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WO2013056067A1 - Composés pour une utilisation dans le traitement de carcinome des cellules basales - Google Patents

Composés pour une utilisation dans le traitement de carcinome des cellules basales Download PDF

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Publication number
WO2013056067A1
WO2013056067A1 PCT/US2012/059976 US2012059976W WO2013056067A1 WO 2013056067 A1 WO2013056067 A1 WO 2013056067A1 US 2012059976 W US2012059976 W US 2012059976W WO 2013056067 A1 WO2013056067 A1 WO 2013056067A1
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nhc
alkyl
compound
optionally substituted
ammo
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PCT/US2012/059976
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English (en)
Inventor
Peter Lamb
Ervin Epstein
Po-Lin So
Grace Wang
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Exelixis, Inc.
Children's Hospital & Research Center At Oakland
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Publication of WO2013056067A1 publication Critical patent/WO2013056067A1/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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Basal Cell Carcinoma is one of the most common human cancers, accounting for approximately one third of all cancers in the United States, with an incidence that is increasing by 4-5% per year. With its high prevalence and morbidity, it is estimated that the annual cost to Medicare alone of treatment of this tumor exceeds $400 million ⁇ Rigel, 2008 #1 ⁇ . Sporadic BCCs usually develop in small numbers (i.e. 1-2), from the fifth or sixth decade of life, whereas an estimated 1 in 60,000 individuals have the heritable disease, basal cell nevus syndrome (BCNS, Gorlin syndrome) and develop multiple BCCs from puberty and throughout their lifetime. As a result, a need remains for new therapeutic options for the treatment of BCCs.
  • BCNS basal cell nevus syndrome
  • methods for treating basal cell carcinoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or of formula II or a single isomer thereof or optionally as a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof:
  • R 51 is hydrogen or alkyl
  • R 52 is hydrogen or halo
  • R 50 , R 53 , and R 54 are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -NiR ⁇ iCiOi-C Ce-alkylene-NiR ⁇ R 5515 , alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(0) 2 NR 55 R 55a , or alkylcarbonylamino and where R 55 and R 55b are independendy 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 3 ;
  • R 3a is cyano, hydroxyarnino, carboxy, alkoxycarbonyl, 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 715 (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 independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, hal
  • R 9 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R 9a is hydrogen, C 2 -C6-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, hal
  • R 10a 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 Ia is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R 11 and R l lb are independently hydrogen, alkyl, alkenyl, aminoalkyl, allcylaminoalkyl, 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 I6a 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, diall ylamino, 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 hetero
  • 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, 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 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 11 and R l lb 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 14b 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 l8b 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 1 and R 21b are independently hydrogen, alkyl, or alkenyl
  • R 22 , R 2 a 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;
  • 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; and
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, or optionally substituted
  • R 2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R* groups;
  • X is -NR 3 -;
  • R 3 is hydrogen
  • R 4 is optionally substituted alkyl
  • R 5 is hydrogen
  • R 6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R 9 groups;
  • each R 8 when present, is independently hydroxy, halo, alkoxy, haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or alkoxyalkylamino;
  • each R 9 when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl, and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R 9 , are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkxy, amino, alkylamino, and
  • 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 is hydrogen, alkyl, alkoxy, or halo; or R and R 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)-Ci-C 6 -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen and R 7a and R are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or
  • the compound of formula I and of formula la is compound A:
  • 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.
  • the compound of formula II is a compound of formula Ila:
  • R 1 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,
  • heterocycloalkylalkyl heteroaryl, or heteroarylalkyl
  • R 2 is hydrogen or alkyl
  • R 4 is alkyl
  • R 5 is hydrogen
  • R 6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are is optionally substituted with 1, 2, 3, 4, or 5 R 9 groups;
  • each R 9 when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R 9 , are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, and
  • the compound of formula II is compound B.
  • Compound B is known by its name 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-ii
  • Compound B is disclosed in WO 2007/044813, the entire contents of which are incorporated herein by reference.
  • Figure 1 provides a Principal Component Analysis of the gene expression array data showing that 10 M tazarotene treatment of ASZOOl cells significantly altered the gene expression profiles at both 10 hours and 24 hours.
  • Figure 2 shows the validation of the Affymetrix gene expression data by realtime qPCR.
  • Figure 3 provides a bioinformatic analysis using Ingenuity software suggested that a possible downstream pathway that thea number of 10 DE genes had in common was one the PI3K/Akt pathway.
  • Figure 4 shows immunohistochemistry with phosphorylated Aktl (p-Akt) antisera on untreated visible BCC that grew on Ptchl +I ⁇ , basal keratinocyte-deleted p53 mice.
  • Figure 5 shows an over-expression of AKT1 in ASZOOl cells reduces the in vitro anti-BCC effect of tazarotene.
  • Figure 6 shows the potential of compound A and compound B as therapies for treating BCC.
  • Figure 7 depicts the in vivo treatment with PI3K inhibitors: Microscopic and visible BCC assessment at age 21 and 28 weeks respectively, after 8 weeks of drug treatment.
  • 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 an -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 orN.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) / v- (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 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
  • pyrrolo[3,2- c]pyridinyl including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like
  • benzopyranyl thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl
  • benzothienyl and the derivatives thereof, or N-oxide or a protected derivative thereof.
  • 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., morpholinylmethyl,
  • 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.
  • Optional or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included.
  • “Optionally substituted” refers to all subsequent modifiers in a term. So, for example, in the term “optionally substituted arylCi -8 alkyl,” optional substitution may occur on both the "Ci -8 alkyl” portion and the "aryl” portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of "substituted.”
  • 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, alkylsulfony
  • 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 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(O) 0-2 -, alkenyl-S(0)o -2 -, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsul
  • 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 Within the optional substituents on “heterocycloalkyl”, the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • 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 Ila has the following structure .
  • Compound B is known by its chemical name 2-amino-8-ethyl-4-methyl-6-( lH-pyi ⁇ ol-5-yl)pyrido[2,3- ⁇ pyrimidin-7(8H)- one.
  • the compound of formula II that is compound B is disclosed in WO 07/044813, the entire contents of which is incorporated herein by reference.
  • Tazarotene is also known by its chemical name ethyl 6- [2-(4,4-dimethyl-3 ,4-dihydro-2H- 1 -benzotlnopyran-6-yl)emynyl]pyridine-3 -carboxylate.
  • GDC0941 (CAS No. 957054-30-7) is a PI3K inhibitor from Genetech.which has
  • GDC0941 is also known by its chemical name 2-(lH-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-l- ylmethyl)-4- mo holm-4-yl-thieno[3,2-d]pyrimidine and is adminsrtered as the bimesylate salt.
  • 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 apphcable 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 refer 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 combinatin or 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 B, or a metabolite thereof, a pharmaceutically acceptable salt or solvate thereof, or a composition comprising compound A or B or a metabolite thereof, or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in the progression of BCC.
  • 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, cyclopentanepropiomc 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.
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of
  • 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.
  • the embodiment includes both the recited compounds as well as individual isomers and mixtures of isomers.
  • 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 cancer comprises administering to a patient an effective amount of a compound of formula I or II or a pharmaceutical composition comprising a compound of formula I or II.
  • methods for treating cancer comprises administering to a patient an effective amount of a compound of formula I or II or a pharmaceutical composition comprising a compound of formula I where the cancer is basal cell carcinoma.
  • the compound of formula I is selected from any of the following embodiments, including from the Representative compounds in the associated Table.
  • R 1 is hydrogen.
  • R 50 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R 55 )C(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 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.
  • Another embodiment (D) of a compound of formula I is where R 52 is hydrogen or halo; and all other groups are as defined in the Summary of the Invention.
  • R is hydrogen or fluoro. In another embodiment, 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 55 )C(0)-Ci-C 6 -alkylene-N(R 5Sa )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, -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 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 3 .
  • R 3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -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-N(R 10a )R 10b ;
  • R 3a is:-NHC(0)CH 2 NH(CH 3 ),
  • -NHC(0)CH 2 (3-methoxyphenyl), -NHC(0)(l-methylcycloprop-l-yl), - NHC(0)(3 -flurophenyl), -NHC(0)(4-dimethylaminophenyl), -NHC(0)(3 ,4-dichlorophenyl), -NHC(0)CH 2 NHCH 2 (2-methylthiophenyl), -NHC(0)CH 2 (2-fluorophenyl), - NHC(0)CH 2 N(CH 2 CH 3 )CH(CH 3 ) 2 , -NHC(0)(thiazol-4-yl), -NHC(0)CH 2 N(CH 3 )benzyl, - NHC(0)CH 2 NHCH 2 (thien-2-yl), -NHC(0)CH 2 NHCH 2 (pyridin-2-yl), -NHC(0)(3- methoxyphenyl), -NHC(0)CH 2 NHCH 2 (3-chloro-4-methylphenyl),
  • NHC(0)CH 2 (2-phenylpyrrolidin-l-yl), - C(0)NHCH(CH 3 )CH 2 N(CH 3 ) 2 , -C(0)NHCH 2 CH 2 N(CH 3 ) 2 , -C(0)NH(pyrrolidin-3-yl), - C(0)NHCH 2 CH 2 (pyirolidin-l-yl), -C(0)NHCH 2 CH 2 NH 2 , -C(0)N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , - C(0)NHCH 2 (piperidin-2-yl), -C(0)NH(l-methylazetidin-3-yl), -C(0)NHCH 2 CH 2 (piperidin- 1-yl), -C(0)NHCH 2 CH 2 N(CH 2 CH 3 ) 2) -C(0)NH(l-methylpiperidin-3-yl),
  • R 3a is 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-N(R 10a )R 10b , -NR 1 'C(0)NR' la R l 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 18b )C(0)R l8a , -NR 24 C(0)-Ci.C 6 -alkylene-OR 24a , or - N(R 20
  • 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 ) 2 , -NHC(0)CH(NH 2 )CH 2 CH3, -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 (azetidm-l-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
  • R 3 is independently halo, alkyl, hydroxyamino, -NiR ⁇ CiOi-d-Ce-alkylene-NiR ⁇ iiR 7 "), -C(0)NR 8 R 8a , -NR 9 C(0)R 9a , -C(O)N(R , 0 )-C 1 -C 6 - alkylene-NtR ⁇ R' ⁇ -NR 1 'C ⁇ NR 1 Ib , -N(R 22 )C(0)-C,-C 6 -alkylene-N(R 22b )- N(R 22c )(R 22a ), -NR 13 C(0)OR 13a , -N(R 18 )C(0)-C,-C 6 -alkylene-N(R 18b )C(0)R 18a , -NR 24 C(0)- Ci.C 6 -alkylene-OR 24a , or -N(R 20 )C(O)-C
  • each R 3 is independently methyl, chloro,
  • R 3 is alkyl or -N(R 7 )C(0)-Ci-C 6 -alkylene- N(R 7a )(R 7b ); and R 7 is hydrogen or alkyl and R 7a and R ⁇ are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined in the Summary of the Invention.
  • each R 3 is independently methyl, -NHC(0)CH 2 NH(CH 3 ), -NHC(0)CH(CH 3 )NH 2 , -NHC(0)C(CH 3 ) 2 NH 2 , -NHC(O)- CH 2 N(CH 3 ) 2 , -NHC(0)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , -NHC(0)CH(NH 2 )CH 2 CH 3 ,
  • B is phenyl, R 3 is not present or R 3 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 7b ), or -C(O)N(R 10 )-Ci-C 6 -alkylene-N(R 10a )R l0b 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 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.
  • 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
  • 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)-Ci-C 6 -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen and R 7a and
  • 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 A:
  • R l in the compound of formula II is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, or optionally substituted heterocycloalkylalkyl. More specifically, R 1 is hydrogen, alkyl, alkyl substituted with one or two hydroxy, alkyl substituted with alkoxy, cycloalkyl, arylalkyl, or heterocycloalkylalkyl. Even more specifically, R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-ethoxyethyl, 3-methoxypropyl,
  • R 1 is ethyl, isopropyl, cyclopentyl, or cyclohexyl. Yet even more specifically, R 1 is ethyl.
  • R 2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R 8 groups. Specifically, R 2 is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three R 8 groups. More specifically, R 2 is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three R groups; and each R 8 , when present, is independently selected from amino, alkylamino, dialkylamino, and halo. Even more specifically, R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, terr-butyl,
  • R 2 is hydrogen or ethyl. Yet even more preferably, R 2 is ethyl.
  • R 2 is hydrogen
  • R 4 is optionally substituted alkyl. Specifically, R 4 is methyl or ethyl. More specifically, R 4 is methyl.
  • R 6 is acyl. More specifically, R 6 is alkylcarbonyl. Even more specifically, R 6 is acetyl.
  • R 6 is phenyl optionally substituted with 1, 2, 3, 4, or 5 R 9 groups. Specifically, R 6 is phenyl optionally substituted with one or two R 9 groups; and each R 9 , when present, is independently selected from aryl, halo, alkoxy, aryloxy, and haloalkyl. More specifically, R 6 is phenyl optionally substituted with one or two R 9 groups; and each R 9 , when present, is independently selected from phenyl, fluoro, chloro, methoxy, phenyloxy, and trifluoromethyl.
  • R 6 is phenyl, phenyl substituted with phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, phenyl substituted with chloro and fluoro, methoxyphenyl, dimethoxyphenyl, phenyloxyphenyl, or trifluoromethylphenyl.
  • R 6 is phenyl, 2-phenyl-phenyl, 3 -phenyl-phenyl, 4-phenyl- phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3 -difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,
  • R 6 is heteroaryl optionally substituted with 1, 2, 3, 4, or 5 R 9 groups.
  • R 6 is a 6-membered heteroaryl optionally substituted with one or two R 9 . More specifically, R 6 is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R 9 wherein R 9 , when present, is halo.
  • R 6 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3-fluoropyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4- yl, each of which is optionally substituted with one or two R 9 .
  • R 6 is pyrazinyl, pyrimidinyl, or pyridazinyl, each of which is optionally substituted with one R 9 wherein R 9 , when present, is halo. Even more specifically, R 6 is pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl.
  • R 6 is a 5-membered heteroaryl optionally substituted with one or two R 9 .
  • R 6 is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R 9 wherein R 9 , when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • R 6 is pyrazol-l-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-l-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3- yl, isoxazol-4-yl, isoxazol-5-yl, l,2,3-oxadiazol-4-yl, l,2,3-oxadiazol-5-yl, l,3,4-oxadiazol-2- yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadia
  • R 6 is pyrazol-3-yl, pyrazol- 4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol- 2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-
  • R 6 is thienyl, pyrrolyl, furanyl, pyrazolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R 9 wherein R 9 , when present, is methyl, benzyl, cyano, phenyl, N-teri-butoxycarbonyl, or chloro.
  • R 6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3- yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-
  • R 9 is methyl, benzyl, cyano, phenyl, N-te -butoxycarbonyl, or chloro.
  • R 6 is thien-2-yl, thien-3-yl, 5-cyano-thien-2-yl, 4-methyl-thien-2-yl, 4-methyl- thien-3-yl, 5-chloro-thien-5-yl, 5-phenyl-thien-2-yl, pyrrol-2-yl, N-tert-butoxycarbonyl- pyrrol-2-yl, N-methyl-pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, N- benzyl-pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl.
  • R 6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan- 3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl, each of which is optionally substituted with one R 9 wherein R 9 , when present, is methyl, benzyl, cyano, phenyl, N-teri-butoxycarbonyl, or chloro.
  • R 6 is indolyl, benzimidazolyl, benzofuranyl,
  • R 6 is indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol- 7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted arylalkyl;
  • X is - ⁇ -;
  • R 2 is hydrogen or alkyl where the alkyl is optionally substituted with one or two R 8 groups;
  • R 4 is alkyl;
  • R 5 is hydrogen;
  • R 6 is phenyl or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with one, two, or three R 9 groups; each R 8 , when present, is independently amino, alkylamino, dialkylamino, or halo; and each R 9 , when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2- yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3- oxadiazol-4-yl, l,2,3-oxadiazol-5-yl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, furan-2-yl, furan-3-yl
  • R 1 is alkyl or cycloalkyl
  • R 4 is methyl
  • R 6 is heteroaryl optionally substituted with one or two R 9 groups.
  • each R 9 when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol- 5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, l,2,3-oxadiazol-4-yl, l,2,3-oxadiazol-5-yl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol
  • R 2 is hydrogen
  • R 2 is methyl or ethyl.
  • R 1 is alkyl or cycloalkyl
  • R 4 is methyl
  • R 6 is phenyl optionally substituted with one or two R 9 groups.
  • each R 9 when present, is independently halo, alkoxy, or haloalkyl.
  • R 1 is alkyl or cycloalkyl
  • R 4 is methyl
  • R 2 is hydrogen
  • R 1 is alkyl or cycloalkyl
  • R 4 is methyl
  • R 2 is optionally substituted alkyl
  • the compound of formula I is a compound of formula Ila:
  • R 1 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,
  • heterocycloalkylalkyl heteroaryl, or heteroarylalkyl
  • R 2 is hydrogen or alkyl
  • R 4 is alkyl
  • R 5 is hydrogen
  • R 6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are is optionally substituted with 1, 2, 3, 4, or 5 R 9 groups;
  • each R 9 when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R 9 , are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, and
  • R is alkyl, cycloalkyl, heterocycloalkylalkyl, or arylalkyl;
  • R is hydrogen or alkyl;
  • R 4 is alkyl;
  • R 5 is hydrogen;
  • R 6 is phenyl or heteroaryl wherein the phenyl and heteroaryl are is . optionally substituted with one, two, or three R 9 groups;.
  • R 4 is methyl
  • R 1 is alkyl, cycloalkyl, or heterocycloalkyl.
  • R 1 is alkyl
  • R 6 is heteroaryl optionally substituted with 1 , 2, or 3 R 9 groups.
  • each R 9 when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • R 6 is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl; each of which is optionally substituted with 1, 2, or 3 R 9 groups.
  • R 6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2- yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3- oxadiazol-4-yl, l,2,3-oxadiazol-5-yl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-3-yl,
  • R 6 is pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with 1, 2, or 3 R 9 groups and R 4 is methyl.
  • R 2 is hydrogen
  • R 4 is methyl
  • R 1 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl
  • R 6 is heteroaryl optionally substituted with 1, 2, or 3 R 9 groups.
  • the compound of formula Ila is selected from:
  • the compound of formula Ila is compound B, which is 2- ammo-8-emyl-4-memyl-6-(lH-pyrazol-5-yl)pyrido[2,3- ⁇ ]pyrimidin-7(8H)-one (compound B) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating BCC in a patient in need of such treatment, comprising administering to the patient an effective amount of letrozole in combination with: or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof.
  • the compound A is administered as a capsule or tablet pharmaceutical composition.
  • the amount of compound A in the tablet or capsule formulation is sufficient to produce saturation of absorption when administered once daily.
  • about 100 mg to about 800 mg of compound A is administered as a capsule composition once daily.
  • about 200 mg to about 700 mg of compound A is administered as a capsule composition once daily.
  • about 500 mg to about 700 mg of compound A is administered as a capsule composition once daily.
  • about 100 mg to about 800 mg of compound A is administered as a tablet composition once daily.
  • 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 100, 150, or 200 mg tablet.
  • the tablet strength will be distinguishable by shape and or size.
  • the tablet formulation contains compound A, 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.
  • the invention provides a method of treating BCC in a patient in need of such treatment, comprising administering to the patient an effective amount of letrozole in combination with:
  • the compound B is administered as a capsule or tablet pharmaceutical composition.
  • the amount of compound B in the tablet or capsule formulation is sufficient to produce saturation of absorption when administered once daily.
  • the amount of compound B in the tablet or capsule formulation is sufficient to produce saturation of absorption when administered twice daily.
  • about 40 mg of compound B is administered as a capsule composition twice daily.
  • about 70 mg of compound B is administered as a capsule composition twice daily.
  • about 80 mg of compound B is administered as a capsule composition twice daily.
  • about 90 mg of compound B is administered as a capsule composition twice daily.
  • about 100 mg of compound B is administered as a capsule composition twice daily.
  • compound A is administered as a capsule consisting of Size 0 capsules filled with 10, 30 or 40 mg of 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.
  • the effective amount of either a compound of formula la or Ila that is administered in the method produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • the improvement of clinical benefit rate is about 20 percent or higher.
  • the therapeutic effect is an increase in overall response rate.
  • the increase in overall response rate is about 10 percent or more or higher.
  • CBR clinical benefit rate
  • the improvement of clinical benefit rate is at least about 20 percent or higher.
  • the improvement of clinical benefit rate is at least about 20 percent or higher.
  • the invention provides pharmaceutical compositions comprising an inhibitor of the PDKs of formula la or Ila and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration is by the oral route.
  • Administration of the compounds of formula la or Ila, 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 la or Ila 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 la or Ila 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,
  • formulations depend 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 la or Ila, 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 la or Ila 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 100 mg to 800 mg per day, orin the range of 200 to 700 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.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.) or Bache (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fisher and Fisher's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rod's Chemistry of Carbon
  • the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 °C to about 150 °C, in another embodiment from about 0 °C. to about 125 °C and most specifically at about room (or ambient) temperature, e.g., about 20 °C. 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.
  • one tautomer of compound A is compound A-l.
  • Compound A-2 is named N-(3- ⁇ [(2Z)-3-[(2-cUoro-5-methoxyphenyl)amino]quinoxalin- 2(lH)-ylidene]sulfamoyl ⁇ phenyl)-2-methylalaninamide.
  • one zwitterionic form of compound A is compound A-3.
  • 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 mtrogen 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
  • 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.
  • 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 quinoxaline).
  • a base such as K 2 C0 3
  • a solvent such as DMF or DMSO.
  • 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.
  • 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 HC1 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.
  • Compound 5 is reacted with NHR a R b or HO-Ci-C6-alkylene-NHR a R b where R a and R b are independently hydrogen or alkyl.
  • the reaction is carried out in the presence of a base, such as 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 7 , R 7a , and R 7b are as defined in the Summary of the Invention;
  • R 100 in Scheme 4 is -C(0)R 9a , -C(0)NR' la R ! lb , -C(0)OR 13a , -C(O)- CrC 6 -alkylene-N(R 18b )C(0)R 18a , -C(O)-Ci-C 6 -alkylene-C(O)R 20a , or -S O ⁇ -Q.Q-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.
  • 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.
  • Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture.
  • a Waters Fractionlynx preparative reverse-phase HPLC equipped with a Waters SunFire Prep CI 8, OCD 5 ⁇ , 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.
  • a CEM microwave reaction vessel was charged with N-(3-(N-(3- cUoroqumoxalin-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. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NHtOAc/ACN to the desired product.
  • a CEM microwave reaction vessel was charged with N-(3-(N-(3- cMoroqumoxalin-2-yl)sulfamoyl)phenyl)-2-(dimemylammo)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 NKjOAc/ACN as eluent to yield the desired product.
  • General Acylation Procedure 2
  • 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.
  • 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-nitrobenzenesulfonamide and 5.5 volumes of acetonitrile were combined and heated to reflux. Solution A and 1 volume of acetonitrile was 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.
  • Compounds of formula II can be made by the synthetic procedures described below.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4 th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • 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.
  • imidazol-5-yl and pyrazol-5-yl each can also exist in their respective tautomeric forms imidazol-4-yl and pyrazol-3-yl. Regardless of which structure or which terminology is used, each tautomer is included within the scope of the Invention.
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of formula II.
  • 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 one enantiomer to the other by asymmetric transformation.
  • 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.
  • a compound of the invention wherein R 1 is optionally substituted alkyl, R 2 is hydrogen or optionally substituted alkyl, R 4 is methyl or ethyl, R 6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R 9 groups (as defined in the Summary of the Invention), and R 2 is hydrogen, can be prepared according to Scheme 8.
  • An intermediate of formula 2 is prepared by reacting an intermediate of formula 1 with a primary amine R'Ntk in a solvent such as water and with heating. 2 is then treated with iodine monochloride in a solvent such as methanol at around 0 °C and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 3. After completion the residue is triturated with acetone. The intermediate 3 is then reacted in a solvent, such as DMA, with ethyl acrylate in the presence of a base, such as triethylamine, and in the presence of a catalyst, such as Pd(OAc) 2 , and (+)BINAP. The reaction is heated to approximately 100 °C and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 4. 4 is then optionally purified by column chromatography.
  • [00267] 5 is prepared by treating 4 with DBU in the presence of a base such as DIPEA at room temperature. The reaction mixture is then heated to reflux and reacted for
  • 6 is prepared by reacting 5 with a brominating agent such as Br 2 in a solvent such as DCM at room temperature. The reaction mixture is then stirred for approximately overnight. The resulting product is filtered and then suspended in a solvent such as DCM and treated with a base such as triethylamine. The mixture is then washed with water and dried over a drying agent such as Na 2 S0 4 to yield 6.
  • a brominating agent such as Br 2
  • a solvent such as DCM
  • a Suzuki coupling is then performed using 6 and a boronic acid (or ester) of formula R 6 B(OH) 2 in a solvent(s) such as a DME-H 2 0 mixture in the presence of a catalyst such as Pd(dpppf ) and a base such as triethylamine at room temperature.
  • a catalyst such as Pd(dpppf )
  • a base such as triethylamine
  • methylthio group of 7 is then oxidized with m-CPBA in a solvent such as DCM at room temperature with stirring for approximately 4 hour. After removal of the solvent under reduced pressure, the product is treated with an amine of formula R 2 NH 2 in a solvent such as dioxane and stirred at room temperature for approximately overnight to yield a compound of formula I.
  • An intermediate of formula 9 is prepared by reacting an intermediate of formula 8 with neat POCI3 and heating. 9 is then treated with a primary amine R'NH 2 in a solvent such as water or THF and triethylamine at 0 °C to form 10. After removal of the solvent under reduced pressure, the intermediate 10 is then reacted with lithium aluminum hydride in a solvent such as THF at 0 °C. After quenching and aqueous workup, solvent removal provided crystalline 11 without further purification. Treatment of 11 with manganese (II) dioxide in a solvent such as methylene chloride or chloroform at room temperature provided aldehyde 12 upon filtration and solvent removal. A Wittig reaction with aldehyde 12 can be employed with (carbethoxymethylene)triphenylphosphorane in refluxing THF to provides the common intermediate 4. 4 can then be used to prepare a compound of formula I using the procedures described in Scheme 1.
  • a compound of the invention where R 1 is optionally substituted alkyl, R 4 is methyl or ethyl, R 6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R 9 groups (as defined in the Summary of the Invention), and R 2 is hydrogen can be prepared according to Scheme 10.
  • An intermediate of formula 14 is prepared by reacting an intermediate of formula 13 with a primary amine R'NH 2 in a solvent such as water and with heating. 14 is then treated with iodine monochloride in a solvent such as methanol at around 0 °C and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 15. After completion the residue is triturated with acetone. The intermediate 15 is then reacted in a solvent, such as DMA, with ethyl acrylate in the presence of a base, such as triethylamine, and in the presence of a catalyst, such as Pd(OAc) 2 , and (+)BINAP.
  • a solvent such as DMA
  • ethyl acrylate in the presence of a base, such as triethylamine
  • a catalyst such as Pd(OAc) 2 , and (+)BINAP.
  • reaction is heated to approximately 100 °C and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 16.
  • 16 is then optionally purified by column chromatography.
  • a compound of formula I can then be prepared from 16 by using the same reaction conditions as described in Scheme 1 (starting at the point of the preparation of 5 from 4).
  • a compound of the invention where R 1 is optionally substituted alkyl, R 4 is methyl or ethyl, R 6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R 9 groups (as defined in the Summary of the Invention), and R 2 is hydrogen can alternatively be prepared according to Scheme 1 1.
  • An intermediate of formula 20 is prepared by reacting an intermediate of formula 19 with neat POCl 3 and heating. 20 is then treated with a primary amine R'NH 2 in a solvent such as water or THF and triethylamine at 0 °C to form 21. After removal of the solvent under reduced pressure, the intermediate 21 is then reacted with lithium aluminum hydride in a solvent such as THF at 0 °C. After quenching and aqueous workup, solvent removal provides crystalline 22 without further purification. Treatment of 22 with manganese (II) dioxide in a solvent such as methylene chloride or chloroform at room temperature provides aldehyde 23 upon filtration and solvent removal.
  • a solvent such as water or THF and triethylamine
  • a Knovenegal-type condensation with 23 and an arylacetonitrile in the presence of a base such as potassium carbonate or sodium hydroxide in a pro tic solvent provides the cyclized imine 24.
  • Acetylation of the imine with acetic anhydride is required prior to hydrolysis, which takes place in the presence of aqueous acid and heating to afford 25.
  • 25 can be oxidized to the corresponding sulfone with Tw-CPBA at room temperature and displaced with ammonium to provide I.
  • Figure 1 provides a Principal Component Analysis of the gene expression array data showing that 10 M tazarotene treatment of ASZ001 cells significantly altered the gene expression profiles at both 10 h and 24 h in a manner that was distinct from those profiles altered by DMSO vehicle control-treated ASZ001 (Figure 1A).
  • Heat map representations, using Partek Genomics Suite, of the standardized array data demonstrated that the expression levels of 4292 genes were differentially expressed with 10 tM tazarotene treatment compared to treatment with 0.1% DMSO.
  • replicate samples were comparable to each other for both the tazarotene- or DMSO treated ASZ001 cells ( Figure 1 B) (p ⁇ 0.05 ANOVA test followed by FDR correction).
  • the greater number of up-regulated than of down-regulated genes at 10 h is consistent with a direct transcriptional activator effect of RARs, which fully dissociate from corepressors/silencing mediators and bind to coactivators in the presence of a retinoid hormone agonist (such as tazarotenic acid) to activate retinoid-target genes ⁇ Rochette-Egly, 2009 #15; Xu, 1999 #16 ⁇ .
  • a retinoid hormone agonist such as tazarotenic acid
  • HH target gene expression was changed by 10 ⁇ tazarotene treatment.
  • DE gene lists for known direct HH target genes (i.e. genes that contain the consensus Gli binding site) such as GUI, Ptchl, Hhipl, Nmycl, Ccndl, Ccndl, Greml, Fst and Pthlh ⁇ Katoh, 2009 #17 ⁇ .
  • Fst and Pthlh were downregulated at 10 h ( Figure 2 and data not shown). Fst was also down- regulated at 24 h.
  • FoxMl genes that are strongly associated with HH signaling are FoxMl, Ccndl, and Gas I.
  • FoxMl expression was down-regulated after 24 h of tazarotene treatment and not at 10 h, suggesting it to be an indirect target of tazarotene signaling.
  • Gasl was down-regulated at 10 and 24 h while Ccndl was not represented.
  • Figure 2 shows the validation of the Affymetrix gene expression data by real-time qPCR.
  • Graphs showing representative values for the amount of fold change compared to the DMSO-treated ASZ001 samples, for a selection of statistically significant DE genes from the microarray Bioconductor gene lists and from qPCR validation.
  • DE genes selected from the 10 h ( Figure 2A) and 24 h DE ( Figure 2B) gene lists were expressed at comparable up- or downregulated levels although the differential expression was generally greater (compared to DMSO control) in the real-time qPCR assays than in the microarray data. These qPCR data confirm the validity of the microarray datasets.
  • Tgm2 upregulation was not related to tazarotene's anti-proliferative effects, but rather to direct effects of retinoid transcriptional activation of target genes involved in other biofunctions related to skin. Therefore, since i) the numbers of DE genes from tazarotene treatment at both 10 h and 24 h were relatively high, and ii) investigating individual DE genes such as Tgm2 may indicate biological processes that are irrelevant to tazarotene's anti-cancer effects, we used bioinformatic software to identify tazarotene-altered pathways and functions.
  • IGF-IR/PI3K/Akt pathway was represented in the analyses of both 10 h and 24 h DE genes lists.
  • the Ingenuity® software suggested three top networks at 10 h, one of which was also the IGF-IR/PI3K/Akt pathway, indicating that it may be a central downstream functional "node" involved in BCC inhibition by tazarotene ( Figure 3)
  • Figure 3 provides a bioinformatic analysis using Ingenuity software suggested that a possible downstream pathway that thea number of 10 DE genes had in common was one the PI3K/Akt pathway.
  • the shaded shapes indicate DE genes from the 10 h Bioconductor list, which when 'networked' suggested that PI3K/Akt signaling may be a downstream target of tazarotene. (p ⁇ 0.05).
  • the different shapes assigned to each 'molecule' that was represented in the 10 h DE list, indicate the type/function of the protein as classified by the IPA analysis software (Ingenuity, CA).
  • the IGF-IR/PI3K/Akt pathway is positively associated with cancer development ⁇ Engehnan, 2009 #18 ⁇ , and has been shown to enhance Hedgehog pathway signaling by indirectly stabilizing Gli protein ⁇ Riobo, 2006 #19 ⁇ .
  • Activated PI3K/Akt signaling also has been linked specifically in humans to BCCs ⁇ Lin, 2007 #20 ⁇ .
  • Figure 4 shows immunohistochemistry with phosphorylated Aktl (p-Akt) antisera on untreated visible BCC that grew on Ptchl + ' ⁇ , basal keratinocyte-deleted p53 mice.
  • pAkt was also detected at moderate levels (compared to -actin levels) in the murine BCC cell line ASZ001 ( Figure 4D).
  • Figure 5 shows an over-expression of AKTl in ASZ001 cells reduces the in vitro anti-BCC effect of tazarotene.
  • ASZ001 cells transfected with HA-tagged AKTl or myristolylated AKTl were selected with G418 to generate stable HA-AKT 1 expressing cell lines that expressed heterogeneous levels of AKTl as measured by the HA tag levels ( Figure 5 A).
  • the higher level of AKTl expression in the HA-AKT compared to the negative control cell line was confirmed by Western blotting with antibodies against AKTl (Figure 5B) and 10 uM tazarotene treatment of these cell lines for 48 h showed that the cell lines
  • constructs containing HA-tagged wildtype AKTl (HA-AKT 1) or constitutively activated (myristolyated) Aktl (myr-HA-AKTl) were transfected into ASZ001 cells. Stable transfection resulted in a heterogenous population with -—10-12% of the cells expressing detectable levels of HA-AKT 1 cells as measured by FACS ( Figure 5A).
  • Pharmacologic PI3K inhibitors inhibit BCC proliferation in vitro
  • LY294002 is a first generation pan class I PI3K inhibitor that inhibits PI3K activity via competitive inhibition of an ATP binding site on the p85 subunit of PI3K. LY294002 not only binds to class I PI3Ks and other PI3K-related kinases, inhibiting PI3K-dependent production of the second messenger PIP3, but also to novel targets unrelated to the PI3K family ⁇ Gharbi, 2007 #21 ⁇ .
  • Compound A is a potent, orally bioavailable, specific inhibitor of class I PI3K kinases ⁇ , ⁇ , ⁇ , and ⁇ .
  • compound B is a bioavailable, highly selective, potent inhibitor of all four Class I PI3K isoforms with IC50 values at nanomolar concentrations in biochemical assays.
  • compound B also inhibits mTOR and DNA-PK with IC50 values in the nanomolar range ⁇ Patnaik, 2007 #23.
  • compound B As well as inhibiting PI3K phosphorylation and consequent PI3K-dependent production of the second messenger PIP3, compound B also inhibits nutrient stimulated mTOR-dependent signaling in cellular assays by inhibiting mTOR-dependent phosphorylation of key PI3K pathway components including AKT, the AKT substrates PRAS40 and GSK3p, p70S6K, and the p70S6K substrate S6, and 4E-BP1.
  • compound B-treated tumors regressed with a decrease in proliferation and angiogenesis, and an increase in apoptosis ⁇ Patnaik, 2007 #23 ⁇ .
  • Figure 6 shows the potential of compound A and compound B as therapies for treating BCC.
  • PI3K inhibitors compound B and compound A, as well as LY294002 inhibited ASZ001 cell proliferation in a dose-dependent manner at micromolar
  • Compound A was the most effective inhibitor at 5 and 10 uM.
  • p53 mutations are very common in sporadic human BCCs ⁇ Reifenberger, 2005 #24; Ling, 2001 #25 ⁇ , and after exposure to ionizing radiation (Cesium 237 or X-rays), these mice develop far greater numbers of microscopic and visible BCCs than do Ptchl +I ⁇ p53 wildtype mice and do so at an accelerated rate (visible BCCs develop from age 5 months vs. from age 9 months) ⁇ Wang, 2011 #26 ⁇ .
  • Figure 7 depicts the in vivo treatment with PI3K inhibitors: Microscopic and visible BCC assessment at age 21 and 28 weeks respectively, after 8 weeks of drug treatment.
  • microscopic BCC assessment dorsal skin biopsies of mice given oral formulations of PI3K inhibitors compound A, compound B, or GDC0941 were analysed to determine the microscopic BCC number ( Figure 7A) and size ( Figure 7B).
  • Figure 7A the microscopic BCC number
  • Figure 7B size
  • mice were given oral formulations of PI3 inhibitors compound A, compound B, or GDC0941 from age 9 weeks to 21 weeks, and monitored thereafter to assess the time of visible BCC appearance.
  • a Kaplan Meier graph showed that only compound B-treated mice had a delay in the first visible BCC appearance (Figure 7C). Mice were assessed at age 28 weeks to determine the visible BCC number ( Figure 7D) and size ( Figure 7E). Again, although different control vehicles were used, there were not significantly different from each other in terms of BCC numbers and size (data not shown), therefore the vehicle groups were combined. Only compound B treatment reduced visible BCC number and volume by statistically significant amounts at the doses tested. There was a delay in the appearance of visible BCCs in mice dosed with compound B compared to the vehicle group however this was not statistically significant (Figure 7E). There was no delay in the appearance of the first BCCs with compound A and GDC0941.
  • mice were monitored for the appearance of their first visible BCC (Figure 7C). Similar to tamoxifen-treated Ptchl + K14-CreER2 p 5 oxed/ fl° xed mice ⁇ Wang, 2011 #26 ⁇ , the vehicle control-treated mice developed visible BCCs from age 20 weeks, and by age 28 weeks almost all mice had a significant burden of macroscopic BCCs (Figure 7C). Under these test conditions, there was no obvious delay in the appearance of the first visible BCC in mice treated with compound A or GDC0941.
  • PI3K inhibitors by acting downstream of retinoid receptors, might overcome resistance to ATRA therapy in those BCCs whose resistance is due to loss of RAR expression.
  • others have suggested that inhibition of PI3K/Akt signaling can reverse resistance to retinoids and other drugs by enhancing apoptosis ⁇ Martelli, 2003 #28; Neri, 2003 #29 ⁇ .
  • inhibition of this pathway can inhibit tumor growth independent of additional pharmacologic interventions.
  • HH signaling can enhance Igf2 transcription in some, albeit not all, contexts and PI3K/Akt/mTOR signaling, again by reducing GSK3-mediated phosphorylation and degradation, can stabilize Gli protein and thereby enhance HH signaling ⁇ Riobo, 2006 #36; Stecca, 2007 #37; Mizuarai, 2009 #38; Singh, 2009 #39 ⁇ .
  • meduUoblastomas may retain their sensitivity to inhibitors of PI3K/Akt inhibitors even after they develop resistance to HH signaling pathway inhibitors ⁇ Buonamici, 2010 #40; Dijkgraaf, 2011 #41 ⁇ , findings which do not support the suggestion that, at least in these tumors, excess HH signaling is the cause of the enhanced PI3K/Akt signaling.
  • ATRA which like tazarotene, inhibits murine BCC carcinogenesis activates PI3K/Akt signaling to induce a differentiation program ⁇ Bastien, 2006 #42; Doi, 2010 #43; Lopez- Carballo, 2002 #44; MA Antonyak et al J Biol Chem 277: 14712, 2002 ⁇ .
  • PI3K/Akt signaling In acute promyelocyte leukemia, in which ATRA treatment results in differentiation, PI3K/Akt signaling also is upregulated by ATRA in his instance thereby promoting cellular survival rather than differentiation ⁇ Billottet, 2009 #45 ⁇ .
  • ATRA induced an early activation of the PI3K/Akt pathway (via RARy:RXR signaling) to initiate F9 cell differentiation into primitive endoderm-like cells, which was followed by an inhibition of Akt activity that resulted in cell growth arrest ⁇ Bastien, 2006 #42 ⁇ .
  • PDK/Akt/mTOR pathway appears to have better anti-tumor efficacy than does inhibition of a single site is not a new one ⁇ Fan, 2007 #46; Fan, 2010 #47 ⁇ .
  • a 2 month dosing regimen of the dual PI3K/mTOR inhibitor compound B started before and during microscopic BCC development could reduce their development by at least 50% and could reduce the development of clinically relevant, visible BCCs by approximately 60% even after the cessation of treatment.
  • BCC cell line treatment and RNA extraction We cultured ASZ001 cells in complete medium (154-CF medium containing 0.05 mM CaCl 2 , 2% chelexed fetal bovine serum), as described previously ⁇ So, 2006 #14 ⁇ . At 80% confluency, the media was removed, and cells were incubated in serum-free media (154-CF medium containing 0.05 mM CaCl 2 and lx Penicillin/Streptomycin) for 2 h.
  • Working concentrations of tazarotene and DMSO were prepared as follows: for tazarotene, the powder was dissolved in 100% DMSO at a stock concentration of 10 mM and diluted to 10 ⁇ working concentration in 154-CF medium containing 0.05 mM Ca and IX penicillin/streptomycin. As a control, DMSO was diluted to 0.1% working concentration. Cells were then incubated with 10 ⁇ tazarotene or 0.1% DMSO for 10 and 24 h in a 5% C02 incubator. Four replicates were done for each treatment.
  • RNA MessageAmpTM II-Biotin Kit (Ambion/Applied Biosystems, CA), according to the manufacturers' instructions. Briefly, reverse transcription of total RNA was carried out using an oligo(dT) primer bearing a T7 promoter using ArrayScriptTM, a reverse transcriptase (RT) engineered to produce high yields of first-strand cDNA. Second-strand synthesis using the cDNA was carried out and purified for use as a template for in vitro transcription in a reaction containing biotin-modified UTP and T7 RNA Polymerase (Ambion/Applied Biosystems, CA).
  • Biotin-labeled amplified RNA was then purified for gene expression analysis on Mouse Genome 430A 2.0 Array GeneChips (Affymetrix, CA), which was carried out by the Gladstone Genomic Core Facility (San Francisco, CA). Assessment of hybridization quality was also performed by the Gladstone Genomic Core Facility (San Francisco, CA), using the Bioconductor software aff PLM, which fitted a specified robust linear model to the probe level data.
  • Preprocessing of the data was performed using an Bioconductor Robust Multiarray Analysis (RMA) algorithm to correct for background; the data was normalized using the quantile method ⁇ Bolstad, 2003 #48 ⁇ to generate lists of statistical significant, differentially expressed (DE) genes (comparing tazarotene and DMSO vehicle control groups).
  • RMA Bioconductor Robust Multiarray Analysis
  • DE differentially expressed genes
  • IHC for phosphorylated-Aktl was carried out on 4 ⁇ paraffin wax sections taken from visible BCCs, using rabbit anti-Aktl (#4058, 1:200 dilution; Cell Signaling Technologies, MA). Briefly, sections were immersed in xylene and then rehydrated from 100% ethanol to 100% water and then PBS. Antigen retrieval was carried out using DeCloaker Solution (Biocare, CA) for 20 min at 98 °C and cooled sections were pre-blocked with 5% goat serum/PBS for 1 h, then incubated with antibodies to p-Aktl Ser473 overnight at 4 °C.
  • DeCloaker Solution Biocare, CA
  • Sections were washed and endogenous biotin, biotin receptors, or avidin binding sites present in tissues were blocked using the Biotin- Avidin System kit (Vector Laboratories, Burlingame, CA). Antigen detection was carried out using the VECTASTAIN ® Elite ABC with the peroxidase-based detection system ((Vector Laboratories, Burlingame, CA). After signal development, slides were washed in water, dehydrated through a series of ethanols and xylene, and then mounted by microscopy.
  • Nucleoporation system (Amaxa-Lonza, MD) ⁇ So, 2006 #14 ⁇ . These plasmids contain the human AKT1 sequence.
  • plasmid # 903 was digested with restriction enzymes to remove the anti-hemagglutinin (HA) tag and most of the AKT1 open reading frame, generating pLNCX'.
  • HA anti-hemagglutinin
  • One million cells were resuspended in transfection reagent and electroporated using program T29. Cells were then mixed with 154-CF complete media and replated. Media was removed after 24 h to remove the dead cells and living cells were allowed to recover for 1-2 days, and when they grew to 70% confluency, the cells were passaged and replated at a lower density.
  • ASZOOl cells containing the pLNCX- Myr-HA-AKTl, pLNCX-HA- AKT 1 or pLNCX' were selected using G418 (Life
  • Proliferation Assay Reagent (Roche, IN) was added to each well and mixed with the media for 1 minute, then incubated for 2 h at 37 °C in a C0 2 incubator. Plates were read on a spectrophotometer at a wavelength of 450 nm, according to manufacturer's instructions (Biorad, CA). For in vitro treatment with PI3K inhibitors the latter were dissolved in 100% DMSO to give a stock concentration of 30 mM (compound A) and 100 mM (compound B and LY942002) respectively, which were further diluted with DMSO to generate working concentrations. Cells were treated and assayed as described for tazarotene. FACS analysis
  • mice All mouse studies were carried out in accordance to IACUC guidelines. Ptchf 1' KU-CreER n ' p5f fl mice were injected i.p. with tamoxifen (0.1 mg/day) for 3 consecutive days at age 1.5 months (to generate Ptchf ' K14-CreER2 p 5 ° xed/ fl° xed m j ce that have deleted p53 sequences in the basal keratinocytes) and irradiated with 4 Gray (Gy) of X- rays at age 8 weeks. A dorsal skin biopsy at age 3 months was taken to confirm the lack of microscopic BCC at 'baseline'.
  • Drug/vehicle treatments were given by oral gavage at age 13 weeks, 5 days/week until age 21 weeks when a dorsal skin biopsy (1 cm x 1 cm) was carried out. All skin biopsies were fixed in 2% glutaraldehyde/0.2% formaldehyde, washed in PBS and stained for ⁇ -galactosidase activity as described previously ⁇ So, 2004 #4 ⁇ . Mice were then monitored for the first visible BCC, and visible BCC burden was assessed at age 28 weeks. Mice that died or were euthanized for unrelated causes were censored in the study.
  • GDC0941 gift from Genentech-Roche
  • compound A or compound B gifts from Exelixis
  • their respective vehicle control
  • GDC0941, compound A and compound B were given in amounts of 50 mg/Kg daily, 100 mg/Kg and 30 mg/Kg/twice a day, respectively.
  • Hedgehog target genes mechanisms of
  • Patched target Igf2 is indispensable for the formation of medulloblastoma
  • Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patchedl heterozygous mice. Cancer Res 68, 8788-8795.
  • Hedgehog and PI-3 kinase signaling converge on Nmycl to promote cell cycle progression in cerebellar neuronal precursors. Development 131, 217-228.
  • Phosphoinositide 3 -kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci U S A 103, 4505-4510.
  • Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. J Biol Chem 277, 25297-25304.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un procédé pour le traitement de BCC chez un patient ayant besoin d'un tel traitement, comprenant l'administration d'une quantité thérapeutiquement efficace d'un composé de formule IIa.
PCT/US2012/059976 2011-10-13 2012-10-12 Composés pour une utilisation dans le traitement de carcinome des cellules basales WO2013056067A1 (fr)

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