinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-[2- (dimethylamino)ethyl]benzamide;
5-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-iV-[2- (dimethylamino)ethyl]-2-fluorobenzamide;
3-{[(3-{[2-chIoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ'-pyrrolidin-3- ylbenzamide;
3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-/V-[2- (dimethylamino)ethyl]benzamide;
//-(S-j^-f P-chloro-S^methyloxyJphenyllaminolquinoxalin^-yOaminolsulfonylJphenyOglycinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-(2-pyrrolidin-l- ylethyl)benzamide;
Figure imgf000473_0001
methylglycinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-yV-(2-piperidin-l- ylethyl)benzamide;
N2,jV2-dimethyl-/V-(3- { [(3- { [6-(methyloxy)quinolin-8-yl]amino } quinoxalin-2- yl)amino]sulfonyl } phenyl)glycinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ'-[2- (diethylamino)ethyl]benzamide; yV-(3-{[(3-{[3,5-bis(methyIoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-alaninamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyI]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylalaninamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-Λ^2,Λf2- dimethylglycinamide;
3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyI} -N-[2- (dimethylamino)ethyl]-N-methylbenzamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-(l-methylpiperidin- 3-yl)benzamide;
JV-(3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]suIfonyl } phenyl)-Λ^2-methyl- D-alaninamide;
//-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-prolinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yI)amino]sulfonyl}-Λ'-piperidin-3- ylbenzamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-[(l-methylpiperidin- 2-yl)methyl]benzamide; yV-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-cyanobenzenesulfonamide;
A'-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-//2-[2- (dimethylamino)ethyl]-iV2-methylglycinamide;
//-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-serinamide;
(2S)-2-amino-Λ^-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)butanamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)azetidine-3- carboxamide;
Λ^-{2-[bis(2-hydroxyethyl)amino]ethyl}-3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl } benzamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-yV-(l-ethylpiperidin-3- yl)benzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-[2- (dimethylamino)ethyl]-Λ^2-methylglycinamide;
JV-(3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfoπyl } phenyl)-//2 ,N2- dimethylglycinamide; yV-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino>quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2,2- dimethylalaninamide;
Λ^-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino> quinoxalin-2-yl)amino]sulfonyl } phenyl)-/V2-methyl-D- alaninamide; 3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzamide;
3-[(3-aminopyrrolidin-l -yl)carbonyl]-7V-(3- {[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
Λ'-(3-{[(3-{[2-bromo-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-/l/2 rΛ'2- dimethylglycinamide; jV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-//2- propylglycinamide;
^-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2-methyl- L-alaninamide;
^-(5-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2-methylphenyl)-beta- alaninamide;
5-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λr-[2- (dimethylamino)ethyl]-2-(methyloxy)benzamide;
7V-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(hydroxyamino)benzenesulfonamide; yV-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-3- carboxamide;
Λ^^-l^-chloro-S-CmethyloxyJphenylJaminoJquinoxalin^-yO-S-lfS-CmethylaminoJpyrrolidin-l- yl]carbonyl } benzenesulfonamide;
3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]suIfonyl } benzoicacid;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-yV-(2-moφholin-4- ylethyl)benzamide;
3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } -N-[( 1 -ethylpyrrolidin- 2-yl)methyl]benzamide;
^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-methyl-l,4- diazepan- 1 -yl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2 v/V2- dimethylglycinamide;
3-[(4-amino-3-oxopyrazolidin-l-yl)carbonyl]-Λ^-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin- 2-yl)benzenesulfonamide;
(2S)-2-amino-Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)butanamide;
A^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-iV2-(2- hydroxypropyl)glycinamide; jV-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxaIin-2-yl)amino]sulfonyl}phenyl)-/V2-(2- fluoroethyl)glycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-iV2-[(2- methylpropyl)oxy]glycinamide;
1 -am\no-N-(3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino} quinoxalin-2- yl)amino]sulfony 1 } pheny^cyclopropanecarboxamide;
/V-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(forτnylamino)benzenesulfonamide;
Λ'-(3-{[(3-{[3,5-bis(methyIoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2- (cyclopropylmethyOglycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-/V2-methyl-L- alaninamide; Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-prolinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-jV-methylbenzamide;
3-[(3-aminoazetidin- 1 -yl)carbonyl]-./V-(3- { [2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide;
^-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}ρhenyl)-2-[3- (dimethylamino)azetidin- 1 -yl]acetamide;
/V-(3-{[(3-{[2-chIoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D- prolinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-//-(pyridin-3- ylmethyl)benzamide; jV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-2- carboxamide;
7V-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)moφholine- 4-carboxamide;
Λ'-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyrrolidin-l- ylacetamide;
7V-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)- N~6~,N~6 — dimethyl-L-lysinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-A^-ethyI-yV2- methylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(l//-imidazol- 4-yl)acetamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-(pyridin-2- ylmethyl)benzamide; l-amino-Λ^-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yljaminolsulfonyljpheny^cyclopentanecarboxamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ'-(2- hydroxyethyl)benzamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-oxopyrazolidin-4- yl)benzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-(2- methylpropyl)glycinamide;
N-(3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-Λf2-ethyl-Λ'2- methylglycinamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l -(l//-imidazol- 4-ylmethyl)azetidine-3-carboxamide;
^-(S-l^-iP-chloro-S^methyloxyJphenylJaminoJquinoxalin^-yOaminolsulfonylJ^-methylphenyl)- N2,/V2-dimethylglycinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-/V-[2-(l//-imidazol-4- yl)ethyl]benzamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l -ethylazetidine- 3-carboxamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyllamino}quinoxalin-2-yl)amino1sulfonyl}phenyl)-yV2-methyl-yV2- ( 1 -methylpyrrolidin-S-yOglycinamide; yV-(3-{[(2-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]sulfonyl}phenyl)-/V2-[2- (dirnethytarnino)ethyl]-N2-rnethylglycinarnide; yV-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(methylamino)benzenesulfonamide;
/V-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{t3-(dimethylamino)pyrrolidin-l- yl]carbonyl } benzenesulfonamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(3S)-3- hydroxypyrrolidin- 1 -yljacetamide; l-amino-^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- y^aminolsulfonyljpheny^cyclobutanecarboxamide;
N-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } phenyl)-jV2- butylglycinamide;
Λ^-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- piperidin- 1 -ylazetidin- 1 -yl)acetamide;
3-[(aminocarbonyl)atnino]-iV-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyI]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l- hydroxycyclopropanecarboxamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ?-(pyridin-4- ylmethyl)benzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,2- dimethylhydrazino)acetamide;
/V-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-[({[2- (dimethylamino)ethyl]amino}carbonyl)amino]benzenesulfonamide;
3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } -N-methy\-N-( 1 - methylpyrrolidin-3-yl)benzamide; yV-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(diethylamino)pyrrolidin-l- yl]carboπyl } benzenesulfonamide;
Λr-(3-{[(3-{[3-fluoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-7V2- methylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- hydroxyacetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridazine-4- carboxamide;
N-Q- {[(3- {[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl} phenyl)- 1- methylpiperidine-4-carboxamide;
3- {[(3- { [2-chloro-5-(methyIoxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl} -N- 1 //-pyrrol- 1 - ylbenzamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-(l- methylethyOglycinamide; l-amino-/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yOaminoJsulfonylJphenyOcyclopentanecarboxamide; l-amino-iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl } phenyOcyclopropanecarboxamide;
Figure imgf000478_0001
Figure imgf000479_0001
carboxamide;
//-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-^V2,yV2- diethylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- methylisoxazol-5-yI)acetamide;
3-{[(3-{[2-chloro-5-(methyloxy)pheπyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ'-[3- (methyloxy)propyl]benzamide;
/*/2f2-dimethyl-Λ'-(3-{[(3-{[2-methyl-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl } phenyl)glycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]suIfonyl}phenyl)-Λ^2-[(3- hydroxyphenyl)methyl]glycinamide;
N-(3-{ [(3- {[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l -methyl- \H- pyrrole-2-carboxamide;
4-amino-Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)tetrahydro-2H-pyran-4-carboxamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4- (methylamino)piperidin- 1 -yl]acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-piperidin-l- ylacetamide;
N-(A- { [(3- { [3,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } phenyl)-7V2,yV2- dimethylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l-methyl-L- prolinamide;
/V-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(methylsulfonyl)benzenesulfonamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-[3- (dimethylamino)propyl]-yV-methylbenzamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-[3- (propyloxy)propyl]benzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)thiophene-3- carboxamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l- (cyclopropylcarbonyl)azetidine-3-carboxamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- methylpiperazin- 1 -yl)acetamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l- (phenylmethyl)azetidine-3-carboxamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- chloropyridine-3-carboxamide; ethyW-[(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl } phenyl)carbonyl]-beta-alaninate;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-//-{3-[(l - methylethyl)oxy]propyl } benzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-4- ylacetamide; 3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-^V-(l,l-dimethyl-2- piperidin- 1 -ylethyl)benzamide;
Λf-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ' -methyl-Λ' - prop-2-en- 1 -ylglycinamide;
Λ^-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{5-[(dimethylamino)methyl]-l,3,4- oxadiazol-2-yl}benzenesulfoπamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)pheπyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-//2- (phenylmethyl)glycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (methyloxy)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l- propanoylazetidine-3-carboxamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridine-3- carboxamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λf2-[2- (methyloxy)ethyl]glycinamide; l-acetyl-Λf-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)piperidine-4-carboxamide;
^-{[(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)amino](dimethylamino)methylidene}-yV-methylmethanaminium;
Λf-(3-{[3,5-bis(methyloxy)phenyl]atnino}quinoxalin-2-yl)-4-[(trifluoromethyl)oxy]benzenesulfonamide;
Λr-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxaIin-2-yl)amino]sulfonyl}phenyl)-2-(2- methylpyrrolidin- 1 -yl)acetamide;
3- {[(3- {[2-chloro-5-(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl} -Λ^-piperidin- 1 - ylbenzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)furan-3- carboxamide;
Λ^2,7V2-dimethyl-Λ^(3-{[(3-{[3-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)glycinamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-Λ^-[l-methyl-2- (methyloxy)ethyl]benzamide;
N-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-6- chloropyridine-3-carboxamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- chlorobenzamide;
^-(S^fCS-IP.S-bis^ethyloxyJphenylJaminojquinoxalin^-yOaminolsulfonylJphenyl^-pyridin^- ylacetamide;
N-(3- ( [(3- {[3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-2-[3- (dimethylamino)azetidin- 1 -yljacetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4- (dimethylamino)piperidin- 1 -yljacetamide;
^^-{^-{[S^-bisCmethyloxyJphenylJaminofquinoxalin^-ylJaminoJsulfonylJphenyl^-pyridin-S- ylacetamide;
N-(3- { [(3- {[3,5-bis(methyloxy)phenyl]amino> quinoxalin-2-yl)amino]sulfonyl } phenyl)-2-(2- chlorophenyl)acetamide; ^^-{[(S-ltS.S-bisCmethyloxyJphenylJaminoJquinoxalin^-yOaminolsulfonylJphenyO-yV2-^- (dimethylamino)propyl]-JV2-methylglycinarnide;
^-(S-ffCS-ltS.S-bisCmethyloxyJphenyljaminoIquinoxalin-Z-yOaminolsulfonylJphenyO-yV^ethyl-yV2^- hydroxyethyl)glycinamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[2- (phenylmethyl)pyrrolidin- 1 -yl]acetamide;
^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)furan-2- carboxamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- chloropyridine-4-carboxamide;
Λf2-acetyl-Λ^3-{[(3-{[3,5-bis(methyloxy)phenyl]arnino}quinoxalin-2- yl)amino]sulfonyl}phenyl)glycinamide;
Λ^-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-4- chlorobenzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- methylbenzamide; l,l-dimethylethyl{2-[(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl }phenyl)amino]-2-oxoethyl } carbamate;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxa!in-2-yl)amino]sulfonyl}-Λ/-(l,l-dimethyl-2- moφholin-4-ylethyl)benzamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l,3- benzodioxole-5-carboxamide;
^■(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-({[2- (methyloxy)phenyl]methyl}oxy)glycinamide;
Λ'-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-({2-[(dimethylamino)methyl]piperidin- 1 -yl } carbonyl)benzenesulfonamide;
Λf-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridine-4- carboxamide;
Λ^-(3-{[(3-{[4-fluoro-3-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2,Λ^2- dimethylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyI}phenyl)-2-[4-(3,4- dichlorophenyl)piperazin- 1 -yl]acetamide;
A^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-pyridin-3- ylpropanamide;
Λf-[3-(butyloxy)propyl]-3- { [(3- { [2-chloro-5-(methyloxy)phenyl]amino } quinoxalin-2- yl)amino]sulfonyl}benzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydrofuran- 3-carboxamide;
^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-[(2- methylphenyl)methyl]glycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfony!}phenyl)-2-(3- fluorophenyl)acetamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]su!fonyl}-yV-[4-(diethylamino)-l- methylbutyl]benzamide; yy-(3-{[(3-{[3,5-bis(methyloxy)phenyl1amino}quinoxalin-2-yl)amino1sulfonyl}phenyl)-/V2-(l -methyl- 1- phenylethyl)glycinamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylcyclopropaπecarboxamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methyl-4- (methyloxy)benzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylpyridine-3-carboxamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- (methyloxy)benzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- ethylpiperazin- 1 -yl)acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)thiophene-2- carboxamide;
Λr-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-2- methylbenzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- bromothiophene-3-carboxamide;
W-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- fluorobenzamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- methylpiperidin- 1 -yl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino>quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylpropanamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pentanamide
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (ethyloxy)acetamide;
N-(3- { [(3- { [3 ,5-bis(methy loxy)phenyl]amino } quinoxalin-2-yl)amino]suIfonyl } phenyl)-jV2-(2- fluorophenyl)glycinamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- (dimethylamino)benzamide;
N-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino} quinoxal in-2-yl)amino]sulfonyl } phenyl)-2-(4- methylpiperidin-1 -yl)acetamide;
3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-iV-(l ,l-dimethyl-2-oxo- 2-piperidin-l-yIethyl)benzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-iV2-(2- propylphenyl)glycinamide; jV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)benzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyrazine-2- carboxamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-f1uoro-4- (methyloxy)benzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,2- dimethylbutanamide; yV-(3-{[(3- {[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino1sulfonyl}phenyl)-2-[(4- fluorophenyl)oxy]acetamide; l-acetyl-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)azetidine-3-carboxamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-jV2-(4- methylphenyl)glycinamide;
N-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]suIfonyl } phenyl)-jV2- phenylglycinamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-prop-2-en- 1 -ylpiperazin- 1 -yl)acetamide;
Λf-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylbenzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- (methyloxy)propanamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-methylfuran-2- carboxamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2- [(phenylmethyl)oxy]glycinamide;
/V-{3-[({3-[(2-chloro-5-hydroxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-A'2 r/V2- dimethylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amiπo]sulfonyl}phenyl)-Λ^2-(3- chlorophenyOglycinamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl } pheny^cyclobutanecarboxamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (methyloxy)phenyl]acetamide;
JV-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } phenyl)- 1 - methylcyclopropanecarboxamide; yV-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-[(4-methylpiperazin-l- yl)carbonyl]benzenesulfonamide;
Λf-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-{[2-(dimethylamino)ethyl]amino} pyridine- 3-sulfonamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- fluorobenzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- (dimethylamino)benzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,4- dichlorobenzamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2-{[2- (methylthio)phenyl]methyl}glycinamide;
Λ^-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl > pheny l)-2-(2- fluorophenyl)acetamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yv2-ethyl-Λ^2-(l- methylethyl)glycinamide;
//-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-l ,3-thiazole-4- carboxamide; Λ'-CB-ltCS-ltS.S-bisCmethyloxyJphenylJaminolquinoxalin-Z-yOaminolsulfonyUphenyO-^-methyl-Λ'2- (phenylmethyl)glycinamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-(2- thienylmethyl)glycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}pheπyl)-Λf2-(pyridin-2- ylmethyl)glycinamide;
N-(3- {[(3- {[3,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } phenyl)-3- (methyloxy)benzamide;
Λf-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2-[(3-chloro-4- methylphenyl)methyl]glycinamide;
N-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyI)-2- methylpentanamide;
N-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-2-(4- chlorophenyl)acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-4- methylbenzamide;
Λf-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(2- methylphenyl)oxy]acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- cyclohexylacetamide;
(lR,2R)-Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- phenylcyclopropanecarboxamide;
Λ^-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(dimethylamino)benzenesulfonamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- chlorobenzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[2- (methyloxy)phenyl]acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[3- (methyloxy)phenyl]propanamide;
ΛL(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-(2-fluoro-4- methylphenyl)glycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2-[(3- fluorophenyl)methyl]glycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyIoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4- (methyloxy)phenyl]acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyI]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- phenylacetamide; iV^-l^-IP.S-bisCmethyloxyJphenylJaminolquinoxalin^-yOaminoJsulfonylJphenyl)^^- dichlorobenzamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- oxocyclohexanecarboxamide;
//-(3-{[(3-{t3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfoπyl}phenyl)-jV2-(3- fluorophenyOglycinamide;
N-(3- { [(3- { [3 ,5-bis(methy loxy)pheπy l]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-2-(3- chlorophenyl)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-(2- phenylpropyl)glycinamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-[(2,4- dimethylphenyl)methyl]glycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- methylpiperidin- 1 -yl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]suIfonyl}phenyl)-Λ^2-[2- (methyloxy)phenyl]glycinamide; jV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3,4- dihydroisoquinolin-2( 1 //)-yl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-(2- m meetthhvyllnphheennvyllW)gllvycciinnaammiiddee:;
N-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-2-(4- oxopiperidin- 1 -yl)acetamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- fluorobenzamide;
Λ'-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-{[2-(dimethylamino)ethyl]oxy}pyridine-3- sulfonamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amiπo]sulfonyl}phenyl)-Λf2-(l- phenylethyl)glycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluoro-6- (methyloxy)benzamide;
^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyI}phenyl)-4-methyl-3- (methyloxy)benzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λr2-[2-(l- methylethyl)phenyl]glycinamide;
^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[2- (methyloxy)phenyl]propanamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- methylpentanamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- phenylmoφholin-4-yl)acetamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)aniino]sulfonyl}phenyl)-3-[4- (methyloxy)phenyl]propanamide;
N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2-cyclopentyl- jV2-prop-2-en- 1 -ylglycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-//2-methyl-//2- [2-(methyloxy)ethyl]glycinamide;
/V-(3-{[(3-{[3,5-bis(methyIoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-cyclopropyl-4- oxobutanamide;
^(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-/V2-[3-(l,l- dimethylethyl)phenyl]glycinamide;
JV-(3- {[(3- { [3,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]suIfonyl } phenyl)-/V2- (cyclopropylmethyl)-iV2-propylglycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- oxocyclopentyl)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ'2-(4- chlorophenyl)glycinamide;
2-( 1 ,4'-bipiperidin- 1 '-yl)-/V-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino } quinoxaIin-2- yl)amino]sulfony 1 } phenyl)acetamide; yV-(3-{[(3-{[3,5-bis(methyIoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- cyclopentylpiperazin- 1 -yl)acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- methylphenyl)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-[(5-fluoro-2- methylphenyl)methyl]glycinamide;
N-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-3 ,3- dimethylbutanamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-(2- chlorophenyl)glycinamide yV-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[2-(piperidin-l-ylmethyl)piperidin-l- yljcarbonyl } benzenesulfonamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-fluoro-2- methylbenzamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-fluoro-3- methylbenzamide;
Λr-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,3- dichlorobenzamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (phenyloxy)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-(2,3- dimethylphenyl)glycinamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluoro-5- methylbenzamide;
N-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } phenyl)-^2- { [(4- methylphenyl)methyl]oxy}glycinamide;
Λ^-(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino} quinoxalin-2-yl)amino]sulfonyl } phenyl)-2-[4-( 1 - methylethyl)piperazin- 1 -yl]acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- fluorophenyl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}pheπyl)-4-methyl-2- (methyloxy)benzamide;
//-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- propylpiperidin- 1 -yl)acetamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(3- methylphenyl)oxy]acetamide;
^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydrofuran- 2-carboxamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (hydroxymethyl)piperidin- 1 -yljacetamide; 1 , 1 -dimethylethyβ- { [(3- { [(3- { [3,5-bis(methyloxy)phenyl]amino } quinoxalin-2- yl)amino]sulfonyl } phenyl)amino]carbonyl } piperidine- 1 -carboxylate; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λ^2-methyl-Λf2- (pyridin-3-ylmethyl)glycinamide;
A^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-ethyl-/V2- phenylglycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-{[2- (methyloxy)ethyl]oxy } acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- cyclopentylpropanamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,5- dichlorobenzamide;
2-(4-acetylpiperazin-l-yl)-/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl } phenyl)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-fluoro-2- (methyloxy)benzamide;
/V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-Λf -cyclohexyl- N2-ethylglycinamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5- methylisoxazole-3-carboxamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- methylpyridine-2-carboxamide;
Λ^-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyI}phenyl)-2- (methyloxy)pyridine-3-carboxamide;
Λ^(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,5- dichlorobenzamide;
Λ^-(3-{[(3-{[3,5-bis(methyIoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(l,3- thiazolidin-3-yl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- formylpiperazin- 1 -yl)acetamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-pyridin-4- ylpiperidin- 1 -yl)acetamide;
N-(3- { [(3- { [3 ,5-bis(methyloxy)phenyl]amino } quinoxalin-2-yl)amino]sulfonyl } phenyl)-2- (methyloxy)benzamide;
Λ'-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-yV2-methyl-Λ^2- (2-methylpropyl)glycinamide;
Λ^-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]suIfonyl}phenyl)-2-(4-formyl-l,4- diazepan- 1 -yl)acetamide; yV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyI)-l- phenylcyclopropanecarboxamide; iV-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyI}phenyl)-2-(2,6- dimethylmorpho!in-4-yl)acetamide;
7V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- phenylpyrrolidin- 1 -yl)acetamide; and /V-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-moφholin-4- ylacetamide; where the Compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
19. The method of Claims 1, 2, 4, 17, or 18 where the treatment is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
20. The method of Claim 19 where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, paclitaxel, carboplatin, lapatinib, erlotinib, and Λ/-(3 ,4-dichloro-2-fluorophenyl)-7-( { [(3a/?,5r,6aS)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
21. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is N-(3,4-dichloro-2- fluorophenyl)-7-({[(3a/?,5r,6a»S)-2-methyloctahydrocyclopenta-[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
22. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is erlotinib.
23. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is lapatinib.
24. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is carboplatin.
25. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is paclitaxel.
26. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is rapamycin.
27. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one antibody selected from bevacizumab, trastuzumab, cetuximab, and panitumumab.
28. The method of Claim 1, 2, 3, 4, 17, or 18 where the treatment is one chemotherapeutic agent where the chemotherapeutic agent is of formula 100:
Figure imgf000490_0001
where q is 1, 2, or 3; E is -NR9-, -O-, or absent and Y is -CH2CH2-, -CH2-, or absent provided that when E is -NR9- or -O-, then Y is -CH2CH2-; R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, and lower alkyl; R8 is selected from -H, lower alkyl, -C(O)OR3, -C(O)N(R3)R4, -SO2R4, and -C(O)R3; R9 is hydrogen or lower alkyl; R3 is hydrogen or R4; R4 is selected from lower alkyl, aryl, lower arylalkyl, heterocyclyl, and lower heterocyclylalkyl; or R3 and R4, when taken together with a common nitrogen to which they are attached, form a five- to seven-membered heterocyclyl, said five- to seven-membered heterocyclyl optionally containing one or more additional heteroatom selected from N, O, S, and P; or a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, additionally optionally as a solvate, and additionally as a hydrate thereof.
PCT/US2008/004570 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer WO2008127594A2 (en)

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UAA200911452A UA98141C2 (en) 2007-04-11 2008-04-08 Methods of treating with quinaxoline inhibitors of pi3k-alpha
PL08742674T PL2139483T3 (en) 2007-04-11 2008-04-08 Combination therapies comprising a quinoxaline inhibitor of pi3k-alpha for use in the treatment of cancer
JP2010503043A JP5726515B2 (en) 2007-04-11 2008-04-08 Method of treatment by inhibition of PI3K-alpha with a quinazoline inhibitor
AU2008239668A AU2008239668B2 (en) 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of PI3K-alpha for use in the treatment of cancer
EA200970935A EA019064B1 (en) 2007-04-11 2008-04-08 Methods of treating cancer by inhibiting with quinaxoline inhibitors of pi3k-alpha
DK08742674.8T DK2139483T3 (en) 2007-04-11 2008-04-08 Combination therapies including a quinoxaline inhibitor of PI3K-alpha for use in the treatment of cancer
EP08742674.8A EP2139483B9 (en) 2007-04-11 2008-04-08 Combination therapies comprising a quinoxaline inhibitor of pi3k-alpha for use in the treatment of cancer
MX2009010929A MX2009010929A (en) 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer.
ES08742674.8T ES2438998T3 (en) 2007-04-11 2008-04-08 Combined therapies comprising a quinaxoline inhibitor of PI3K alpha for use in cancer treatment
RS20130486A RS53020B (en) 2007-04-11 2008-04-08 Combination therapies comprising a quinoxaline inhibitor of pi3k-alpha for use in the treatment of cancer
NZ580009A NZ580009A (en) 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer
MEP-2009-304A ME00937B (en) 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer
US12/595,236 US8481001B2 (en) 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of P13K-alpha for use in the treatment of cancer
BRPI0810208-2A2A BRPI0810208A2 (en) 2007-04-11 2008-04-08 COMBINATION OF THERAPIES UNDERSTANDING QUINOXALINE-BASED P13K-ALPHA INHIBITORS FOR USE IN CANCER TREATMENT.
CN2008800173944A CN101959516B (en) 2007-04-11 2008-04-08 Methods of treating by inhibiting with quinaxoline inhibitors of PI3K-alpha
CA002684056A CA2684056A1 (en) 2007-04-11 2008-04-08 Combination therapies comprising quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer
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IL201211A IL201211A (en) 2007-04-11 2009-09-29 Quinoxaline inhibitors of pi3k-alpha for use in combination with chemotherapeutic agents for use in the treatment of cancer
TNP2009000399A TN2009000399A1 (en) 2007-04-11 2009-09-30 TREATMENT METHODS INVOLVING INHIBITION OF PI3K-ALPHA USING QUINAXOLIN-TYPE INHIBITORS
MA32313A MA31335B1 (en) 2007-04-11 2009-10-30 TREATMENT METHODS INVOLVING INHIBITION OF PI3K-ALPHA USING QUINAXOLIN-LIKE INHIBITORS
EC2009009723A ECSP099723A (en) 2007-04-11 2009-11-09 USE OF PI3K-ALFA QUINAXOLINE INHIBITING COMPOUNDS FOR CANCER TREATMENT
HK10106504.4A HK1140141A1 (en) 2007-04-11 2010-07-05 Combination therapies comprising a quinoxaline inhibitors of pi3k-alpha for use in the treatment of cancer
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010053182A1 (en) * 2008-11-10 2010-05-14 協和発酵キリン株式会社 Kynurenine production inhibitor
DE102009049679A1 (en) 2009-10-19 2011-04-21 Merck Patent Gmbh Pyrazolopyrimidinderivate
WO2012006552A1 (en) 2010-07-09 2012-01-12 Exelixis, Inc. Combinations of kinase inhibitors for the treatment of cancer
DE102010049595A1 (en) 2010-10-26 2012-04-26 Merck Patent Gmbh quinazoline derivatives
WO2012052420A1 (en) 2010-10-20 2012-04-26 Merck Serono S.A. Geneva Method for preparing substituted n-(3-amino-quinoxalin-2-yl)-sulfonamides and their intermediates n-(3-chloro-quinoxalin-2-yl)sulfonamides
WO2012052102A1 (en) 2010-10-20 2012-04-26 Merck Patent Gmbh Quinoxaline derivates
WO2012065057A2 (en) 2010-11-12 2012-05-18 Exelixis, Inc. Phosphatidylinositol 3-kinase inhibitors and methods of their use
WO2013040337A1 (en) * 2011-09-14 2013-03-21 Exelixis, Inc. Phosphatidylinositol 3-kinase inhibitors for the treatment of cancer
WO2013056067A1 (en) 2011-10-13 2013-04-18 Exelixis, Inc. Compounds for use in the treatment of basal cell carcinoma
WO2013063000A1 (en) * 2011-10-28 2013-05-02 Novartis Ag Method of treating gastrointestinal stromal tumors
WO2013067306A1 (en) * 2011-11-02 2013-05-10 Exelixis, Inc. Phosphatidylinositol 3-kinase inhibitors for the treatment of childhood cancers
WO2013067141A1 (en) * 2011-11-01 2013-05-10 Exelixis, Inc. N- (3- { [ (3- { [2-chloro-5- (methoxy) phenyl] amino} quinoxalin- 2 -yl) amino] sulfonyl} phe nyl) - 2 -methylalaninamide as phosphatidylinositol 3 - kinase inhibitor for the treatment of lymphoproliferative malignancies
WO2013052699A3 (en) * 2011-10-04 2013-06-06 Gilead Calistoga Llc Novel quinoxaline inhibitors of pi3k
WO2013152717A1 (en) 2012-04-10 2013-10-17 上海昀怡健康管理咨询有限公司 Fused pyrimidine compound, and preparation method, intermediate, composition, and uses thereof
WO2015043398A1 (en) 2013-09-30 2015-04-02 上海璎黎药业有限公司 Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof
WO2015055071A1 (en) 2013-10-16 2015-04-23 上海璎黎药业有限公司 Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
US9487526B2 (en) 2012-08-13 2016-11-08 Takeda Pharmaceutical Company Limited Quinoxaline derivatives as GPR6 modulators
US10179783B2 (en) 2014-02-14 2019-01-15 Taketa Pharmaceutical Company Limited Tetrahydropyridopyrazines as modulators of GPR6

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2513165T3 (en) * 2005-10-07 2014-10-24 Exelixis, Inc. N- (3-amino-quinoxalin-2-yl) -sulfonamide derivatives and their use as phosphatidylinositol-3-kinase inhibitors
EA016945B1 (en) * 2005-10-07 2012-08-30 Экселиксис, Инк. PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kα
AU2007284562B2 (en) 2006-08-16 2013-05-02 Exelixis, Inc. Using PI3K and MEK modulators in treatments of cancer
BRPI0810206A2 (en) * 2007-04-10 2014-10-21 Exelixis Inc CANCER TREATMENT METHOD
TW201139436A (en) 2010-02-09 2011-11-16 Exelixis Inc Methods of treating cancer using pyridopyrimidinone inhibitors of PI3K and mTOR in combination with autophagy inhibitors
WO2012037204A1 (en) 2010-09-14 2012-03-22 Exelixis, Inc. Inhibitors of pi3k-delta and methods of their use and manufacture
WO2013101964A1 (en) * 2011-12-27 2013-07-04 Kadmon Corporation, Llc Methods for treatment of breast cancer nonresponsive to trastuzumab
US9950194B2 (en) 2014-09-09 2018-04-24 Mevion Medical Systems, Inc. Patient positioning system
WO2019119206A1 (en) 2017-12-18 2019-06-27 Merck Sharp & Dohme Corp. Purine inhibitors of human phosphatidylinositol 3-kinase delta

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1599196A4 (en) * 2003-01-17 2006-05-31 Threshold Pharmaceuticals Inc Combination therapies for the treatment of cancer
KR20080049767A (en) * 2005-08-26 2008-06-04 라보라뚜와르 세로노 에스. 에이. Pyrazine derivatives and use as pi3k inhibitors
ES2513165T3 (en) 2005-10-07 2014-10-24 Exelixis, Inc. N- (3-amino-quinoxalin-2-yl) -sulfonamide derivatives and their use as phosphatidylinositol-3-kinase inhibitors
EA016945B1 (en) 2005-10-07 2012-08-30 Экселиксис, Инк. PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kα
AU2007284562B2 (en) 2006-08-16 2013-05-02 Exelixis, Inc. Using PI3K and MEK modulators in treatments of cancer
WO2008101979A1 (en) * 2007-02-22 2008-08-28 Merck Serono S.A. Quinoxaline compounds and use thereof
BRPI0810206A2 (en) 2007-04-10 2014-10-21 Exelixis Inc CANCER TREATMENT METHOD
JP4623164B2 (en) * 2008-08-21 2011-02-02 セイコーエプソン株式会社 projector

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US8673908B2 (en) 2008-11-10 2014-03-18 Kyowa Hakko Kirin Co., Ltd. Kynurenine production inhibitor
DE102009049679A1 (en) 2009-10-19 2011-04-21 Merck Patent Gmbh Pyrazolopyrimidinderivate
WO2011047770A2 (en) 2009-10-19 2011-04-28 Merck Patent Gmbh Pyrazolopyrimidine derivatives
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