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WO2016001789A1 - Dérivés de pyrimidine en tant qu'inhibiteurs de pi3k destinés à être utilisés dans le traitement du cancer - Google Patents

Dérivés de pyrimidine en tant qu'inhibiteurs de pi3k destinés à être utilisés dans le traitement du cancer Download PDF

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Publication number
WO2016001789A1
WO2016001789A1 PCT/IB2015/054632 IB2015054632W WO2016001789A1 WO 2016001789 A1 WO2016001789 A1 WO 2016001789A1 IB 2015054632 W IB2015054632 W IB 2015054632W WO 2016001789 A1 WO2016001789 A1 WO 2016001789A1
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WO
WIPO (PCT)
Prior art keywords
membered
compound
methyl
optionally substituted
hydrogen
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PCT/IB2015/054632
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English (en)
Inventor
Ping Chen
Hengmiao Cheng
Mehran Jalaie
John Charles Kath
Suvi Tuula Marjukka Orr
Mason Alan Pairish
Hong Shen
Original Assignee
Pfizer Inc.
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Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO2016001789A1 publication Critical patent/WO2016001789A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel pyrimidine derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals.
  • the present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
  • Phosphoinositide 3-kinases comprise a family of lipid kinases that catalyze the synthesis of the phosphatidylinositol (“PI") second messengers PI(3)P (“PIP"), PI(3,4)P 2 (“PIP 2 "), and PI(3,4,5)P 3 (“PIP 3 ")- (Fruman et al., "Phosphoinositide kinases", Annu. Rev. Biochem. 67 (1998), pp. 481 -507; Knight et al., "A
  • Pharmacological Map of the PI3-K Family Defines a Role for p1 10a in Insulin
  • lipids mediate diverse physiological processes including cell growth, survival, differentiation, and chemotaxis.
  • PI3K family comprises at least 15 different lipid and serine/threonine kinases, sub-classified by structural homology, with distinct substrate specificities, expression patterns, and mode of regulation.
  • Class I PI3Ka is the main PI3-kinase isoform in cancer, and consists of catalytic (p1 10a) and adapter (p85) subunits. (Stirdivant et al., "Cloning and mutagenesis of the p1 10a subunit of human phosphoinositide 3'-hydroxykinase", Bioorg. Med. Chem. 5 (1997), pp. 65-74.)
  • the 3-phosphorylated phospholipid, PIP 3 acts as a second messenger recruiting kinases with lipid binding domains (including plekstrin homology ("PH") regions), such as Akt, the product of the human homologue of the viral oncogene v-Akt, and phosphoinositide-dependent kinase-1 ("PDK1 ").
  • PH plekstrin homology
  • Akt the product of the human homologue of the viral oncogene v-Akt
  • PDK1 phosphoinositide-dependent kinase-1
  • Binding of Akt to PIP 3 induces Akt to translocate to the plasma membrane, bringing Akt into contact with PDK1 , which activates Akt.
  • the PI3Ks, Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation.
  • PI3Ka is thus an attractive target for cancer drug development because PI3Ka inhibitors would be expected to inhibit proliferation and summon resistance to cytotoxic agents in cancer cells.
  • Embodiments described herein relate to a compound of formula (I)
  • R 1 is hydrogen or methyl
  • ring A is 6 membered heteroaryl
  • R 2a and R 2b are each independently hydrogen, halogen, -CN, CrC 4 alkyl, -CHF 2 , -CF 3 , hydroxy, methoxy, -NH 2 , or C3-C 4 cycloalkyl;
  • R 3 is hydrogen, halogen, -CN, C-1 -C3 alkyl, -CF 3 , or methoxy;
  • each R 4a is independently fluorine, -CN, methyl, hydroxy, or methoxy;
  • R 5 is hydrogen, C1 -C3 alkyl, or C3-C 4 cycloalkyi;
  • R 6 is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by methyl, -(CH 2 ) 2 OH , or -(CH 2 )2CN;
  • R 7 is hydrogen, -CN, C C 4 alkyl, -CF 3 , -N(R 18 )(R 19 ), -S0 2 (d-C 3 alkyl), C 3 -C 6 cycloalkyi, 4-6 membered heterocycloalkyi, -(CH 2 )m-(phenyl), or -(CH 2 )n-(5-10 membered heteroaryl), wherein the Ci -C 4 alkyl is optionally substituted by hydroxy, further wherein the C 3 -C 6 cycloalkyi and the 4-6 membered heterocycloalkyi are each
  • -(CH 2 )m-(phenyl) and the -(CH 2 )n-(5-10 membered heteroaryl) are each independently optionally substituted by one or two substituents selected from the group consisting of halogen, -CN, methyl, -CF 3 , C1 -C3 alkoxy, -NH 2 , and cyclopropyl;
  • R 8 is hydrogen, methyl, hydroxy, methoxy, or NH 2 ,
  • R 8 cannot be hydroxy, methoxy or NH 2 , when R 7 is -N(R 18 )(R 19 ); R 9 is hydrogen or C1-C6 alkyl,
  • R 7 may form a 5-6 membered heterocycloalkyi ring with R 5
  • R 7 may form a C3-C6 cycloalkyi ring or a 4-8 membered heterocycloalkyi ring with R 9
  • R 8 may form a C 3 -C 6 cycloalkyi ring with R 9 , wherein the 5-6 membered heterocycloalkyi ring, the C3-C6 cycloalkyi ring, and the 4-8 membered heterocycloalkyi ring formed are each
  • R 10 and R 1 1 are each independently CrC 4 alkyl, -(CH 2 )x-(C 3 -C 5 cycloalkyi), - (CH 2 )y-(4-6 membered heterocycloalkyi), or -(CH 2 )z-(5-6 membered heteroaryl), wherein the CrC 4 alkyl is optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, -CF 3 , C1 -C3 alkoxy, and -N(R 18 )(R 19 ), further wherein the -(CH 2 )x-(C 3 -C 5 cycloalkyi) is optionally substituted by one or two fluorine atoms, even further wherein the -(CH 2 )y-(4-6 membered heterocycloalkyi) and the - (CH 2 )z-(5-6 membered heteroaryl) are each independently optionally substituted by one or two substituents selected from the group
  • R 10 or R 1 1 may form a 4-7 membered heterocycloalkyi ring with R 5 , wherein the 4-7 membered heterocycloalkyi ring formed is optionally substituted by one
  • R 12 is hydrogen or Ci -C 4 alkyl, provided that R 11 and R 12 may form a 4-8 membered heterocycloalkyl ring, wherein the 4-8 membered heterocycloalkyl ring formed is optionally substituted by one or two R 21 groups, further wherein a carbon atom of the 4-8 membered heterocycloalkyl ring formed is optionally replaced by a nitrogen atom or an oxygen atom;
  • R 13 is C C 4 alkyl or C 3 -C 6 cycloalkyl
  • R 13 may form a 5-6 membered heterocycloalkyl ring with R 5 , wherein the 5-6 membered heterocycloalkyl ring formed is optionally substituted by one
  • R 14 and R 15 are each independently hydrogen, C1-C3 alkyl, or C3-C 4 cycloalkyl, provided that R 14 may form a 5-6 membered heterocycloalkyl ring with R 5 or R 14 and R 15 may form a 4-8 membered heterocycloalkyl ring, wherein the 5-6 membered
  • heterocycloalkyl ring formed is optionally substituted by one or two R groups, further wherein the 4-8 membered heterocycloalkyl ring formed is optionally substituted by one or two R 21 groups, even further wherein a carbon atom of the 4-8 membered
  • heterocycloalkyl ring formed is optionally replaced by a nitrogen atom or an oxygen atom;
  • R 16 and R 17 are each independently hydrogen or C1-C3 alkyl
  • R 16 and R 17 may form a 4-6 membered heterocycloalkyl ring, wherein the 4-6 membered heterocycloalkyl ring formed is optionally substituted by one
  • each R 18 and R 19 is independently hydrogen or methyl
  • g is O, 1 , 2, 3, or 4;
  • j is O, 1 , or 2;
  • n 0, 1 , or 2;
  • n O or l ;
  • x is 0 or 1 ;
  • y is 0, 1 , or 2;
  • z is 0 or 1 .
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is 6-membered heteroaryl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is pyridine.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is pyrimidine.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is -NH 2 .
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2b is hydrogen, halogen, Ci-C 4 alkyl, -CHF 2 , or -CF 3 .
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2b is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen. Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein g is 0.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein g is 1 .
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or C1-C3 alkyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is 5-6 membered heteroaryl optionally substituted by methyl, -(CH 2 ) 2 OH, or -(CH 2 ) 2 CN.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, -CN, Ci-C 4 alkyl, -CF 3 , -NH 2 , or - S0 2 CH 3 .
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is C 3 -C 6 cycloalkyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is -(CH 2 )m-(phenyl) or -(CH 2 )n-(5-10 membered heteroaryl), wherein the -(CH 2 )n-(5-10 membered heteroaryl) is optionally substituted by one or two substituents selected from the group consisting of halogen and methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is Ci-C 4 alkyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, methyl, hydroxy, or methoxy. Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxy.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 is ethyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, R 8 is hydrogen, and R 9 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, R 8 is hydroxy, and R 9 is hydrogen.
  • Some embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is Ci-C 4 alkyl, R 8 is hydroxy, and R 9 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 9 form a C 3 -C 6 cycloalkyl ring optionally substituted by one or two fluorine groups.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 9 form a 4-6 membered heterocycloalkyi ring.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 form a C 3 -C 6 cycloalkyl ring optionally substituted by one or two substituents selected from the group consisting of fluorine, - CN, and methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is CrC 4 alkyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 is C 3 -C 5 cycloalkyl. Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 10 and R 5 form a 5-6 membered heterocycloalkyl ring.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is Ci-C 4 alkyl or -(CH 2 )x-(C3-C5 cycloalkyi), further wherein the CrC 4 alkyl is optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, -CF 3 , C1-C3 alkoxy, and -N(CH 3 ) 2 , even further wherein the -(CH 2 )x-(C3-C5 cycloalkyi) is optionally substituted by one or two fluorine atoms.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is -(CH 2 )y-(4-6 membered heterocycloalkyl) optionally substituted by methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 is -(CH 2 )z-(5-6 membered heteroaryl) optionally substituted by methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 12 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 form a 4-6 membered heterocycloalkyl ring optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, methyl, and hydroxy.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 11 and R 5 form a 5-6 membered heterocycloalkyl ring.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is -(CH 2 )j-N(R 16 )(N 17 ).
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (la)
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (lb)
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (lc)
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (Id)
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (le)
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (If)
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having formula (Ig)
  • Embodiments described herein relate to a compound of formula (II)
  • R 1 is hydrogen or methyl
  • R 2a and R 2b are each independently hydrogen, halogen, -CN, C C 4 alkyl, -CHF 2 , -CF 3 , hydroxy, methoxy, -NH 2 , or C3-C 4 cycloalkyl;
  • R 3 is hydrogen, halogen, -CN, C1-C3 alkyl, -CF 3 , or methoxy;
  • R 4 is (e
  • each R 4a is independently fluorine, -CN, methyl, hydroxy, or methoxy;
  • R 5 is hydrogen, C1-C3 alkyl, or C3-C 4 cycloalkyi
  • R 6 is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by methyl, -(CH 2 ) 2 OH, or -(CH 2 )2CN;
  • R 7 is hydrogen, -CN, C C 4 alkyl, -CF 3 , -N(R 18 )(R 19 ), -S0 2 (C 1 -C 3 alkyl), C 3 -C 6 cycloalkyi, 4-6 membered heterocycloalkyi, -(CH 2 )m-(phenyl), or -(CH 2 )n-(5-10 membered heteroaryl), wherein the Ci-C 4 alkyl is optionally substituted by hydroxy, further wherein the C 3 -C 6 cycloalkyi and the 4-6 membered heterocycloalkyi are each
  • -(CH 2 )m-(phenyl) and the -(CH 2 )n-(5-10 membered heteroaryl) are each independently optionally substituted by one or two substituents selected from the group consisting of halogen, -CN, methyl, -CF 3 , Ci-C 3 alkoxy, -NH 2 , and cyclopropyl;
  • R 8 is hydrogen, methyl, hydroxy, methoxy, or NH 2 ,
  • R 8 cannot be hydroxy, methoxy or NH 2 , when R 7 is -N(R 18 )(R 19 ); R 9 is hydrogen or C1-C6 alkyl,
  • R 7 may form a 5-6 membered heterocycloalkyi ring with R 5
  • R 7 may form a C 3 -C6 cycloalkyi ring or a 4-8 membered heterocycloalkyi ring with R 9
  • R 8 may form a C 3 -C 6 cycloalkyi ring with R 9 , wherein the 5-6 membered heterocycloalkyi ring, the C 3 -C 6 cycloalkyl ring, and the 4-8 membered heterocycloalkyi ring formed are each
  • R 10 and R 1 1 are each independently CrC 4 alkyl, -(CH 2 )x-(C 3 -C5 cycloalkyl), - (CH 2 )y-(4-6 membered heterocycloalkyi), or -(CH 2 )z-(5-6 membered heteroaryl), wherein the CrC 4 alkyl is optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, -CF 3 , C1 -C3 alkoxy, and -N(R 18 )(R 19 ), further wherein the -(CH 2 )x-(C 3 -C5 cycloalkyl) is optionally substituted by one or two fluorine atoms, even further wherein the -(CH 2 )y-(4-6 membered heterocycloalkyi) and the - (CH 2 )z-(5-6 membered heteroaryl) are each independently optionally substituted by one or two substituents selected from the group
  • R 10 or R 1 1 may form a 4-7 membered heterocycloalkyi ring with R 5 , wherein the 4-7 membered heterocycloalkyi ring formed is optionally substituted by one
  • R 12 is hydrogen or Ci -C 4 alkyl
  • R 1 1 and R 12 may form a 4-8 membered heterocycloalkyi ring, wherein the 4-8 membered heterocycloalkyi ring formed is optionally substituted by one or two R 21 groups, further wherein a carbon atom of the 4-8 membered heterocycloalkyi ring formed is optionally replaced by a nitrogen atom or an oxygen atom;
  • R 13 is C C 4 alkyl or C 3 -C 6 cycloalkyl
  • R 13 may form a 5-6 membered heterocycloalkyi ring with R 5 , wherein the 5-6 membered heterocycloalkyi ring formed is optionally substituted by one
  • R 14 and R 15 are each independently hydrogen, Ci -C 3 alkyl, or C 3 -C 4 cycloalkyl, provided that R 14 may form a 5-6 membered heterocycloalkyi ring with R 5 or R 14 and R 15 may form a 4-8 membered heterocycloalkyi ring, wherein the 5-6 membered
  • heterocycloalkyi ring formed is optionally substituted by one or two R groups, further wherein the 4-8 membered heterocycloalkyi ring formed is optionally substituted by one or two R 21 groups, even further wherein a carbon atom of the 4-8 membered
  • heterocycloalkyi ring formed is optionally replaced by a nitrogen atom or an oxygen atom;
  • R 16 and R 17 are each independently hydrogen or Ci-C 3 alkyl, provided that R 16 and R 17 may form a 4-6 membered heterocycloalkyl ring, wherein the 4-6 membered heterocycloalkyl ring formed is optionally substituted by one
  • each R 18 and R 19 is independently hydrogen or methyl
  • each R 22 and R 23 is independently hydrogen or methyl
  • g is O, 1 , 2, 3, or 4;
  • j is O, 1 , or 2;
  • n 0, 1 , or 2;
  • n O or l ;
  • x is 0 or 1 ;
  • y is 0, 1 , or 2;
  • z is 0 or 1 .
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 2a is -NH 2 .
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 2b is hydrogen, halogen, Ci-C 4 alkyl, -CHF 2 , or -CF 3 .
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 2b is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein g is 0.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein g is 1 .
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or C1-C3 alkyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, -CN, Ci-C 4 alkyl, -
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is C3-C6 cycloalkyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is -(CH 2 )m-(phenyl) or -(CH 2 )n-(5- 10 membered heteroaryl), wherein the -(CH 2 )n-(5-10 membered heteroaryl) is optionally substituted by one or two substituents selected from the group consisting of halogen and methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is CrC 4 alkyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, methyl, hydroxy, or methoxy.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxy.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 9 is methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 9 is ethyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, R 8 is hydrogen, and R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, R 8 is hydroxy, and R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 is Ci-C 4 alkyl, R 8 is hydroxy, and R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 9 form a C3-C6 cycloalkyi ring optionally substituted by one or two fluorine groups.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 9 form a 4-6 membered heterocycloalkyl ring.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 form a C 3 -C 6 cycloalkyi ring optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, and methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 10 is Ci-C 4 alkyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 10 is methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 10 is C3-C5 cycloalkyi.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 10 and R 5 form a 5-6 membered heterocycloalkyl ring.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 11 is Ci-C 4 alkyl or -(CH 2 )x-(C 3 -C5 cycloalkyi), further wherein the Ci-C 4 alkyl is optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, -CF 3 , C1-C3 alkoxy, and -N(CH 3 ) 2 , even further wherein the -(CH 2 )x-(C3-C5 cycloalkyi) is optionally substituted by one or two fluorine atoms.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 11 is -(CH 2 )y-(4-6 membered heterocycloalkyl) optionally substituted by methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 11 is -(CH 2 )z-(5-6 membered heteroaryl) optionally substituted by methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen. Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 12 is methyl.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 form a 4-6 membered heterocycloalkyl ring optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, methyl, and hydroxy.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 11 and R 5 form a 5-6 membered heterocycloalkyl ring.
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 4 is -(CH 2 )j-N(R 16 )(N 17 ).
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, having formula (I la)
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceuticall acceptable salt thereof, having formula (Mb)
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceuticall acceptable salt thereof, having formula (lie)
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, having formula (lid)
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceuticall acceptable salt thereof, having formula (lie)
  • Embodiments described herein relate to a compound of formula (II), or a pharmaceuticall acceptable salt thereof, having formula (llf)
  • Embodiments described herein relate to a having formula (llg)
  • R 1 is hydrogen or methyl
  • R 3 is hydrogen, halogen, -CN, C1-C3 alkyl, -CF 3 , or methoxy;
  • R 4 is
  • each R 4a is independently fluorine, -CN, methyl, hydroxy, or methoxy;
  • R 5 is hydrogen, C1-C3 alkyl, or C3-C 4 cycloalkyi
  • R 6 is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by methyl, -(CH 2 ) 2 OH, or -(CH 2 )2CN;
  • R 7 is hydrogen, -CN, C C 4 alkyl, -CF 3 , -N(R 18 )(R 19 ), -S0 2 (C 1 -C 3 alkyl), C 3 -C 6 cycloalkyi, 4-6 membered heterocycloalkyi, -(CH 2 )m-(phenyl), or -(CH 2 )n-(5-10 membered heteroaryl), wherein the Ci-C 4 alkyl is optionally substituted by hydroxy, further wherein the C 3 -C 6 cycloalkyi and the 4-6 membered heterocycloalkyi are each
  • -(CH 2 )m-(phenyl) and the -(CH 2 )n-(5-10 membered heteroaryl) are each independently optionally substituted by one or two substituents selected from the group consisting of halogen, -CN, methyl, -CF 3 , Ci-C 3 alkoxy, -NH 2 , and cyclopropyl;
  • R 8 is hydrogen, methyl, hydroxy, methoxy, or NH 2 ,
  • R 8 cannot be hydroxy, methoxy or NH 2 , when R 7 is -N(R 18 )(R 19 ); R 9 is hydrogen or C1-C6 alkyl,
  • R 7 may form a 5-6 membered heterocycloalkyi ring with R 5
  • R 7 may form a C 3 -C6 cycloalkyi ring or a 4-8 membered heterocycloalkyi ring with R 9
  • R 8 may form a C 3 -C 6 cycloalkyi ring with R 9 , wherein the 5-6 membered heterocycloalkyi ring, the C 3 -C 6 cycloalkyl ring, and the 4-8 membered heterocycloalkyi ring formed are each
  • R 10 and R 1 1 are each independently CrC 4 alkyl, -(CH 2 )x-(C 3 -C5 cycloalkyl), - (CH 2 )y-(4-6 membered heterocycloalkyi), or -(CH 2 )z-(5-6 membered heteroaryl), wherein the CrC 4 alkyl is optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, -CF 3 , C1 -C3 alkoxy, and -N(R 18 )(R 19 ), further wherein the -(CH 2 )x-(C 3 -C5 cycloalkyl) is optionally substituted by one or two fluorine atoms, even further wherein the -(CH 2 )y-(4-6 membered heterocycloalkyi) and the - (CH 2 )z-(5-6 membered heteroaryl) are each independently optionally substituted by one or two substituents selected from the group
  • R 10 or R 1 1 may form a 4-7 membered heterocycloalkyi ring with R 5 , wherein the 4-7 membered heterocycloalkyi ring formed is optionally substituted by one
  • R 12 is hydrogen or Ci -C 4 alkyl
  • R 1 1 and R 12 may form a 4-8 membered heterocycloalkyi ring, wherein the 4-8 membered heterocycloalkyi ring formed is optionally substituted by one or two R 21 groups, further wherein a carbon atom of the 4-8 membered heterocycloalkyi ring formed is optionally replaced by a nitrogen atom or an oxygen atom;
  • R 13 is C C 4 alkyl or C 3 -C 6 cycloalkyl
  • R 13 may form a 5-6 membered heterocycloalkyi ring with R 5 , wherein the 5-6 membered heterocycloalkyi ring formed is optionally substituted by one
  • R 14 and R 15 are each independently hydrogen, Ci -C 3 alkyl, or C 3 -C 4 cycloalkyl, provided that R 14 may form a 5-6 membered heterocycloalkyi ring with R 5 or R 14 and R 15 may form a 4-8 membered heterocycloalkyi ring, wherein the 5-6 membered
  • heterocycloalkyi ring formed is optionally substituted by one or two R groups, further wherein the 4-8 membered heterocycloalkyi ring formed is optionally substituted by one or two R 21 groups, even further wherein a carbon atom of the 4-8 membered
  • heterocycloalkyi ring formed is optionally replaced by a nitrogen atom or an oxygen atom;
  • R 16 and R 17 are each independently hydrogen or Ci-C 3 alkyl, provided that R 16 and R 17 may form a 4-6 membered heterocycloalkyl ring, wherein the 4-6 membered heterocycloalkyl ring formed is optionally substituted by one
  • each R 18 and R 19 is independently hydrogen or methyl
  • each R 22 and R 23 is independently hydrogen or methyl
  • g is O, 1 , 2, 3, or 4;
  • j is O, 1 , or 2;
  • n 0, 1 , or 2;
  • n O or l ;
  • x is 0 or 1 ;
  • y is 0, 1 , or 2;
  • z is 0 or 1 .
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein g is 0.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein g is 1 .
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or C1-C3 alkyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 6 is 5-6 membered heteroaryl optionally substituted by methyl, -(CH 2 ) 2 OH, or -(CH 2 ) 2 CN.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, -CN, Ci-C 4 alkyl, - CF 3 , -NH 2 , or -S0 2 CH 3 .
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is C3-C6 cycloalkyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is -(CH 2 )m-(phenyl) or -(CH 2 )n-(5- 10 membered heteroaryl), wherein the -(CH 2 )n-(5-10 membered heteroaryl) is optionally substituted by one or two substituents selected from the group consisting of halogen and methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is CrC 4 alkyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.
  • Embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, methyl, hydroxy, or methoxy.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxy.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 9 is methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 9 is ethyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, R 8 is hydrogen, and R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, R 8 is hydroxy, and R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 is Ci-C 4 alkyl, R 8 is hydroxy, and R 9 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 9 form a C 3 -C 6 cycloalkyi ring optionally substituted by one or two fluorine groups.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 9 form a 4-6 membered heterocycloalkyl ring.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 form a C 3 -C 6 cycloalkyi ring optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, and methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 10 is Ci-C 4 alkyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 10 is methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 10 is C 3 -C 5 cycloalkyi.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 10 and R 5 form a 5-6 membered heterocycloalkyl ring.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 11 is Ci-C 4 alkyl or -(CH 2 )x-(C3-C5 cycloalkyi), further wherein the CrC 4 alkyl is optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, -CF 3 , C1-C3 alkoxy, and -N(CH 3 ) 2 , even further wherein the -(CH 2 )x-(C 3 -C5 cycloalkyi) is optionally substituted by one or two fluorine atoms.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 11 is -(CH 2 )y-(4-6 membered heterocycloalkyl) optionally substituted by methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 11 is -(CH 2 )z-(5-6 membered heteroaryl) optionally substituted by methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 12 is methyl.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 form a 4-6 membered heterocycloalkyl ring optionally substituted by one or two substituents selected from the group consisting of fluorine, -CN, methyl, and hydroxy.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 11 and R 5 form a 5-6 membered heterocycloalkyl ring.
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R is
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 4 is -(CH 2 )j-N(R 16 )(N 17 ).
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceuticall acceptable salt thereof, having formula (Ilia)
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, having formula (1Mb)
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, having formula (III c)
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, having formula (llld)
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, having formula (llle)
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, having formula (lllf)
  • Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, having formula (lllg)
  • the compound is selected from:
  • Embodiments relate to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the embodiments of the compounds of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Embodiments relate to a combination of a compound of any of the embodiments of the compounds of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, with an anti-tumor agent or with radiation therapy, for the treatment of cancer.
  • Embodiments relate to a combination of a compound of any of the embodiments of the compounds of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, with an anti-tumor agent, for the treatment of cancer.
  • Embodiments relate to a method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of any of the embodiments of the compounds of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, that is effective in treating abnormal cell growth.
  • Embodiments relate to the method of treating abnormal cell growth, wherein the abnormal cell growth is cancer.
  • Embodiments relate to the method of treating cancer, wherein the cancer is selected from the group consisting of basal cell cancer, medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the
  • carcinoma of the cervix carcinoma of the vagina, carcinoma of the vulva
  • Hodgkin's disease cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, spinal axis tumors, brain stem glioma and pituitary adenoma, or a
  • Embodiments relate to the method of treating cancer, wherein the cancer is selected from the group consisting of lung cancer, cancer of the head or neck, colon cancer, breast cancer, and ovarian cancer, or a combination of one or more of the foregoing cancers.
  • TMS-CI trimethylsilyl chloride
  • TMSI trimethylsilyl iodide
  • Tris tris(hydroxymethyl)aminomethane
  • halogen refers to a fluorine, chlorine, bromine, or iodine atom or fluoro, chloro, bromo, or iodo. Additionally, the term “halogen” refers to F, CI, Br, or I. The terms fluorine, fluoro and F, for example, are understood to be equivalent herein.
  • alkyl refers to saturated monovalent hydrocarbon radicals containing, in certain embodiments, from one to six, or from one to three carbon atoms, having straight or branched moieties.
  • d-Ce alkyl refers to an alkyl radical containing from one to six carbon atoms, having straight or branched moieties.
  • C-,-C 6 alkyl includes within its definition the terms “C r C 3 alkyl” and "d-C4 alkyl".
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, fe/f-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl,
  • cycloalkyl refers to a monocyclic, fused or bridged bicyclic or tricyclic carbocyclic ring group containing, in certain embodiments, from three to ten carbon atoms.
  • cycloalkyl also includes spirocyclic cycloalkyl groups, including multi-ring systems joined by a single atom.
  • C 3 -Ci 0 cycloalkyl contains from three to ten, from three to seven, from three to six, from three to five, from three to four, and from five to seven carbon atoms, respectively.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1 ]heptanyl, bicyclo[3.2.1 ]octanyl, bicyclo[5.2.0]nonanyl, adamantanyl, and the like.
  • heterocycloalkyl refers to a non-aromatic
  • monocyclic, fused or bridged bicyclic or tricyclic or spirocyclic ring group containing, in certain embodiments, a total of three to ten ring atoms, in which one to four ring atoms are heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the sulfur atom may be optionally oxidized with one or two oxygen atoms, the remaining ring atoms being carbon, with the proviso that such ring systems may not contain two adjacent oxygen atoms or two adjacent sulfur atoms.
  • such groups may be bonded to the remainder of the compounds of embodiments disclosed herein through either a carbon atom or a heteroatom, if possible.
  • membered heterocycloalkyl contain from three to ten, from three to seven, from four to eight, from four to seven, from four to six carbon atoms, and from five to six carbon atoms, respectively.
  • saturated heterocycloalkyl groups include, but are not limited to:
  • aryl refers to a group derived from an aromatic hydrocarbon containing in certain embodiments, from five to ten carbon atoms.
  • C5-C10 aryl contains from five to ten carbon atoms. Examples of such groups include, but are not limited to, phenyl and naphthyl.
  • aryl also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include, but are not limited to, 1 -naphthyl, 2-naphthyl, 1 -anthracyl and 2- anthracyl.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
  • heteroaryl refers to an aromatic monocyclic or bicyclic heterocyclic group having a total of from 5 to 12 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from nitrogen, oxygen, and sulfur, with the proviso that the ring of said group does not contain two adjacent oxygen atoms or two adjacent sulfur atoms.
  • heteroaryl refers to an aromatic monocyclic or bicyclic heterocyclic group having a total of from 5 to 12 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from nitrogen, oxygen, and sulfur, with the proviso that the ring of said group does not contain two adjacent oxygen atoms or two adjacent sulfur atoms.
  • the terms “5-12 membered heteroaryl”, “5-10 membered heteroaryl”, “5-6 membered heteroaryl”, and “4-6 membered heteroaryl” contain from five to twelve, from five to ten, from five to six, and
  • heteroaryl groups include benzo- fused ring systems.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, thiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, furo[3,2-Jb]pyridinyl, benzothiazolyl,
  • benzo-fused unsaturated oxygen or nitrogen heterocycles which refer to a heterocyclic group in which a heteroatomic ring is fused to one or more aromatic rings.
  • examples include, but are not limited to, 2,3-dihydrobenzofuran, indolinyl, 1 ,3- dihydroisobenzofuran, isoindolinyl, tetrahydroquinohnyl, tetrahydroisoquinohnyl, and the like.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • an "effective" amount refers to an amount of a substance, agent, compound, or composition that is of sufficient quantity to result in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction - either as a single dose or according to a multiple dose regimen, alone or in combination with other agents or substances.
  • the subject may be a human or non-human mammal (e.g., rabbit, rat, mouse, monkey or other lower-order primate).
  • Embodiments disclosed herein include isotopically-labeled compounds, which are identical to those recited in formula (I), formula (II), or formula (III), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the embodiments disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 p 32p 35g i 8p Qn( ⁇ 36Q
  • isotopically-labeled compounds of the embodiments disclosed herein for example, those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage
  • Isotopically-labed compounds of embodiments disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and
  • compositions described herein relate to the pharmaceutically acceptable salts of the compounds described herein.
  • Pharmaceutically acceptable salts of the compounds described herein include the acid addition and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • suitable acid addition salts i.e., salts containing pharmacologically acceptable anions, include, but are not limited to, the acetate, acid citrate, adipate, aspartate, benzoate, besylate,
  • Suitable base addition salts are formed from bases which form nontoxic salts.
  • suitable base salts include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • the compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as the hydrochloride,
  • the compounds described herein that include a basic moiety, such as an amino group may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such
  • pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the compounds of the embodiments described herein include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds described herein (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers. While all stereoisomers are encompassed within the scope of our claims, one skilled in the art will recognize that particular stereoisomers may be preferred.
  • the compounds described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present embodiments. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present embodiments includes all tautomers of the present compounds.
  • the present embodiments also include atropisomers of the compounds described herein.
  • Atropisomers refer to compounds that can be separated into rotationally restricted isomers.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • solvate is used herein to describe a molecular complex comprising a compound described herein and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the compounds described herein may also exist in unsolvated and solvated forms. Accordingly, some embodiments relate to the hydrates and solvates of the compounds described herein.
  • tautomeric isomerism ('tautomerism') can occur.
  • This can take the form of proton tautomerism in compounds described herein containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety.
  • a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound described herein contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where a compound described herein contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • tumor cells tumor cells that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine/threonine kinase activation; (5) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs; (6) any tumors that proliferate by aberrant signaling, metabolic, epigenetic and transcriptional mechanism; and (7) benign and malignant cells of other proliferative diseases in which aberrant signaling, metabolic, epigenetic and transcriptional mechanism.
  • Further embodiments relate to methods of treating abnormal cell growth in a mammal. Additional embodiments relate to a method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound described herein that is effective in treating abnormal cell growth.
  • the abnormal cell growth is cancer.
  • the cancer is selected from the group consisting of lung cancer, mesothelioma ,bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter
  • Additional embodiments relate to methods of treating cancer solid tumors in a mammal. Some embodiments relate to the treatment of cancer solid tumor in a mammal comprising administering to the mammal an amount of a compound described herein that is effective in treating said cancer solid tumor.
  • the cancer solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, or bladder.
  • compositions for treating abnormal cell growth in a mammal comprising an amount of a compound described herein that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
  • Additional embodiments relate to a method of treating abnormal cell growth in a mammal, including a human, comprising administering to the mammal an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, that is effective in treating abnormal cell growth.
  • the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms
  • the method comprises comprising administering to a mammal an amount of a compound described herein that is effective in treating said cancer solid tumor.
  • the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder cancer.
  • said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
  • Some embodiments relate to a method of treating abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, that is effective in treating abnormal cell growth in combination with an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • Additional embodiments relate to a pharmaceutical composition for treating abnormal cell growth in a mammal, including a human, comprising an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, that is effective in treating abnormal cell growth, and a
  • said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,
  • compositions for treating abnormal cell growth contemplate a pharmaceutical composition for treating abnormal cell growth wherein the composition includes a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, that is effective in treating abnormal cell growth, and another antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • another antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • Yet more embodiments relate to a method of treating a disorder associated with angiogenesis in a mammal, including a human, comprising administering to said mammal an amount of a compound described herein, as defined above, or a
  • disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid treatment; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus.
  • Some embodiments relate to a method of (and to a pharmaceutical composition for) treating abnormal cell growth in a mammal which comprise an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with an amount of one or more substances selected from anti- angiogenesis agents, signal transduction inhibitors inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell), and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.
  • signal transduction inhibitors inhibitor e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell
  • antiproliferative agents which amounts are together effective in treating said abnormal cell growth.
  • Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound described herein in the methods and pharmaceutical compositions described herein.
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix-metalloprotienase 9 inhibitors
  • COX-II cyclooxygenase II
  • Examples of useful COX- II inhibitors include CELEBREXTM (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib).
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1 . More preferred, are those that selectively inhibit MMP-2 and/or MMP- 9 relative to the other matrix-metalloproteinases (i.e. MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-1 1 , MMP-12, and MMP-13).
  • MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-1 1 , MMP-12, and MMP-13 matrix-metalloproteinases
  • VEGF inhibitors for example, sutent and axitinib
  • VEGF inhibitors can also be combined with a compound described herein.
  • VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883, 1 13 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 1 1 , 1998), U.S. Patent No. US
  • VEGF inhibitors 6,653,308 (issued November 25, 2003), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are herein incorporated by reference in their entirety.
  • Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland,
  • Avastin an anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California
  • angiozyme a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).
  • ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with a compound described herein.
  • erbB2 inhibitors include Herceptin, 2C4, and pertuzumab.
  • Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety.
  • ErbB2 receptor inhibitors useful in the embodiments described herein are also described in United States Provisional
  • erbb2 receptor inhibitors include TAK- 165 (Takeda) and GW-572016 (Glaxo-Wellcome).
  • EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published January 25, 1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992) refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties.
  • World Patent Application WO 92/20642 (published November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation.
  • Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with a compound of the presentation invention.
  • EGFR inhibitors include gefinitib, erlotinib, icotinib, afatinib and dacomitinib.
  • Monoclonal antibody inhibitors of EGFR, such as cetuximab, may also be combined with a compound of the present invention.
  • PI3K inhibitors such as PI3K beta inhibitors, may be administered in combination with a compound of the presentation invention.
  • Mammalian target of rapamycin (mTOR) inhibitors may be administered in combination with a compound of the presentation invention.
  • mTOR inhibitors include rapamycin analogs and ATP competitive inhibitors.
  • c-Met inhibitors may be administered in combination with a compound of the presentation invention.
  • Such c-Met inhibitors include crizotinib and ARQ-197.
  • Monoclonal antibody inhibitors of c-Met such as METMab, may also be combined with a compound of the present invention.
  • CDK inhibitors may be administered in combination with a compound of the presentation invention.
  • mTOR inhibitors include palbociclib.
  • MEK inhibitors may be administered in combination with a compound of the presentation invention.
  • Such MEK inhibitors include PD-325901 .
  • PARP inhibitors may be administered in combination with a compound of the presentation invention.
  • JAK inhibitors may be administered in combination with a compound of the presentation invention.
  • An antagonist of a Programmed Death 1 protein may be administered in combination with a compound of the presentation invention.
  • antiproliferative agents that may be used with the compounds described herein include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998);
  • a compound described herein may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the "Background" section, supra.
  • CTLA4 cytotoxic lymphocyte antigen 4
  • anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the "Background" section, supra.
  • Specific CTLA4 antibodies that can be used in the present embodiments include those described in United States Provisional Application 60/1 13,647 (filed December 23, 1998) which is herein incorporated by reference in its entirety.
  • a compound described herein may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, oxaliplatin, carboplatin and cyclophosphamide; anti-metabolites, for example 5- fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
  • mitotic inhibitors for example vinblastine
  • alkylating agents for example cis-platin, oxaliplatin, carboplatin and cyclophosphamide
  • anti-metabolites for example 5- fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
  • the compounds described herein may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents.
  • the compounds described herein may be used with cytotoxic agents, e.g., one or more selected from the group consisting of a camptothecin, irinotecan HCI (Camptosar), edotecarin, SU-1 1248, epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof.
  • cytotoxic agents e.g., one or more selected from the group consisting of a camptothecin, irinotecan HCI (Camptosar), edotecarin, SU-1 1248, epirubicin (Ellence), docetaxe
  • a compound described herein alone or in combination with one or more supportive care products, e.g. , a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • supportive care products e.g. , a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • the compounds described herein may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers.
  • antitumor agents alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers.
  • secondary agents that may be used with the compounds described herein.
  • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin.
  • Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1 , gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1 , melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine,
  • Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin.
  • Hormonal therapy agents e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'- (trifluoromethyl)propionanilide) and combinations thereof.
  • Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel.
  • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan,
  • mitoxantrone pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof.
  • Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1 a or interferon gamma-n1 .
  • Other agents include PF3512676, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab
  • thymalasin thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge.
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.
  • agents include krestin, lentinan, sizofiran, picibanil, or ubenimex.
  • anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine,
  • anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain and Vitaxin.
  • Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin.
  • Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan.
  • Tyrosine kinase inhibitors include, for example, Iressa and SU5416.
  • Antibodies include, for example, Herceptin, Erbitux, Avastin, and Rituximab.
  • Interferons include, for example, interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1 a and interferon gamma-n1 .
  • Biological response modifiers include agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.
  • agents include, for example, krestin, lentinan, sizofiran, picibanil, and ubenimex.
  • antitumor agents include, for example, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, and tretinoin. Additionally, PI3K inhibitors and RAS-targeted cancer treatments may be combined with the compounds described herein.
  • Some embodiments also relate to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions which comprises mixing a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the daily dosage of the compound formula (I), formula (II), or formula (III), or pharmaceutically acceptable salt thereof may be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.
  • the present embodiments also encompass sustained release compositions.
  • Administration of the compounds descrbed herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
  • the active compound may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No.
  • mitotic inhibitors for example vinblastine
  • alkylating agents for example cis-platin, carboplatin and cyclophosphamide
  • anti-metabolites for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound described herein as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • salt forms were occasionally isolated as a consequence of the mobile phase additives during HPLC based chromatographic purification.
  • salts such as formate, trifluorooacetate and acetate were isolated and tested without further processing. It will be recognized that one of ordinary skill in the art will be able to realize the free base form by standard methodology (such as using ion exchange columns, or performing simple basic extractions using a mild aqueous base).
  • the compounds described herein may be prepared by processes known in the chemical arts, particularly in light of the description contained herein.
  • a pyrimidine A-1 is subjected to chlorine displacement with an amine A-2 in the presence of a suitable base (such as DIPEA, NaH, K 2 C0 3 , or CsF) in a suitable solvent (such as DMSO, MeCN, NMP, THF, or DMF) to afford A-3.
  • A-3 is treated under demethylation conditions known in the art with sodium iodide and TMS-CI in MeCN to provide A-4.
  • a suitable base such as DIPEA, NaH, K 2 C0 3 , or CsF
  • a suitable solvent such as DMSO, MeCN, NMP, THF, or DMF
  • a guanidine A-1' and a malonate A-2' are subjected to a condensation to afford A-4.
  • A-4 is treated with POCIs to afford A-5.
  • A-5 is subjected to selective chlorine displacement with an alkoxide A-6 (using parent alcohol in the presence of a suitable base ⁇ NaH, NaHMDS, KHMDS, K 2 CO 3 or DIPEA ⁇ ) in a suitable solvent (such as iPrOH, MeCN, THF or DMF) to afford A-7.
  • A-7 is treated under Suzuki cross-coupling conditions known in the literature with a boronic acid or a boronic ester to yield A-9.
  • the intermediate A-5 is treated under Suzuki cross-coupling conditions known in the literature with a boronic acid or a boronic ester to yield A-8.
  • A-8 is subjected to chlorine displacement with an alkoxide A-6(using parent alcohol in the presence of a suitable base ⁇ NaH, NaHMDS, KHMDS, K 2 CO 3 or DIPEA ⁇ ) in a suitable solvent (such as iPrOH, MeCN, THF or DMF) to afford A-9.
  • a suitable base ⁇ NaH, NaHMDS, KHMDS, K 2 CO 3 or DIPEA ⁇
  • a suitable solvent such as iPrOH, MeCN, THF or DMF
  • the R 4 group contains an amine protecting group, such as a Boc group or a CBZ group
  • the protecting group may be deprotected under procedures known to one of skill in the art.
  • the Boc group may be deprotected under acidic conditions (such as HCI or TFA) and the CBZ group may be deprotected under hydrogenation conditions.
  • the resultant amine may be subjected to amide, carbamate, urea, sulfonamide, sulfamide or phosphinic amide formation.
  • Amide formation can be achieved using a suitable amide coupling agent (such as CDI, EDCI, HATU) in the presence of a suitable base (such as DIPEA, TEA) and an appropriate carboxylic acid.
  • Carbamate formation can be achieved using an appropriate chloroformate in the presence of a suitable base (such as DIPEA or TEA).
  • Urea formation can be achieved by using an appropriate isocyanate in the presence of a suitable base (such as TEA), or in the presence of triphosgene or phosgene and an amine in the presence of a suitable base (such as sodium carbonate, sodium bicarbonate, or TEA).
  • Sulfonamide formation can be achieved with a sulfonyl chloride in the presence of a suitable base (such as DIPEA or TEA).
  • Sulfamide formation can be achieved with sulfamoyl chloride or sulfamoylcarbamate in the presence of a suitable base (such as DIPEA or TEA).
  • Phosphinic amide formation can be achieved with phosphinic chloride in the presence of a suitable base (such as DIPEA or TEA).
  • a suitable base such as DIPEA or TEA.
  • trichloropyrimidine B-1 is subjected to a selective chlorine displacement with an alkoxide A-6 (using parent alcohol in the presence of a suitable base ⁇ NaH, NaHMDS, KHMDS, K 2 C0 3 or DIPEA ⁇ ) in a suitable solvent (such as iPrOH, MeCN, THF or DMF) to afford B-2.
  • B-2 is subjected to another selective chlorine displacement with amine A-2 in the presence of a suitable base ⁇ NaH,
  • A-7 is treated under Suzuki cross-coupling conditions known in the literature with a boronic acid or a boronic ester to yield A-9.
  • the R 4 group contains an N-Boc group or an N-CBZ group, it may be suitably deprotected and subjected to amide, carbamate, urea, sulfonamide, sulfamide, or phosphinic amide formation either before or after the Suzuki cross- coupling step as described above in Scheme A.
  • Step 1 Preparation of te f-butyl(frans-3- ⁇ [6-chloro-2-(morpholin-4-yl)pyrimidin-4- ylloxylcvclobutvDmethylcarbamate
  • reaction mixture was quenched with water (0.5 mL), and washed with brine (75 mL).
  • the aqueous layer was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (25 mL), dried
  • Step 3 Preparation of /V-(frans-3- ⁇ [6-chloro-2-(morpholin-4-yl)pyrimidin-4-
  • Step 4 Preparation of /V-(frans-3-([2'-amino-2-(morpholin-4-yl)-4,5'-bipyrimidin-6- yl1oxy)cvclobutyl)-2-hvdroxy-/V-methylacetamide
  • dichloromethane (68 mg, 0.083 mmol) was added and the vessel was sealed. The mixture was heated in the microwave at 140 °C for 15 min. The mixture was filtered through a 0.45 micron syringe filter, and the filtrate was poured to a brine solution (150 ml_) and the resulting precipitate was collected by filtration and rinsed with water. The filtrate was extracted with EtAOc (3 x 50 ml_). The solids were washed with methylene chloride, the washings were combined with the EtOAc extracts, dried (MgS0 4 ) and reduced under reduced pressure.
  • Step 1 Preparation of fe/f-butyl (frans-3- ⁇ [2'-amino-2-(morpholin
  • Step 2 Preparation of 6- ⁇ [frans-3-(methylamino)cvclobutyl1oxy)-2-(morpholin-4- yl)-4,5'-bipyrimidin-2'-amin hydrochloride
  • Step 3 Preparation of 1 -(frans-3- ⁇ [2'-amino-2-(morpholin-4-yl)-4,5'-bipyrimidin-6- yl1oxy)cvclobutyl)-1 ,3-dimethylurea
  • the mixture was purified by SFC column (SFC/ZymorSpher HADP 150 x 21 .2 mm; with 15-30 % MeOH at 3%/min, 140 bar, 55 mL/min) to give 20.5 mg (57 % yield) of the title compound as a white solid.
  • Step 1 Preparation of fe/f-butyl ⁇ frans-3-[(2,6-dichloropyrimidin-4- vDoxylcvclobutvDmethylcarbamate
  • Step 2 Preparation of fe/f-butyl [frans-3-( ⁇ 6-chloro-2-[(3S)-3-methylmorpholin-4-
  • Step 3 Preparation of frans-3-( ⁇ 6-chloro-2-[(3S)-3-methylmorpholin-4- yllPyrimidin-4-yl)oxy)-/ ⁇ /-meth lcvclobutanamine hydrochloride
  • Step 4 Preparation of A/-rfrans-3-( ⁇ 6-chloro-2-r(3S)-3-methylmorpholin-4- yllPyrimidin-4-yl)oxy)cvclobut l1-/V-methylacetamide
  • Step 5 Preparation of /V-rfrans-3-( ⁇ 2'-amino-2-r(3S)-3-methylmorpholin-4-yl1-4,5'- bipyrimidin-6-yl)oxy)cvclobutyl1-/V-methylacetamide
  • Enantiomeric excess 98.41 % (Chiralcel OZ-3 150x4.6 mm I.D., 3 ⁇ , retention time: 9.72 min, mobile phase: 25 % MeOH (0.05 % diethylamine) in C0 2 , flow rate: 2.35 mL/min).
  • Step 1 Preparation of 5-fluoro-2- morpholin-4-yl)pyrimidine-4,6-diol
  • Step 1 Preparation of frans-3- ⁇ [6-chloro-2-(morpholin-4-yl)pyrimidin-4- ylloxylcyclobutanamine hydrochloride
  • Step 3 Preparation of 4-(4-chloro-6- ⁇ [frans-3-(1 ,1 -dioxido-1 ,2-thiazolidin-2- yl)cvclobutvHoxy)pyrimidin-2-yl)morpholine
  • Step 1 Preparation of A/-(2-chloroethyl)-/V'-(frans-3- ⁇ r6-chloro-2-(morpholin-4- yl)pynmidin-4-vHoxy)cvclobutyl)sulfuric diamide
  • Step 2 Preparation of 4-(4-chloro-6- ⁇ [frans-3-(1 , 1 -dioxido-1 ,2,5-thiadiazolidin-2- yl)cvclobutvHoxy)pyrimidin-2-yl)morpholine
  • Step 1 Preparation of fe/f-butyl [fran -3-(benzyloxy)cvclobutvHcarbamate
  • Step 3 Preparation of fe/f-butyl (2- ⁇ trans-3- (benzyloxy)cvclobutyl1amino)ethyl)carbamate
  • Step 4 Preparation of /V-[fran -3-(benzyloxy)cvclobutyl1ethane-1 ,2-diamine
  • Step 5 Preparation of 1 -[frans- -(benzyloxy)cvclobutvHimidazolidin-2-one
  • Step 6 Preparation of 1 -(frans-3-hvdroxycvclobutyl)imidazolidin-2-one
  • Step 1 Preparation of fe/f-butyl (3- ⁇ trans-3- (benzyloxy)cvclobutvHamino)propyl)carbamate
  • Step 2 Preparation of /V-[frans-3-(benzyloxy)cvclobutyllpropane-1 ,3-diamine
  • Step 3 Preparation of 1 -[frans-3-(benzyloxy)cvclobutyl1tetrahydropyrimidin-2(1 /-/)- one
  • Step 4 Preparation of 1 -(trans-3-hvdroxycvclobutyl)tetrahydropyrimidin-2(1 H)- one
  • PF-CD05 Column Xbridge C18 2.1 x50mm 5 ⁇ ; Temperature 40 °C; Mobile Phase A 0.05% NH 4 OH in water; Mobile Phase B 100% MeCN; Gradient: 5% B to 100% B; Flow rate 0.8 ml_ / min; Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD.
  • PF-AB01 Column Xbridge C18 2.1 x50mm 5 ⁇ ; Temperature 40 °C; Mobile Phase A 0.0375% TFA in water; Mobile Phase B 0.01875% TFA in MeCN; Gradient: 1 % B to 100% B; Flow rate 0.8 ml_ / min; Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD.
  • PF-AB10 Column Xbridge C18 2.1 x50mm 5 ⁇ ; Temperature 40 °C; Mobile Phase A 0.0375% TFA in water; Mobile Phase B 0.01875% TFA in MeCN; Gradient: 10% B to 100% B; Flow rate 0.8 mL / min; Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD. Table 2
  • PF-CD05 Column Xbridge C18 2.1 x50mm 5pm; Temperature 40 °C; Mobile Phase A 0.05% NH 4 OH in water; Mobile Phase B 100% MeCN; Gradient: 5% B to 100% B; Flow rate 0.8 mL / min; Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD.
  • PF-AB01 Column Xbridge C18 2.1 x50mm 5pm; Temperature 40 °C; Mobile Phase A 0.0375% TFA in water; Mobile Phase B 0.01875% TFA in MeCN; Gradient: 1 % B to 100% B; Flow rate 0.8 mL / min; Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD. Table 3
  • Genes encoding for full length p1 10a and p85a subunits of PI3Ka complex were subcloned from existing constructs into pFASTBAC Dual vector (Life Technologies, Carlsbad, CA) using standard cloning procedures. Gene encoding p1 10a subunit was subcloned into polyhedrine promoter while gene encoding p85a subunit was subcloned into p10 promoter. Additionally, sequence encoding for histidine tag and Tobacco Etch Virus ("TEV”) cleavage site preceded p1 10a ORF (Open Reading Frame).
  • TSV Tobacco Etch Virus
  • MOI multiplicity of infection
  • Cells were lyzed in 50 mM Tris pH 8.0, 250 mM NaCI, 5% glycerol, 0.25 mM TCEP, and 20 mM imidazole.
  • the PI3Ka complex was purified from clarified supernatant using Immobilized Metalo Affinity Chromatography (“IMAC").
  • the protein was eluted from the column using 50 mM Tris pH 8.0, 200 mM NaCI, 5% glycerol, 0.25 mM TCEP, and 200 mM imidazole, and further desalted into 50 mM Tris pH 8.0, 20 mM NaCI, and 0.25 mM TCEP prior to loading on MonoQ sepharose (GE Healthcare, Piscataway, NJ).
  • PI3Ka complex was eluted from MonoQ sepharose over 20 column volumes using 0-30% gradient of buffer B (50 mM Tris pH 8.0, 1 M NaCI, and 0.25 mM TCEP).
  • nSH2 p85a aminoacids 322-600 subunits of PI3Ka complex were subcloned from existing constructs into pFASTBAC Dual vector (Life Technologies, Carlsbad, CA) using standard cloning procedures. Gene encoding p1 10a subunit was subcloned into polyhedrine promoter while gene encoding p85a niSH2 domains was subcloned into p10 promoter. Additionally, Human Rhinovirus 3C Protease ("HRV 3C”) site was introduced between nSH2 and iSH2, replacing aminoacids 431 -438 of p85a with HRV 3C Protease
  • MOI multiplicity of infection
  • the p1 10a-niSH2 p85a complex was purified from clarified supernatant using Immobilized Metalo Affinity Chromatography ("IMAC").
  • IMAC Immobilized Metalo Affinity Chromatography
  • the protein was eluted from the column using 50 mM Tris pH 8.0, 200 mM NaCI, 0.25 mM TCEP, and 200 mM imidazole.
  • the mixture of p1 10a-iSH2 p85a complex and cleaved nSH2 was recovered in reverse IMAC 40 mM imidazole flow through and 60 mM imidazole wash fractions. Those fractions were pulled together and loaded on Superdex 200 26/60 SEC column equilibrated in 25 mM Tris, pH 8.0, 100mM NaCI, 2% glycerol, and 2 mM TCEP. Following SEC,
  • biochemical assays of kinase activity of full-length PI3Ka (full-length p1 10 ⁇ / ⁇ 85 ⁇ ) or truncated PI3Ka (p1 10a/iSH2 p85a) were conducted using a
  • PI3Ka enzyme PI3KA_Act or PI3KA_FL
  • DMSO or test compound 12-point 3-fold serial dilution, 3 ⁇ top dose, 2 % DMSO final concentration
  • 5 mM MgCI 2 50 mM HEPES pH 7.4, 150 mM NaCI, 1 mM DTT, and 0.05% 3-[(3-cholamidopropyl)dimethylammonio]-1 -propanesulfonate (“CHAPS").
  • the reactions were initiated by the addition of ATP (41 ⁇ , ⁇ Km-level, for full-length p1 10a/p85 or 1 mM ATP for p1 10a/iSH2 p85), following a 15-min
  • detector/probe mixture containing 480 nM GST-Grp1 PH domain protein (University of Dundee, Dundee, UK) and 12 nM carboxytetramethylrhodamine ('TAMRA')-tagged fluorescent phosphatidylinositol (3,4,5)-triphosphate ("PIP3") (Echelon Biosciences, Inc., Salt Lake City, UT) in assay buffer, was mixed with 15 ⁇ _ of kinase reaction mixture. The plate was shaken for 30 minutes and fluorescence polarization values were measured on an LJL Analyst HT plate reader (Molecular Devices, Sunnyvale, CA). The inhibitors were shown to be ATP-competitive from kinetic and crystallographic studies.
  • the inhibition constants (Ki) were calculated by fitting fluorescence polarization values, corresponding to initial reaction rates, to the Morrison equation (Morrison, J. F. (1969) Kinetics of the reversible inhibition of enzyme catalysed reactions by tight-binding inhibitors. Biochim. Biophys. Acta 185, 269-286) for tight-binding competitive inhibitors using non-linear regression method (GraphPad Prism, GraphPad Software, San Diego, CA).

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Abstract

La présente invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables correspondants, le cycle A, R1, R2a, R2b, R3, R4, R4a, R5- R23, g, j, m, n, x, y et z étant tels que définis dans la description. Ces nouveaux dérivés de pyrimidine sont utiles dans le traitement d'une croissance cellulaire anormale, telle que le cancer, chez des mammifères. D'autres modes de réalisation concernent des compositions pharmaceutiques contenant les composés, ainsi que des procédés d'utilisation des composés et des compositions dans le traitement d'une croissance cellulaire anormale chez des mammifères.
PCT/IB2015/054632 2014-06-30 2015-06-19 Dérivés de pyrimidine en tant qu'inhibiteurs de pi3k destinés à être utilisés dans le traitement du cancer WO2016001789A1 (fr)

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Cited By (3)

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US9758538B2 (en) 2015-07-15 2017-09-12 Pfizer Inc. Pyrimidine derivatives
JP2020531486A (ja) * 2017-08-23 2020-11-05 スプリント バイオサイエンス アクティエボラーグ ピリジルピリドン化合物
JP2020531488A (ja) * 2017-08-23 2020-11-05 スプリント バイオサイエンス アクティエボラーグ ピリジンアミン−ピリドンおよびピリミジンアミン−ピリドン化合物

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JP2020531486A (ja) * 2017-08-23 2020-11-05 スプリント バイオサイエンス アクティエボラーグ ピリジルピリドン化合物
JP2020531488A (ja) * 2017-08-23 2020-11-05 スプリント バイオサイエンス アクティエボラーグ ピリジンアミン−ピリドンおよびピリミジンアミン−ピリドン化合物
JP7199737B2 (ja) 2017-08-23 2023-01-06 スプリント バイオサイエンス アクティエボラーグ ピリジルピリドン化合物
JP7201260B2 (ja) 2017-08-23 2023-01-10 スプリント バイオサイエンス アクティエボラーグ ピリジンアミン－ピリドンおよびピリミジンアミン－ピリドン化合物

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