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WO2013067306A1 - Inhibiteurs de la phosphatidylinositol 3-kinase pour le traitement de cancers chez les enfants - Google Patents

Inhibiteurs de la phosphatidylinositol 3-kinase pour le traitement de cancers chez les enfants Download PDF

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Publication number
WO2013067306A1
WO2013067306A1 PCT/US2012/063247 US2012063247W WO2013067306A1 WO 2013067306 A1 WO2013067306 A1 WO 2013067306A1 US 2012063247 W US2012063247 W US 2012063247W WO 2013067306 A1 WO2013067306 A1 WO 2013067306A1
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Prior art keywords
nhc
compound
alkyl
nhch
hydrogen
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PCT/US2012/063247
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English (en)
Inventor
Arthur Decillis
Dana T. Aftab
Malcolm A. Smith
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Exelixis, Inc.
Sanofi
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Application filed by Exelixis, Inc., Sanofi filed Critical Exelixis, Inc.
Publication of WO2013067306A1 publication Critical patent/WO2013067306A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • methods for treating childhood cancer comprising administering to a patient in of such treatment a therapeutically effective amount of a Compound
  • R 51 is hydrogen or alkyl
  • R 52 is hydrogen or halo
  • R ⁇ R ⁇ and R 54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, ⁇ N(R 55 )C(0)-C 1 -C 6 -alkylene-N(R 55a )R 55b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(0) 2 NR 55 R 55a , or alkylcarbonylamino and where R 55 and R 55b are independently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R 53 and R 54 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl
  • B is phenyl substituted with R 3a and optionally further substituted with one, two, or three R 3 ; or
  • B is heteroaryl optionally substituted with one, two, or three R ;
  • R 3a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino;
  • alkylcarbonyl haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy;
  • R 7 is hydrogen, alkyl, or alkenyl and R 7a and R 7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R 7a and R 7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroaryl;
  • R 8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R 8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl,
  • R 9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R 9a is hydrogen, C 2 -C 6 -alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R 9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo,
  • R IOa is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R 10 and R 10b are independently hydrogen, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl;
  • R 1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R n and R Ub are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
  • R 12 is heterocycloalkyl optionally substituted with 1 , 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl;
  • R 13 is hydrogen, alkyl, or alkenyl and R 13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl;
  • R 14 , R 14a , and R 14b are independently hydrogen, alkyl, or alkenyl;
  • R 15 , R 15a , and R I b are independently hydrogen, alkyl, or alkenyl;
  • R 16a is alkyl or alkenyl
  • R 18a is hydrogen, alkyl, alkenyl, or alkoxy and R 18 and R 18b are independently hydrogen, alkyl, or alkenyl;
  • R 19a is amino, alkylamino, dialkylamino, or heterocycloalkyl
  • R 20 is hydrogen, alkyl, or alkenyl
  • R 20a is cycloalkyl or heterocycloalkyl
  • R 21a and R 21b are independently hydrogen, alkyl, or alkenyl
  • R 22 , R 22a and R 22b are independently hydrogen, alkyl, or alkenyl;
  • R 23 , R 23a and R 23b are independently hydrogen, alkyl, or alkenyl; or
  • R 24 is hydrogen, alkyl, or alkenyl and R 24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and where each of the alkylene in R 3a is independently optionally further substituted with 1, 2, 3,
  • each R 3 (when R 3 is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo; alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino;
  • dialkylamino alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy;
  • alkylaminoalkyloxy dialkylaminoalkyloxy; or
  • R 7 is hydrogen, alkyl, or alkenyl and R 7a and R 7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R 7a and R 7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroaryl;
  • R 8 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R 8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R 8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are
  • alkyl independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(0)H;
  • R 9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R 9a is hydrogen, C2-C 6 -alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R 9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, halo
  • R 10a is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or hydroxyalkyl and R 10 and R 10b are independently hydrogen, alkyl, alkenyl, haloalkyl, or hydroxyalkyl;
  • R 1 la is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R n and R Ub are independently hydrogen, alkyl, alkenyl, aminoalkyl,
  • alkylaminooalkyl dialkylaminoalkyl
  • R 12 is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl;
  • R 13 is hydrogen, alkyl, or alkenyl and R 13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl);
  • R 14 , R 14a , and R I4b are independently hydrogen, alkyl, or alkenyl
  • R 15 , R 15a , and R 15b are independently hydrogen, alkyl, or alkenyl;
  • R 16 is hydrogen, alkyl, or alkenyl and R 16a is alkyl or alkenyl; k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
  • R 18a is hydrogen, alkyl, alkenyl, or alkoxy and R 18 and R 18b are independently hydrogen, alkyl, or alkenyl;
  • R 19a is amino, alkylamino, dialkylamino, or heterocycloalkyl
  • R 20 is hydrogen, alkyl, or alkenyl
  • R 20a is cycloalkyl or heterocycloalkyl
  • R 21a and R 21b are independently hydrogen, alkyl, or alkenyl
  • R 24 is hydrogen, alkyl, or alkenyl and R 24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl;
  • each of the alkylene in R 3 is independently optionally further substituted with 1, 2, 3,
  • R 50 and R 52 are hydrogen, R 51 is hydrogen or methyl, R 53 is hydrogen or methoxy, and R 54 is hydrogen or methoxy, then B is not 2,3-dihydro-l,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R 3 where R 3 is halo.
  • the com ound of Formula I is a compound of Formula la
  • R 50 is hydrogen; R 51 is methyl;
  • R 52 is hydrogen
  • R 53 is hydrogen or alkoxy
  • R 54 is hydrogen, alkyl, alkoxy, or halo; or R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl;
  • R 3 is halo or methyl
  • R 3a is -N(R 7 )C(0)-C ! -C 6 -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen and R 7a and R 7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or
  • the compound of Formula I and of Formula la is Compound A:
  • the cancer is a leukemia such as acute lymphocytic leukemia.
  • the cancer is a solid tumor such as neuroblastoma.
  • the cancer is a sarcoma such as rhabdomyosarcoma
  • the compound of Formula I or Formula la is administered as a tablet or capsule pharmaceutical composition.
  • the compound of Formula I or Formula la is administered as a tablet pharmaceutical composition.
  • Figure 1 depicts the activation of the PI3K pathway in vitro by Compound A.
  • Figure 2 depicts the in vitro expression of PI3KCA and PI3KCD isoforms at the
  • RNA level lymphoma cell lines and xenografts treated with Compound A RNA level lymphoma cell lines and xenografts treated with Compound A.
  • Figure 3 depicts the in vivo activity of Compound A in various tumor types.
  • Figure 4 depicts the in vitro activity of Compound A.
  • Figure 5 depicts the in vivo objective response activity of Compound A.
  • the figure on the left is a colored heat map that depicts group response scores.
  • the figure on the right is a representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease).
  • a substituent "R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the two "R's" may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • Acyl means a -C(0)R radical where R is optionally substituted alkyl, optionally substituted alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl,
  • Acylamino means a -NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy and R' is acyl, as defined herein.
  • Acyloxy means an -OR radical where R is acyl, as defined herein, e.g.
  • administering in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkenyl means a means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, l-but-3-enyl, and l-pent-3-enyl, and the like.
  • Alkoxy means an -OR group where R is alkyl group as defined herein.
  • Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Alkoxyalkyl means an alkyl group, as defined herein, substituted with at least one, preferably one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.
  • Alkoxyalkylamino means an -NRR' group where R is hydrogen, alkyl, or alkoxyalkyl and R' is alkoxyalkyl, as defined herein.
  • Alkoxyalkylaminoalkyl means an alkyl group substituted with at least one, specifically one or two, alkoxyalkylamino group(s), as defined herein.
  • Alkoxycarbonyl means a -C(0)R group where R is alkoxy, as defined herein.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
  • Alkylamino means a -NHR group where R is alkyl, as defined herein.
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Alkylaminoalkyloxy means an -OR group where R is alkylaminoalkyl, as defined herein.
  • Alkylcarbonyl means a -C(0)R group where R is alkyl, as defined herein.
  • Alkynyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyN-2-yl and the like.
  • Amino means -NH 2 .
  • aminoalkyl means an alkyl group substituted with at least one, specifically one, two or three, amino groups.
  • aminoalkyloxy means an -OR group where R is aminoalkyl, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Arylalkyl means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl and phenethyl, and the like.
  • Aryloxy means an -OR group where R is aryl, as defined herein.
  • Carboxyalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, -C(0)OH group(s).
  • Cycloalkyl means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to ten carbon ring atoms.
  • Fused bicyclic hydrocarbon radical includes bridged ring systems.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3 - enyl, and the like.
  • Cycloalkylalkyl means an alkyl group substituted with at least one, specifically one or two, cycloalkyl group(s) as defined herein.
  • Dialkylamino means a -NRR' radical where R and R' are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino, and the like.
  • Dialkylaminoalkyl means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
  • Dialkylaminoalkyloxy means an -OR group where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(N,N-diethylamino)-ethyloxy, and the like.
  • fused-polycyclic or "fused ring system” means a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
  • Halogen or "halo” refers to fluorine, chlorine, bromine or iodine.
  • Haloalkoxy means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2 -trifluoroethoxy, and the like.
  • Haloalkyl mean an alkyl group substituted with one or more halogens, specifically one to five halo atoms, e.g., trifluoromethyl, 2-chloroethyl, and 2,2-difluoroethyl, and the like.
  • Heteroaryl means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from -0-, -S(0)N- (n is 0, 1, or 2), -N-, -N(R X )-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic.
  • R x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl.
  • Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. When the point of valency is located on the nitrogen, R x is absent.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl or 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl
  • benzothienyl and the derivatives thereof, or N-oxide or a protected derivative thereof.
  • Heteroarylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two heteroaryl group(s), as defined herein.
  • Heteroatom refers to O, S, N, or P.
  • Heterocycloalkyl means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, specifically one, two, three, or four ring heteroatoms independently selected from O, S(0) n (n is 0, 1, or 2), N, N(R y ) (where R y is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon.
  • Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, R y is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl,
  • Heterocycloalkylalkyl means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein, e.g., mo holinylmethyl,
  • N-pyrrolidinylethyl N-pyrrolidinylethyl, and 3-(N-azetidinyl)propyl, and the like.
  • Heterocycloalkylalkyloxy means an -OR group where R is heterocycloalkylalkyl, as defined herein.
  • saturated bridged ring system refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system.
  • Spirocyclyl or "spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • Optionally substituted alkoxy means an -OR group where R is optionally substituted alkyl, as defined herein.
  • Optionally substituted alkyl means an alkyl radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl,
  • alkylcarbonyloxy alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(0)o-2-, alkenyl-S(0)o-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NR c - (where R° is hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylamino
  • Optionally substituted alkenyl means an alkyl radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(0)o- 2 -, alkenyl-S(0)o-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl
  • alkoxycarbonylamino alkylaminocarbonylamino, dialkylaminocarbonylamino,
  • alkoxyalkyloxy and -C(0)NR a R b (where R a and R b are independently hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).
  • Optionally substituted amino refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, acyl, carboxy, alkoxycarbonyl, -S(0)2-(optionally substituted alkyl), -S(0)2-optionally substituted aryl), -S(0) 2 -(optionally substituted heterocycloalkyl), -S(0) 2 -(optionally substituted heteroaryl), and -S(0) 2 -(optionally substituted heteroaryl).
  • “optionally substituted amino” includes diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino.
  • Optionally substituted aminoalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted amino group(s), as defined herein.
  • Optionally substituted aryl means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on "aryl", the optional substituents
  • alkyl in alkoxycarbonyl are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted arylalkyl means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
  • Optionally substituted cycloalkyl means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently selected from acyl, acyloxy, acylamino, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, carboxy, and
  • alkyl and alkenyl are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl .
  • Optionally substituted cycloalkylalkyl means an alkyl group substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined herein.
  • Optionally substituted heteroaryl means a heteroaryl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy.
  • alkyl and alkenyl are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted heteroarylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heteroaryl group(s), as defined herein.
  • Optionally substituted heterocycloalkyl means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl.
  • heterocycloalkyl the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are optional substituents on “heterocycloalkyl.
  • Optionally substituted heterocycloalkylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heterocycloalkyl group(s) as defined herein.
  • “Pharmaceutical composition” comprises 1) a Compound of Formula I or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof; and 2) a pharmaceutically acceptable carrier, excipient, or diluent.
  • Formula la has the following structure .
  • Compound A is known by its chemical name N-(3- ⁇ [(3- ⁇ [2-chloro-5-(methoxy)phenyl]amino ⁇ quinoxalin-2- yl)amino]sulfonyl ⁇ phenyl)-2-methylalaninamide. As discussed in more detail below, the compound may exist in several tautomeric or zwitterionic forms.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
  • terapéuticaally effective amount refers to a sufficient amount of an agent to provide the desired biological, therapeutic, and or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay development.
  • an effective amount is an amount sufficient to prevent or delay recurrence.
  • An effective amount can be administered in one or more administrations. The effective amount of the drug or
  • composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • an "effective amount" for therapeutic uses is the amount of Compound A or a metabolite thereof, a pharmaceutically acceptable salt or solvate thereof, or a composition comprising Compound A or a metabolite thereof or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in the progression of EC.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid,
  • 2-naphthalenesulfonic acid 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like.
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine,
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.
  • Metal refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • treating means inhibiting the disease, disorder, or syndrome, that is, arresting its development; and relieving the disease, disorder, or syndrome, that is, causing regression of the disease, disorder, or syndrome.
  • adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
  • Prevention means preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
  • Childhood cancer refers to a cancer that commonly affects children from the age of 1 to 15, as provided by National Cancer Institute.
  • “Childhood cancers” include leukemia and cancers of the brain and central nervous system, such as acute lymphoblastic leukemia, solid tumors such as brain tumors (e.g., gliomas and medulloblastomas), neuroblastomas, Wilms tumors, and sarcomas such as rhabdomyosarcoma and osteosarcoma.
  • EFS T/C value Event Free Survual (EFS) T/C value.
  • An EFS T/C value is defined by the ratio of the median time to event of a treatment group and the median time to event of the respective control group. If the treatment group does not have a median time to event, then EFS T/C is defined as greater than the ratio of the last day of the study for the treatment group divided by the median time to event for the control group.
  • agents are considered highly active if they meet three criteria: a) an EFS T/C > 2; b) a significant difference in EFS distributions (p ⁇ 0.050), and c) a net reduction in median tumor volume for subjects in the treated group at the end of treatment as compared to treatment initiation.
  • the embodiment includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof.
  • methods for treating a childhood cancer, which method comprises administering to a patient an effective amount of a Compound of Formula I or la or a pharmaceutical composition comprising a Compound of Formula I or la.
  • methods for treating cancer comprises administering to a patient an effective amount of a Compound of Formula I or a pharmaceutical composition comprising a Compound of Formula I where the cancer is acute lymphoblastic leukemia, rhabdosarcoma, or neuroblastom.
  • the Compound of Formula I is selected from any of the following embodiments, including from the Representative Compounds in Table 1.
  • R 50 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(0)-C 1 -C 6 -alkylene-N(R 55a )R S5b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(0) 2 NR 55 R 55a , or alkylcarbonylamino; where R 55 and R 55b are independently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention.
  • R 50 is hydrogen.
  • R 51 is hydrogen or alkyl; and all other groups are as defined in the Summary of the Invention.
  • R 51 is alkyl; in another embodiment, R 51 is methyl.
  • R 52 is hydrogen or halo; and all other groups are as defined in the Summary of the Invention.
  • R is hydrogen or fluoro.
  • R is hydrogen.
  • R 53 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(0)-Ci-C 6 -alkylene-N(R 55a )R 55b , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(0) 2 NR 55 R 55a , or
  • R 55 and R 55b are independently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention.
  • R 53 is hydrogen, alkoxy, nitro, amino, or -N(R S5 )C(0)-C 1 -C 6 -alkylene-N(R 55a )R 55b .
  • R 53 is hydrogen, methoxy, nitro, amino, or -NHC(0)CH 2 N(CH 3 ) 2 .
  • R 53 is hydrogen or methoxy.
  • R 54 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -NCR ⁇ CCO ⁇ Q-Q-alkylene-NCR 553 ⁇ 5515 , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(0) 2 NR 55 R 55a , or
  • R 55 and R 55b are independently hydrogen, alkyl, or alkenyl and R 55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of the Invention.
  • R 54 is hydrogen, alkyl, alkoxy, or halo.
  • R 54 is hydrogen, methyl, methoxy, bromo, or chloro.
  • R 54 is hydrogen, methoxy, or chloro.
  • Another embodiment (G) is directed to a compound of Formula I where R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention.
  • R 50 , R 52 , and R 53 are hydrogen and R 54 is chloro or methoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is methoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form pyridinyl. Even more specifically, R 50 , R 52 , and R 53 are hydrogen and R 54 is chloro or methoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is methoxy.
  • embodiment G is a compound of Formula I where R 51 is methyl.
  • B is heteroaryl optionally substituted with one, two, or three R 3 .
  • B is thien-3-yl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, or thiazolyl, each of which is optionally substituted with one or two R 3 .
  • B is thien-3-yl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4- yl, isoxazol-5-yl, imidazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, each of which is optionally substituted with one or two R 3 .
  • B is thien-3-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R 3 .
  • B is pyridin-3-yl, 2-hydroxy-pyridin-5-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R .
  • R 3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R 7 )C(0)-C 1 -C 6 -alkylene- N(R 7a )(R 7b ); -C(0)NR 8 R 8a ; -NR 9 C(0)R 9a ; -C(O)N(R 10 )-C,-C 6 -alkylene-N(R 10a )R 10b ;
  • heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or
  • R 3a is:
  • -NHC(0)CH 2 (4-methylcarbonylpiperazin- 1 -yl), -NHC(0)(5-fluoro-2-methoxyphenyl), -NHC(0)CH 2 N(CH 2 CH 3 )cyclohexyl, -NHC(0)(5-methyl-l,2-oxazol-3-yl), -NHC(0)(3-methylpyridin-3-yl), -NHC(0)(2-methoxypyridin-3-yl),
  • R 3a is hydroxyamino, -N(R 7 )C(0)-C 1 -C 6 -alkylene- N(R 7a )(R 7b ), -C(0)NR 8 R 8a , -NR 9 C(0)R 9a , -C(O)N(R 10 )-Ci-C 6 -alkylene-N(R 10a )R 10b ,
  • R 3a is -NHC(0)CH 2 NH(CH 3 ), -NHC(0)CH(CH 3 )NH 2 , -NHC(0)C(CH 3 ) 2 NH 2 , -NHC(0)CH 2 N(CH 3 ) 2 , -NHC(0)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 25 -NHC(0)CH( H 2 )CH 2 CH 3 , -NHC(0)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , -NHC(0)CH(CH 3 )NH(CH 3 ), -NHC(0)H,
  • -NHC(0)CH 2 (azetidin- 1 -yl), -NHC(0)(pyrrolidin-2-yl), -NHC(0)CH(NH 2 )CH 2 OH, -NHC(0)(azetidin-4-yl), -NHC(0)C(CH 3 ) 2 NH(CH 3 ), -NH 2 , -NHC(0)CH 2 NH(CH 2 CH 2 CH 3 ), -NHC(0)CH 2 CH 2 NH 2 , -NHOH, or -NHC(0)(piperidin-3-yl).
  • R 3a is -NHC(0)CH 2 NH(CH 3 )
  • Embodiment (N) provides a compound of Formula I where each R 3 is
  • heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or
  • each R 3 is independently methyl, bromo, chloro, fluoro, -NHC(0)CH 2 NH(CH 3 ), -NHC(0)CH 2 NH(CH 2 CH 3 ), -NHC(0)CH(CH 3 )NH 2 ,
  • -NHC(0)CH 2 (4-methyl-l,4-diazepan-l-yl), -NHC(0)CH(NH 2 )(CH 2 CH 3 ), - NHC(0)CH 2 NH(CH 2 CH(OH)(CH 3 )), -NHC(0)CH 2 NHCH 2 CH 2 F, - NHC(0)CH 2 NH(OCH 2 CH(CH 3 ) 2 ), -NHC(0)(1 -aminocycloprop- 1 -yl),
  • -NHC(0)CH 2 (4-methylamino-piperidin- 1 -yl), -NHC(0)(piperidin- 1 -yl), -NHC(0)(N-methyl- pyrrolidin-2yl), -NHC(0)(thien-3yl), -NHC(0)(N-(cyclopropylcarbonyl)azetidin-3-yl),
  • -NHC(0)CH 2 (2-methyl-pyrrolidin- 1 -yl), -NHC(0)(furan-3-yl), -NHC(0)CH 2 N(CH 3 )2, -NHC(0)(2-chloro-pyridin-5-yl), -NHC(0)(2-chlorophenyl), -NHC(0)CH 2 (pyridin-2-yl), -NHC(0)CH 2 (3-dimethylamino-azetidin- 1 -yl), -NHC(0)CH 2 (pyridin-3-yl),
  • -NHC(0)CH 2 0phenyl, -NHC(0)CH 2 NH(2,3-dimethylphenyl), -NHC(0)(2-fluoro-5-methylphenyl), -NHC(0)CH 2 NHOCH 2 (4-methylphenyl), -NHC(0)CH 2 (4-isopropylpiperazin- 1 -yl), -NHC(0)CH 2 (4-fluorophenyl),
  • -C(0)NHC(CH 3 ) 2 C(0)(piperidin-l-yl), -C(0)(4-methylpiperazin-l-yl), -C(0)(2-piperidin- 1-ylmethyl-piperidin-l-yl), cyano, -NHCH 3 , -CH(CH 3 )NHCH 2 CH 2 N(CH 3 ) 2 , -C(0)CH 3 , -S(0) 2 NHCH 2 CH 2 N(CH 3 ) 2 , -S(0) 2 NH(CH 2 ) 3 N(CH 3 ) 2 , 5-(N,N-dimethylaminomethyl)- l,3,4-oxadiazol-2-yl, -NHCH 2 CH 2 N(CH 3 ) 2 , -N(CH 3 ) 2 , -OCH 2 CH 2 N(CH 3 ) 2 ,
  • R 3 is independently halo, alkyl, hydroxyamino, -N(R 7 )C(0)-Ci-C 6 -alkylene-N(R 7a )(R 7b ), -C(0)NR 8 R 8a , -NR 9 C(0)R 9a , -C(O)N(R 10 )-Ci-C 6 - alkylene-NCR ⁇ R' ⁇ -NR 1 'CCOiNR 1 lb , -N(R 22 )C(0)-Ci-C 6 -alkylene-N(R 22b )- N(R 22c )(R 22a ), -NR 13 C(0)OR 13a , -N(R 18 )C(0)-Ci-C 6 -alkylene-N(R 18 )C(0)R 18a , -NR 2 C(0)- d.Ce-alkylene-OR 243 , or -N(R 20 )C(O)-
  • each R 3 is independently methyl, chloro,
  • -NHC(0)CH 2 (azetidin- 1 -yl), -NHC(0)(pyrrolidin-2-yl), -NHC(0)CH(NH 2 )CH 2 OH, -NHC(0)(azetidin-4-yl), -NHC(0)C(CH 3 ) 2 NH(CH 3 ), -NH 2 , -NHC(0)CH 2 NH(CH 2 CH 2 CH 3 ), -NHC(0)CH 2 CH 2 NH 2 , -NHOH, or -NHC(0)(piperidin-3-yl).
  • R 3 is alkyl or
  • each R 3 is independently methyl, -NHC(0)CH 2 NH(CH 3 ), -NHC(0)CH(CH 3 )NH 2 ,
  • B is phenyl, R is not present or R is halo, alkyl, or alkoxy;
  • R 3a is -C(0)NR 8 R 8a , -NR 9 C(0)R 9a , -N(R 7 )C(0)-Ci-C 6 -alkylene-N(R 7a )(R 7 ), or -C(O)N(R 10 )-Ci-C 6 -alkylene-N(R 10a )R 10b where each of the alkylene in R 3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention.
  • R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or R 50 and R 52 are hydrogen and R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined in the Summary of the Invention.
  • R so , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy; or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy.
  • R 51 is methyl.
  • the compound of Formula I is a compound of Formula la:
  • R 50 is hydrogen
  • R 51 is methyl
  • R 52 is hydrogen
  • R 53 is hydrogen or alkoxy; and R 54 is hydrogen, alkyl, alkoxy, or halo; or R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and
  • R 3 is halo or methyl
  • R 3a is -N(R 7 )C(0)-C 1 -C -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen and R 7a and R n are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or
  • R 51 is methyl; and R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or a single stereoisomer or mixture of stereoisomers thereof.
  • R 3a is -NHC(0)CH 2 NH(CH 3 ), -NHC(0)CH(CH 3 )NH 2 ,
  • the compound of Formula la is:
  • the compound of Formula I and of Formula la is Compound
  • the invention provides a method of treating a childhood cancer in a patient, comprising administering to the patient an effective amount of Compound A.
  • the Compound A as a capsule or tablet pharmaceutical composition.
  • Compound A is administered as a capsule consisting of Size 0 capsules filled with drug substance only. There are no additional excipients other than the capsule gelatin and coloring agents.
  • the composition of the hard gelatin capsule shell and color demarcation are presented in the table below.
  • Compound A is administered as a tablet.
  • the tablet strength will be distinguishable by shape and/or size.
  • the tablet formulation contains N-(3- ⁇ [(3 - ⁇ [2-chloro-5 -(methoxy)phenyl] amino ⁇ quinoxalin-2-yl)amino] sulfonyl ⁇ phenyl)-2- methylalaninamide, silicified microcrystalline cellulose, partially pregelatinized maize starch, sodium starch glycolate, hypromellose, colloidal silicon dioxide, stearic acid, and magnesium stearate. All three tablet strengths are manufactured from a common blend with the composition listed in the following Table. Composition of the Compound 100-, 150-, and 200-mg Tablets
  • the invention provides pharmaceutical compositions comprising an inhibitor of the PBKs of Formula I or la and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration is by the oral route.
  • Administration of the compounds of Formula I or la, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • the Compound of Formula I or la can be administered in the same or separate vehicles.
  • Administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a Compound of Formula I or la as the/an active agent.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example
  • One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like;
  • solubilizing agents and emulsifiers as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol,
  • oils in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of Formula I or la, or their pharmaceutically acceptable salts or solvates are administered in an effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of Formula I or la can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day, or in the range of 50 to 400 mg per day ,100 mg to 800 mg per day, or in the range of 100 mg to 350 mg per day, or in the range of 200 to 700 mg per day, or in the range of 150 mg to 300 mg per day, or in the range of 300 to 600 mg per day.
  • a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used for children will generally be lower due to the smaller size and weight of children, and the doses can be adjusted according to size and weight factors, as well as additional factors.
  • the dosage can depend on additional factors including the requirements of the child, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular child is well known to one of ordinary skill in the art. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within approved dosage ranges.
  • Compounds of Formula I or la may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 °o to about 150 °o, in another embodiment from about 0 c o. to about 125 c o and most specifically at about room (or ambient) temperature, e.g., about 20 c o. Unless otherwise stated (as in the case of a hydrogenation), all reactions are performed under an atmosphere of nitrogen.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.
  • the compounds of the invention may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure.
  • Compounds of Formula I that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • Some of the compounds of the invention may exist as tautomers.
  • the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention, and to the extent that one structure is used to depict a compound, it includes all such tautomeric forms.
  • ring B in the Compound of Formula I or B can be 2- hydroxy-pyridinyl, also described as its structure:
  • Both 2-hydroxy-pyridinyl and the above structure 14 include, and are equivalent to, pyridin- 2(lH)-one and its structure 15:
  • Compound A-2 is named N-(3- ⁇ [(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin. 2(lH)-ylidene]sulfamoyl ⁇ phenyl)-2-methylalaninamide.
  • interconversion can also exist between the uncharged tautomeric forms and the zwitterionic forms.
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I.
  • compounds of Formula I when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • compounds of Formula I When compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group” or "protective group.”
  • a comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
  • stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art.
  • optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid
  • enantiomeric form Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomers enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • an intermediate of formula 3 can be prepared by briefly heating an appropriately substituted quinoxaline (for example, commercially available 2,3-dichloroquinoxaline) and an appropriately substituted sulfonamide of formula 2 (which are commercially available or can be prepared by one of ordinary skill in the art), a base such as K2CO3, in a solvent, such as DMF or DMSO. Upon completion (about 2 hours), the reaction mixture is then poured into water and followed by 2 N HCl. The product is then extracted into a solvent such as ethyl acetate and washed with water and brine. The organic layers are combined and dried over a drying agent such as sodium sulfate, filtered, and concentrated under vacuum to provide a compound of formula 3.
  • a base such as K2CO3
  • a solvent such as DMF or DMSO
  • the intermediate of formula 3 is then treated with an intermediate of formula 4 in a solvent such as DMF or p-xylene at reflux temperature. Upon completion of the reaction (about 16 hours or less), the reaction is allowed to cool, extracted into DCM, washed with 2 N HCl and brine, dried over a drying agent such as sodium sulfate or magnesium sulfate, filtered, and concentrated to give a compound of Formula I.
  • a solvent such as DMF or p-xylene at reflux temperature.
  • quinoxaline derivatives are known to one skilled in the art and include, but are not limited to S. V. Litvinenko, V. I. Savich, D. D. Bobrovnik, Chem. Heterocycl. Compd. (Engl. Transl), 1994, 30, 340 and W. C. Lumma, R. D. Hartman, J. Med. Chem. 1981, 24, 93.
  • LG is a leaving group such as chloro.
  • the reaction is carried out in the presence of a base, such as KHC0 3 , in a solvent such as DMF.
  • reaction is carried out in the presence of a base such as NaH in a solvent such as DMF.
  • R 100 in Scheme 4 is -C(0)R 9a , -C(0)NR' lb , -C(0)OR 13a , -C(O)- Ci-C 6 -alkylene-N(R 18b )C(0)R 18a , -C(O)-C 1 -C 6 -alkylene-C(O)R 20a , or -SCOk-C -alkylene- N(R 21b )R a .
  • the reaction is carried out under standard amide coupling conditions known to one of ordinary skill in the art.
  • reaction is carried out in the presence of a coupling agent such as HATU, a base such as DIEA, and in a solvent such as DMF.
  • a coupling agent such as HATU
  • a base such as DIEA
  • a solvent such as DMF.
  • the N-protecting group is then removed using procedures known to one of ordinary skill in the art, such as treating with acid where PG is Boc.
  • 12 l(f) LG is a leaving group such as bromo or chloro. 12 is reacted with NH(R 7b )R 7a in the presence of a base, such as DIEA, in a solvent such as ACN.
  • a base such as DIEA
  • 1(h) LG in Scheme 6 is a leaving group such as chloro.
  • the reaction can be carried out by irradiating in a solvent such as DMA. Alternatively, the reaction can be carried out in the presence of acetic acid in a solvent such as DMA and by heating.
  • a CEM microwave reaction vessel was charged with N-(3-(N-(3- chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide (30 mg, 0.071 mmol), prepared using procedures similar to those described in Example 374, the desired aniline (16 mg, 0.14 mmol, 2 eq), and 0.5 mL of dimethylacetamide.
  • the vessel was sealed and the reaction mixture was heated under microwave radiation for 70 min at 140 °C in a CEM Discover microwave instrument. The solvent was then removed by rotary-evaporation. Purif i cation of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NH 4 OAc/ACN to the desired product.
  • a CEM microwave reaction vessel was charged with N-(3-(N-(3- chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide (62 mg, 0.147 mmol), prepared using procedures similar to those in Example 374, the desired aniline (0.567 mmol, 4 eq), and 1.0 mL of toluene.
  • the vessel was sealed and the reaction mixture was heated under microwave radiation for 60 min at 180 °C in a CEM Discover microwave instrument. The solvent was removed on a rotary-evaporator. Purification of the final product was done by preparatory HPLC with NRjOAc/ACN as eluent to yield the desired product.
  • N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)- sulfamoyl)phenyl)azetidine-3-carboxamide (125 mg, 0.23 mmol), prepared using procedures similar to those described in Example 372, was dissolved into 5 mL DCE in a 10 mL round- bottom flask. DIEA (1.17 mmol, 5.0 equiv.) was then added with stirring followed by acid chloride (0.47 mmol, 2.0 equiv.). The reaction was then stirred at room temperature for 1 hour or until complete as indicated by LCMS. The solvent was subsequently removed under reduced pressure on a rotary evaporator.
  • a solution was prepared with 0.585 kg of 2-chloro-5-methoxyaniline-HCl, 3.5 volumes of acetonitrile and 0.46 kg of DBU (solution A). Separately, 1 kg of N-(3-chloroquinoxalin-2- yl)-3 -mtrobenzenesulfonamide and 5.5 volumes of acetonitrile were combined and heated to reflux. Solution A and 1 volume of acetonitrile were then added to the reaction mixture, and the resulting mixture was heated at reflux. After completion of the reaction, the mixture was cooled down at 20 °C, diluted with 10 volumes of methanol and filtered. The resulting filter cake was washed 3 times with 5 volumes of methanol and then dried under vacuum.
  • Compound A was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical testing Program (PPTP). See http://pptp.nchresearch.org/documents.html (last visited October 18, 201 1). Compound A was tested against the PPTP's in vitro cell line panel at concentrations ranging from 10.0 nM to 100 ⁇ using the PPTP's standard 96 hour exposure period. For in vivo testing, a Compound A dose of 100 mg/kg was administered orally daily for 14 days with a total planned observation period of 6 weeks. Background: PPTP In Vitro Cell Lines and In Vivo Xenograft Models and Testing
  • the model parameters are the following: a, which denotes the value of response for the minimal curve asymptote (theoretically, the level of response produced by an infinitely high concentration of drug); b, which denotes the value of response for the maximal curve asymptote (theoretically, the level of response, if any, in the absence of drug); c, which denotes the EC50 or the concentration at the half maximal effect; and d, which denotes the slope of the dose-response curve (often used as a measure of the sensitivity of the system to increments in drug concentrations).
  • the parameters in the model are estimated using
  • IC50 values are determined from the actual curve fit outputs generated by Kaleidagraph. To compare activity between cell lines, the ratio of the median IC50 to individual cell line IC50 values is used (larger values connote greater sensitivity).
  • mice CB17SC-M scid-/- female mice (Taconic Farms, Germantown NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described [2- 4]. Mice bearing subcutaneous tumors each received drug when tumors reached between 200 mm3 and 500 mm3.
  • mice Human leukemia cells were propagated by intravenous inoculation in female non-obese diabetic ( ⁇ )/ scid-/- mice as described previously [5]. Mice were randomized to groups of 10 for solid tumor-bearing and groups of 8 for ALLbearing animals. All mice were maintained under barrier conditions and experiments were conducted using protocols and conditions approved by the institutional animal care and use committee of the appropriate consortium member. Each agent tested was given a code number, and the identity of each was revealed to testing sites only after complete data sets had been deposited in the database.
  • Tumor volumes (cm 3 ) [solid tumor xenografts] or percentages of human CD45- positive [hCD45] cells [ALL xenografts] were measured for each tumor at the initiation of the study and weekly for up to 42 days after study initiation. Assuming tumors to be spherical, tumor volumes were calculated from the formula ( ⁇ /6)- ⁇ 3 , where d represents the mean diameter.
  • TGD tumor growth delay
  • Event-free survival An event in the solid tumor xenograft models was defined as a quadrupling of tumor volume from the initial tumor volume. Event-free survival was defined as the time interval from initiation of study to the first event or to the end of the study period for tumors that did not quadruple in volume. The time to event was determined using interpolation based on the formula:
  • xt is the interpolated day to event
  • t ⁇ is the lower observation day bracketing the event
  • t ⁇ is the upper observation day bracketing the event
  • Vj is the tumor volume (or hCD45 percentage) on day 3 ⁇ 4
  • V 2 is the tumor volume (or hCD45 percentage) on day
  • V e is the event threshold (4 times initial tumor volume for solid tumor xenografts, 25% for ALL xenografts).
  • ALL Acute Lymphoblastic Leukemia
  • Individual mice were categorized as PD if their percentage of hCD45 cells never dropped below 1% and they had an event before the end of the study period.
  • An event is defined as hCD45 cells above 25% in the peripheral blood with times to event calculated as above.
  • Individual mice were classified as SD if their percentage of hCD45 cells never dropped below 1% and no event occurred before the end of the study.
  • PR was assigned if the percentage of cells dropped below 1% for any one time point regardless of whether the percentage eventually reached 25%.
  • a CR was assigned if the percentage of hCD45 cells dropped below 1% for 2 consecutive weeks of the study and regardless of whether the percentage reached 25% or not.
  • a CR was considered maintained if the percentage of hCD45 was less than 1% for the last three measurements of the study.
  • PD was further classified into PD1 and PD2 according to the TGD value.
  • Tumor Volume T/C value Relative tumor volumes (RTV) for control (C) and treatment (T) mice were calculated at day 21 or when all mice in the control and treated groups still had measurable tumor volumes (if less than 21 days). The mean relative tumor volumes for control and treatment mice for each study were then calculated and the T/C value was the mean RTV for the treatment group divided by the mean RTV for the control group.
  • RTV Relative tumor volumes
  • T/C response measure agents producing a T/C of ⁇ 15% are considered highly active, those with a mean tumor volume T/C of ⁇ 45% but > 15% are considered to have intermediate activity, and those with mean T/C values > 45% are considered to have low levels of activity [6].
  • EFS T/C value An EFS T/C value was defined by the ratio of the median time to event of the treatment group and the median time to event of the respective control group. If the treatment group did not have a median time to event, then EFS T/C was defined as greater than the ratio of the last day of the study for the treatment group divided by the median time to event for the control group.
  • agents are considered highly active if they meet three criteria: a) an EFS T/C > 2; b) a significant difference in EFS distributions (p ⁇ 0.050), and c) a net reduction in median tumor volume for animals in the treated group at the end of treatment as compared to at treatment initiation.
  • Agents meeting the first two criteria, but not having a net reduction in median tumor volume for treated animals at the end of the study are considered to have intermediate activity.
  • Agents with an EFS T/C ⁇ 2 are considered to have low levels of activity.
  • Xenografts in which the median EFS for the control line was greater than one-half of the study period or in which the median EFS for the control line did not exist are considered not evaluable for the EFS T/C measure of activity.
  • Compound A was tested in vivo using a 100 mg/kg dose administered orally daily for 14 days .
  • 10 mice bearing SC tumors initiated treatment when the tumors were between 0.2-0.5 cm3.
  • Two perpendicular tumor diameters were measured at either once or twice weekly intervals with digital vernier calipers.
  • Acute lymphoblastic leukemia (ALL) testing For each xenograft line, 8 mice were inoculated with 3-5 x 1 6 mononuclear ceils purified from the spleens of secondary recipient mice. Engrafiment was monitored weekly by flow cytometry,, and treatment was initiated when the proportion of human CD45+ cells in the peripheral blood reached 1 %. The proportion of human CD45+ cells in the peripheral blood was monitored weekly throughout the course of treatment
  • Compound A was tested in the tumor types listed in Table 3. Red shading in the p-value columns indicates a significant difference in EFS distribution or Tumor Volume T/C between treated and control groups. Shading in the EFS columns indicates xenografts that have either high (dark blue), intermediate (light blue), low (gray), or indeterminant (white) activity.
  • PD1 Progressive Disease 1 means a greater than 25 percent increase in tumor volume with a tumor growth delay (TGD) value of less than or equal to 1.5
  • PD2 Progressive Disease 2 means a greater than 25 percent increase in tumor volume with a TGD value of greater than 1.5
  • SD Stable Disease
  • Figure 3 further summarizes the in vivo results for Rhl 0, Rhl 8, Rh41 , and ALL7 tumor types.
  • Compound A demonstrated cytotoxic activity, with Y mm values approaching 0% for all of the cell lines at the highest concentration tested (100 ⁇ ).
  • the median relative iC 50 value for the PPTP cell lines was 10.9 ⁇ , with a range from 2.7 ⁇ (CHLA-10) to 24.5 ⁇ (TC-71). There were no significant differences by histotype in median relative IC 50 values. though there was a trend for lower values for the rhabdomyosarcoma panel (median IC 50 5.6 ⁇ ) and higher values for the neuroblastoma panel (median IC50 19.5 ⁇ ).
  • Compound A was tested against 31 solid tumor xenografts and 7 acute lymphoblastic leukemia (ALL) xenografts. A dose of 100 mg/kg administered orally daily for 14 days for a total planned observation period of 6 weeks was utilized. Compound A was generally well tolerated, with a ⁇ 1% toxicity rate in the treated groups, similar to that observed for control animals.
  • Compound A induced significant differences in EFS distribution compared to control in 26 of 30 (87%) of the evaluable solid tumor xenografts and in 2 of 7 (29%) of the evaluable ALL xenografts.
  • Compound A induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 3 of 29 (10%) evaluable solid tumor xenografts (2 of 6 rhabdomyosarcoma and 1 of 5 neuroblastoma), and intermediate or high EFS T/C activity was observed for 2 of 7 (29%) evaluable ALL xenografts.
  • PI3 kinase pathway Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Compound A is evaluated against childhood cancer cell lines and xenografts.
  • Phosphatidylinositol 3-kinase plays a key role in signal transduction from viral oncoproteins and in transmitting signals from ligand-activated receptor tyrosine kinases [7-11].
  • Class I PDKs catalyze phosphorylation of phosphatidylinositol 4,5-biphosphate to phosphatidylinositol-3,4,5-triphosphate (PIP3), which binds to A T and PDK1 at the plasma membrane.
  • AKT is activated by phosphorylation by PDK1 at T308 and by mTOR/Rictor (TORC2) at S473.
  • AKT promotes cell survival and proliferation by phosphorylation of GSK3a/p, FoxO, MDM2, BAD, and p27 KIPI [12].
  • AKT also activates the mTOR/Raptor (TORC1) complex which regulates protein synthesis and cell growth [13].
  • TORC1 mTOR/Raptor
  • Mutations in PIK3CA the gene that encodes the p 110a class IA PI3K catalytic subunit are present in a variety of cancers that arise in adults [10,14].
  • the PTEN phosphatase modulates PIP3 activity and has been identified as a tumor suppressor that is frequently inactivated in cancer by gene mutation and/or deletion and by promoter methylation [15,16].
  • Tyrosine kinase oncogenes e.g., Bcr-Abl, HER2, MET, KIT, and others
  • Bcr-Abl e.g., Bcr-Abl
  • HER2 e.g., HER2, MET, KIT, and others
  • PI3K PI3K pathway
  • PI3K antagonists have been developed, all of which are ATP mimetics that act by binding reversibly to the ATP pocket of PI3K pi 10 [11].
  • Compound A is one such pan-PI3K inhibitor that has shown activity against breast, lung, and prostate cancer xenografts [11]. It has shown an acceptable toxicity profile as a single agent in an adult phase I study that also demonstrated an objective partial response and evidence of stable disease [19].
  • the NCI Pediatric Preclinical Testing Program has previously tested agents acting against other components of the PI3K signaling pathway, including rapamycin [20,21], the mTOR kinase inhibitor AZD8055 [22], and the AKT inhibitors GSK690693 and MK-2206 [23,24], all of which showed modest in vivo activity against the PPTP models.
  • rapamycin 20,21
  • mTOR kinase inhibitor AZD8055 [22]
  • AKT inhibitors GSK690693 and MK-2206 [23,24]
  • Compound A was tested against the PPTP in vitro cell line panel at concentrations from 10 nM to 100 ⁇ and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily for 14 days.
  • EFS T/C > 2 Compound A induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for 2 of 7 (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts.
  • rICso relative IC 50
  • HillSlope describes the steepness of the dose-response curve
  • Top and Bottom are the plateaus in the T/C% values at low and high concentrations, respectively.
  • Absolute IC 50 values represent the concentration at which the agent reduces cell survival to 50%» of the control value [26].
  • the ratio of the median relative IC50 to individual cell line's relative IC50 value is used (larger values connote greater sensitivity).
  • the lowest T/C% value is the Y m j n .
  • Compound A demonstrated cytotoxic activity, with Y m j n values approaching 0% for all of the cell lines at the highest concentration tested (100 ⁇ ).
  • the median relative IC50 (rIC 50 ) value for the PPTP cell lines was 10.9 ⁇ , with a range from 2.7 ⁇ (CHLA-10) to 24.5 ⁇ (TC-71), Table 4. There were no significant differences by histotype in median rIC 50 values, though there was a trend for lower values for the rhabdomyosarcoma panel (median rICso 5.6 ⁇ ) and higher values for the neuroblastoma panel (median rIC 5 o 19.5 ⁇ ).
  • Compound A is the ratio of the median rIC 50 of the entire panel to that of each cell line, Figure 4.
  • Each bar represents the ratio of the panel rICso to the rIC 50 value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity. Higher ratios are indicative of greater sensitivity to Compound A and are shown in the figure by bars to the right of the midpoint line.
  • Figure 4 illustrates the higher sensitivity for the rhabdomyosarcoma cell lines and the lower sensitivity for the neuroblastoma cell lines.
  • Compound A demonstrated micromoiar level activity against the panel of 23 pediatric cancer cell lines, with a median rICso of 10.9 ⁇ . ⁇ .
  • the micromoiar level rJC $ o values for Compound A contrast with its enzymatic activity on PI3 alpha, delta and gamma (ICso in the 20-40 nM range), which may reflect its hig serum protein binding [31 ].
  • the pattern of response to Compound A against the PPTP in vitro models showed some similarities to that observed for the A T inhibitors GSK690693 [25] and M -2206 [14].
  • the rhabdomyosarcoma cell lines Rh41 and Rhl8 and the Ewing cell line CHLA-10 showed relative sensitivity to all three agents.
  • the activity pattern of the AKT inhibitors differed from that of Compound A in the greater relative sensitivity of the ALL cell lines to the AKT inhibitors compared to Compound A.
  • Heterogeneity was evident in the in vitro response of the Ewing cell lines to Compound A ( Figure 4), which may be the result of as yet unidentified differences in dependence on the PI3K pathway of various Ewing tumors.
  • CB17SC scid-/- female mice (Taconic Farms, Germantown NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing,
  • osteosarcoma osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described [27].
  • mice were maintained under barrier conditions and experiments were conducted using protocols and conditions approved by the institutional animal care and use committee of the appropriate consortium member. Eight to ten mice were used in each control or treatment group. Tumor volumes (cm 3 ) [solid tumor xenografts] or percentages of human CD45-positive [%hCD45+] cells [ALL xenografts] were determined and responses were determined using three activity measures as previously described [27]. An in-depth description of the analysis methods is included in the Response and Events Definitions section.
  • Compound A was provided to the Pediatric Preclinical Testing Program by Exelixis Inc., through the Cancer Therapy Evaluation Program (NCI). Powder was stored at room temperature, protected from light. Drug was formulated in 10 mM HC1, in sterile water for injection, sonicated to form a fine suspension, and made fresh prior to administration. Compound A was administered orally (PO) at 100 mg/kg to mice using a daily schedule for 14 days, with a further 4 weeks of observation. Compound A was provided to each consortium investigator in coded vials for blinded testing.
  • NCI Cancer Therapy Evaluation Program
  • this column is the average relative tumor volume at the day T/C was assessed (day 21 or before); • 11 P value testing the relative tumor volumes between treatment and control groups at the day T/C was assessed (day 21 or before) (the exact Wilcoxon rank_sum test was used).
  • CR Complete response: disappearance of measurable tumor mass ( ⁇ 0.10 cm3 ) for at least one time point.
  • Tumor Volume T/C value Relative tumor volumes (RTV) for control (C) and treatment (T) mice were calculated at day 21 or when all mice in the control and treated groups still had measurable tumor volumes (if less than 21 days).
  • PD2 progressive disease with EFS T/C > 1.5.
  • EFS T/C values the ratio of the median time to event of the treatment group and the median time to event of the respective control group.
  • High activity requires: a) an EFS T/C > 2; b) a significant difference in EFS distributions, and c) a net reduction in median tumor volume for animals in the treated group at the end of treatment as compared to at treatment initiation.
  • Intermediate activity criteria a) and b) above, but not having a net reduction in median tumor volume for treated animals at the end of the study.
  • Low activity EFS T/C ⁇ 2.
  • the EFS T/C activity measure additionally requires an EFS T/C value of > 2.0 for intermediate activity and indicates a substantial agent effect in slowing tumor growth. High activity further requires a reduction in final tumor volume compared to the starting tumor volume.
  • Intermediate activity for the EFS T/C metric was observed in the following panels: rhabdomyosarcoma (2 of 6), neuroblastoma (1 of 5), medulloblastoma (1 of 2) and rhabdoid tumor (1 of 3).
  • RhlO rhabdomyosarcoma xenografts were completely inhibited for the duration of Compound A treatment.
  • 2 of 7 (29%) xenografts met criteria for intermediate EFS T/C activity.
  • Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different. The latter analysis demonstrates relative tumor sensitivities around the midpoint score of 5 (stable disease). Examples of tumor growth curves meeting criteria for intermediate EFS T/C activity (Rhl8, Rh41, and ALL-7) or showing significant tumor growth delay (RhlO) are presented in Figure 6.
  • Rhabdomyosarcomas (RhlO, Rhl8, Rh41): Kaplan-Meier curves for EFS (left), median relative tumor volume graphs (center), and individual tumor volume graphs (right) are shown for selected lines.
  • ALL-7 bottom panels: Kaplan-Meier curves showing the EFS (left), median leukemia engraftment (center) as detected in peripheral blood, and individual leukemia engraftment (right).
  • Controls gray lines
  • Treated black lines
  • p values statistical significance
  • PIK3CB The gene expression pattern of Class I PI3K isoforms is shown in Figure 7A. There is less variation in expression for PIK3CA than for other isoforms, and its expression is highest for the osteosarcoma and ALL xenografts and is lower for the rhabdomyosarcoma xenografts. PIK3CB is expressed at highest levels in low grade (BT-35 and BT-40) and high- grade glioma xenografts (e.g., GBM2 and BT-39).
  • Phospho-AKT and PTEN expression for solid tumor xenografts are shown in Figure 7B.
  • Phospho-AKT is detectable for many xenografts in the PPTP solid tumor panels, while PTEN low expression (consistent with PTEN deletion) is uncommon.
  • EFS T/C EFS T/C
  • PTEN low expression consistent with PTEN deletion
  • Phospho-AKT levels are not distinctive for the 4 xenografts with EFS T/C > 2 (KT-16, Rh41, Rhl8, and NB-EBcl) compared to the remaining xenografts.
  • TGD tumor growth delay
  • Event-free survival An event in the solid tumor xenograft models was defined as a quadrupling of tumor volume from the initial tumor volume. Event-free survival was defined as the time interval from initiation of study to the first event or to the end of the study period for tumors that did not quadruple in volume. The time to event was determined using interpolation based on the formula: where t is the interpolated day to event, t ⁇ is the lower observation day bracketing the event, t 2 is the upper observation day bracketing the event, V ⁇ is the tumor volume on day t ⁇ , 2 is the tumor volume on day t 2 and V e is the event threshold (4 times the initial tumor volume for solid tumor xenografts).
  • ALL Acute Lymphoblastic Leukemia
  • mice were categorized as PD if their percentage of hCD45 cells never dropped below 1% and they had an event before the end of the study period.
  • An event is defined as hCD45 cells above 25% in the peripheral blood with times to event calculated as above.
  • Individual mice were classified as SD if their percentage of hCD45 cells never dropped below 1% and no event occurred before the end of the study.
  • PR was assigned if the percentage of cells dropped below 1% for any one time point regardless of whether the percentage eventually reached 25%.
  • a CR was assigned if the percentage of hCD45 cells dropped below 1% for 2 consecutive weeks of the study and regardless of whether the percentage reached 25% or not.
  • a CR was considered maintained if the percentage of hCD45 was less than 1% for the last three measurements of the study.
  • PD was further classified into PD1 and PD2 according to the TGD value.
  • Tumor Volume T/C value Relative tumor volumes (RTV) for control (C) and treatment (T) mice were calculated at day 21 or when all mice in the control and treated groups still had measurable tumor volumes (if less than 21 days). The mean relative tumor volumes for control and treatment mice for each study were then calculated and the T/C value was the mean RTV for the treatment group divided by the mean RTV for the control group.
  • RTV Relative tumor volumes
  • T/C response measure agents producing a T/C of ⁇ 15% are considered highly active, those with a mean tumor volume T/C of ⁇ 45% but > 15% are considered to have intermediate activity, and those with mean T/C values > 45% are considered to have low levels of activity [7].
  • EFS T/C value An EFS T/C value was defined by the ratio of the median time to event of the treatment group and the median time to event of the respective control group. If the treatment group did not have a median time to event, then EFS T/C was defined as greater than the ratio of the last day of the study for the treatment group divided by the median time to event for the control group.
  • agents are considered highly active if they meet three criteria: a) an EFS T/C > 2; b) a significant difference in EFS distributions (p ⁇ 0.050), and c) a net reduction in median tumor volume for animals in the treated group at the end of treatment as compared to at treatment initiation.
  • Agents meeting the first two criteria, but not having a net reduction in median tumor volume for treated animals at the end of the study are considered to have intermediate activity.
  • Agents with an EFS T/C ⁇ 2 are considered to have low levels of activity.
  • Xenografts in which the median EFS for the control line was greater than one-half of the study period or in which the median EFS for the control line did not exist are considered not evaluable for the EFS T/C measure of activity.
  • the PIK3CD specific inhibitor GS- 1101 (C AL- 101 ) has shown preclinical and clinical activity against adult lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), but its activity in ALL is not yet defined [32].
  • Compound A shows approximately equal enzyme inhibitory activity against PI 3CA and PIK3CD [31,33].
  • PI3K pathway genes recurring genomic alterations in PI3K pathway genes appear to be uncommon in high-risk B-precursor ALL cases [44].
  • PIK3CA mutations are also uncommon in medulloblastoma tumor specimens [46-48].
  • genomic alterations in target genes have been the most reliable predictor of robust antitumor activity for molecularly targeted agents, the paucity of mutations in PI3K family genes reported for pediatric cancers argues against the expectation of single agent in vivo activity for PI3K inhibitors in the pediatric setting, consistent with our findings.
  • PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo.
  • neuroblastomas identifies a wide diversity of somatic mutation. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research 2011 :Abstr 4756.

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Abstract

L'invention concerne une méthode pour traiter les cancers chez les enfants, comprenant la leucémie lymphoïde aigüe, le neuroblastome et le rhabdomyosarcome, laquelle méthode comprend l'administration d'un composé de Formule (I) à un patient ayant besoin d'un tel traitement.
PCT/US2012/063247 2011-11-02 2012-11-02 Inhibiteurs de la phosphatidylinositol 3-kinase pour le traitement de cancers chez les enfants WO2013067306A1 (fr)

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WO2014072937A1 (fr) 2012-11-08 2014-05-15 Rhizen Pharmaceuticals Sa Compositions pharmaceutiques contenant un inhibiteur de pde4 et un inhibiteur de pi3 kinase delta ou un double inhibiteur de pi3 kinase delta et gamma

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WO2014072937A1 (fr) 2012-11-08 2014-05-15 Rhizen Pharmaceuticals Sa Compositions pharmaceutiques contenant un inhibiteur de pde4 et un inhibiteur de pi3 kinase delta ou un double inhibiteur de pi3 kinase delta et gamma

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