EP2755654A1 - Phosphatidylinositol-3-kinase-hemmer zur behandlung von krebs - Google Patents

Phosphatidylinositol-3-kinase-hemmer zur behandlung von krebs

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Publication number
EP2755654A1
EP2755654A1 EP12766542.0A EP12766542A EP2755654A1 EP 2755654 A1 EP2755654 A1 EP 2755654A1 EP 12766542 A EP12766542 A EP 12766542A EP 2755654 A1 EP2755654 A1 EP 2755654A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
compound
nhc
amino
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12766542.0A
Other languages
English (en)
French (fr)
Inventor
Arthur Decillis
Rodrigo RUIZ SOTO
Gary Thomas EMMONS
Joanne LAGER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Exelixis Inc
Original Assignee
Sanofi SA
Exelixis Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA, Exelixis Inc filed Critical Sanofi SA
Publication of EP2755654A1 publication Critical patent/EP2755654A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

  • Endometrial cancer (EC) and breast cancer affect thousands of patients in the United States and internationally every year. Endometrial cancer is currently the most common gynecologic malignancy in the United Sta es and the fourth most common cancer am ng women. The American Cancer Society estimates that there will he 42, 160 new cases cl: uterine cancer in 2009 and 7,7-80 related deaths. Ninety percent of cases occur in women older than 50 years, and the median age at diagnosis is 62 years. Endometrial cancer is more common among white- ' women than black women, yet mortality rates are higher in the latter. The overall annual ' mortality rate in the United S tates has increased more than 100 ' percent during the past two decades and is currently four deaths per 100,000 women per year.
  • EC is a heterogeneous disease that has been classified into two subtype based on distinct elmicapathologicai and molecular characteristics.
  • Type f is estrogen dependent and represents approximately 80% of sporadic eases. This subtype is well differentiated (Grade I or 2 endometrioid histology) and has a favorable prognosis.
  • Phosphatase and fensiu homolog • on chromosome 10 (PTEN) loss (32-83%) and RAS mutations ( 10-30%) have been predominantl identified in Type 1 EC (Oda et at.
  • Type ⁇ is poorly differentiated (Grade 3 endometrioid, clear cell, and papillary serous carcinoma) and not associated with increased circulating estrogens. This subtype has an aggressive clinical course and poor prognosis, p3 i frequently mutated in Type- II EC (Doll et ah 2008). There is evidence that the P1IC3CA pathway may be- activated in both type 1 and type II EC and by differing mechanisms (Saivesen 2009).
  • Aromatas.ft# Two highly- selective nonsteroidal aromatase inhibitors anasirozole (Arimidex$) and ietrozole (Femara®) and the steroidal aromatase inhibitor exciuestane (Aromas.ft#) are approved for use in both early- and advanced-stage breast ' cancers in postmenopausal women.
  • Aromatase inhibitors such as lejrozole are effective in treatment o hormone receptor-positive breast cancer; ho wever, many minors become resistant t aromatase inhibitors.
  • methods for treating endometrial 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 pharaYaeetiticaliy acceptable salt, tautomer, hydrate, or solvate thereof:
  • ⁇ N an .the remaining are -C(R f ⁇ :;:; ; and where each R ! is independently hydrogen, alkyl, haSoalkyl, iiitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkyl amino. Of djaikyiamino;
  • R* s is hydrogen or alkyl
  • R ii! , R 55 , and R S i are independently hydrogen, a!kyi, alkenyl halo, haioa!kyl, ha!oaikenyl hydroxy, alkoxy, alkenyioxy, haloalkoxy, niiro, amino, alkyiarnmo, dialkylamino, -N(R 55 ⁇ C(0)-CrC 6 -alkyleac- (R )R 53 ⁇ 4 ⁇ alkylc ' srfomyl, alkenykarhonyl, earboxy, aikoxyearbonyi, cyano, a!kyifhio,
  • R >>B are independentit hydrogen, atkyl, or alkenyl and ⁇ is hydrogen, alkyl alkenyl hydroxy, or alkoxy; or R s" and R ! together with the carbons to which they are attached form a 5- or S-membered. heteroaryl or 5- or 6-membered beteroeyctoalkyJ;
  • B is phenyl substituted ws.ih : R ',il and optionally iurther substituted with one, two, or three R ! ; or
  • B is heteroaryl optionally substituted with one, two, or three R 3 ;
  • R' 3 is cyano; hydroxyamino; carboxy; aikoxyearbonyi; alkylaraino; dialkylamino;
  • alkylearhonyk haloalkoxy alkylsulfonyl; aminoaikyloxy; alfcylaminoa!kyloxy;
  • R 7 is hydrogen, alkyl, or alkenyl and R' a and R'* are independently hydrogen, alkyl, alkenyl, hydroxyalkyl hatoaikyl, alkoxy, alkoxyalkyl,.
  • R 5 is hydrogen, hydroxy, alkoxy. alkyl, alkenyl, haloalkyl,. or haloalkoxy and ⁇ is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl,
  • heteroeycloalkylalkyl and heieroaryiaikyl ⁇ are from aikyl, alkenyi, alkoxy, halo, haioalkyl, haloalkoxy, hydroxy, hydroxyalkyl, ox.6, amino, aikyiamino, dlalkylamiao, alkyJcarboayl, aminoalkyl, alkylaminoalkyl, diaikyiaminoalkyi, alkoxycarbpnyl, and -Cf )H;
  • heterocyeloaikyl rings in R 3 ⁇ 4 are independently optionally substituted with 1, 2, or 3 groups independently selected from alky].
  • aryf optionalally subsiiteied with one or two halo
  • ary!alkyi heidfoaryl.
  • R ! is hydrogen, hydroxy, alkoxy, alkyL alkenyi, haioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R'" and * are ' independently hydrogen, a!kyl, alkenyi, haioalkyl, aramoaikyt, alkylaminoalkyl, dialkylaminoalkyl. or hydroxyatkyk
  • R l is hydrogen, alkyl, aSkenyi, hydroxy, or alkoxy and R u and R' ! 3 ⁇ 4> are independently hydrogen, alky I, alkenyi, amitioaikyl, alkylaminpalkyl, or dialkylaminoalkyl;
  • u is heterocyeloaikyl optionally substituted with 1 , 2, or 3 groups selected from alkyl, oxo, amino, alkylanSino, and he.teroeycloalkylal.kyl;
  • R is hydrogen, alkyl, or alkenyi and R ! 3 ⁇ 4 is aminoalkyl, .alkylaminoalkyl, diaikylammoalkyk aryl, or arylalkyl;
  • R ! s , and R i4b are independently hydrogen, alkyL or alkenyi;
  • R lk ⁇ R' ft , and R !ib are independently hydrogen, alkyl, or alkenyi;
  • R l " is hydrogen, aikyl, or alkenyi
  • R ! i i is alkyl or aikenyi
  • heteroaryl optionally substituted with one -or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl: independently hydrogen, aikyl, of alkenyi;
  • R t Sn is hydrogen, a!kyt, alkenyi, or alkoxy and R 5 and R 1 b are ' iadepeiideijtly -hydrogen, -alkyl, or alkenyi;
  • R ' 3 is amino, alfcylamino. dialkylamino, or heterocycloaikyl
  • R- 26 is hydrogen, -aikyl, or alkenyi
  • R 3 ⁇ 4la is cycteiky!. or heterocyei alkyl
  • R 21 S(0)rCrCV ⁇ Ikykne-N ⁇ R 2,fe ⁇ R 2
  • R 2S is hydrogen, aikyl or alkenyi
  • 2 fa and R 2i3 ⁇ 4 are independently hydrogen, alkyl, or alkenyi
  • R 2 ⁇ R 2Sa and R 23b are independently .hydro-gen, alkyl, or alkenyi; or
  • aikoxyaikyl or aryi optionally substituted with one or two halo: or alkyl; and where each of the -aikylene in R 3 ⁇ 4 is - independently Optionally further substituted with 1, 2, 3,
  • each R " ' (when R 1 is present) is independently alkyl; alkenyi; alkynyl; halo; hydroxy; oxo; alkoxy; eyano hydro syaniino; earhoxy; alfcoxye rbonyl; amino; alkylaraino;
  • dialkylamino aikylearbonyl; hatoaikoxy; alkylsultbnyl; aminoa!kyloxy;
  • alkyla inoatkyloxy dialfcyiammoalkyloxy
  • R 7 is hydrogen, alkyl, or aikenvi and R :a and R ;b are Independently hydrogen, alkyl, alkenyi, hydroxyalkyl, haioalkyl, alkoxy, aikoxyaikyl-, atninoaikyL aiky!araiooa!kyl dialkyla moaikyi, cycloalfcyi, eyeioalkylaikyl, heteroeycloalkyi, heteroeycloaikylaikyl heteroary ' L .heter arylalkyl, aryi, arylalkyl, or aryklkyioxy and where the aryi, cyeloalkyi, heieroeyeioalkyl and lieteroaryl rings in R' ' * and R' h (either alone or as part of ary!
  • R sa is hydrogen, aikyl, alkenyi, hydroxyalkyl, eyanoalkyi, aikoxyaikyl, alkylthioalkyl, heterocycloaikyl heierocycioidkylalkyl, cyeloalkyi, cyeloaiky!, heteroaryl, and heterocyeloalkyl rings in R* 3 (cither alone or as part of arylalkyi, cyeloal ylaikyS, hcteroeye alkylalkyl and heiemaryiaSkyl) are
  • alkyl independently optionally substituted with I, 2, or 3 groups independently selected from alkyl. alkenyl, alkoxy. halo, lialoalkyl, haioalkoxy,- hydroxy, hydroxyalkyi, oxo, amino, alkySarnino, dtalkylamino, aikylearbonyl, aminoalkyl, alkylarninoalkyl, iiialkylaminoaikyl, alkoxycarbony!, and -C(0)H;
  • c) ⁇ NR*C(Q)R 3 ⁇ 4 where is hydrogea, hydroxy, alkoxy, alkyk alkenyl, lialoalkyl, or haioalkoxy and s'a is hydrogen, C; ⁇ CVa!kyl, alkenyl, hydroxyalkyi, alkoxyalkyk eycioa!kyl, cycioaikylaikyl, heterocyeloalkyl, heteroeycloalkyiaikyl, heteroaryl heteroaryia!kyi aryl or arylalkyi; where the aryl cycioalkyi, heteroaryl, and heterocyeloalkyi rings in R a (either alone or as part of arylalkyi, cyeioaikylalkyl heteroeycloalkyiaikyl and heteroarykikyl ⁇ are independently optionally substituted with 1 , 2, or 3 groups independently selected froni
  • R ! ] :i is hydrogen, aikyl, alkenyl, hydroxy, or alkoxy and R ! i and R ui> are independently hydrogen, aikyl alkenyl, aminoalkyl,
  • R ;2 is heteroeycioaikyl optionally substituted with 1, 2, or 3 groups selected ftom alkyl, oxo, amino, alkylanuno, and heteroeyeloalkyialkyl;
  • R H , R m , and R 5 b are independently hydrogen, alkyl, or alkenyl;
  • R 13 , R iS and R J 5h are independently hydrogen, alkyl, or alkenyl;
  • R tS is hydrogen, alkyl or alkenyl and R ; ⁇ 3 ⁇ 4i is alky! or alkenyl; dialkylaminoalkyl;
  • R i?> and R m ⁇ are independently hydrogen, alkyl, or alkenyi;
  • 1 5 8 is amino, aikylammi dialkvlaramo, or heiereeyeloalkyl
  • R" 3 ⁇ 4> is eycioalkyl or fieteroeycloalky!
  • R " i!i and R m are independently hydrogen, alkyk or alkenyi;
  • R 22 , R 22a and R" 3 ⁇ 4 are independently hydrogen, alkyk or alkeayl;
  • R 3 R 25a and ft 2 * are independently hydrogen, alkyl, or alkenyi; or
  • R 24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl;
  • each of the alkyl ene in R' is independently optionally i ' urther substituted with i . 2, 3,
  • R 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and diaikylamino; and provided that when R > and R ⁇ are hydrogen, R 3i is hydrogen or methyl, R ' " ' is hydrogen or methoxy, and R " " is hydrogen or tnethoxy, then B is not 2,3-dihydn -i ,4-be:iiz;odios.fnyi, tliien-2- ⁇ , o thien-2 ⁇ yi substituted, with one R' where R is halo
  • K is hydrogen, optionally substituted alkyk optionally substituted eycioalkyl, optionally substituted cydoaikylalkyk optionally substituted ary optionally substituted arylalkyl, optionally substituted heteroeycloalkyS, optionally substituted hetemaryklkyl;
  • * is hydrogen or alkyl where the alky! is optionally substituted ' with. 1 , , 3, 4, or 5 R ' groups;
  • X is -NR 3 -;
  • R* optionally substituted alkyl
  • R" is phenyl, acyl, or heteroaryl wherein the phenyl and hetero&ryl are optionally substituted with 1 , 2, 3, 4, or 5 R 'J groups;
  • each R s when present, is independently hydroxy, halo, aikoxy, haloaikoxy, amino, alkyiaroino, dialky!ammoalkyl, or alkoxyalky!amino;
  • each Rvwheti present is independently halo, alkyl, haloalkyl, aikoxy, ha!oalkox , c ariOj amino, alkyiamino, dia!kylamtno, altoxvalkyl, carhoxya!kyl, alkoxycarbonyl, amin alkyL eycloaikyi, aryi, arylalkyi, aryloXy * heteraeyclOalkyl, or heteroaryi and where the eycloaikyi, aryi hetepoeyeloalkyl, and lieteroaryh each either alone or as part : bf another group within R ⁇ are independently optionally substituted with 1, 2, 3, or 4 groups selected .from. halo, alkyl, ba alkyi hydroxy, aikoxy, haioalkxy, amino, alkylanii.no, -and
  • the compound of Formula I is a compound of .Formula la
  • R ' is hydrogen
  • A is methyl
  • R '' ⁇ is hydrogen
  • R i" ⁇ is hydrogen or ' aikoxy; and which they are attached form a ⁇ -membered heteroaryl; arid
  • R" is hal or meihy!.
  • R 3 * is -N(R ? )C ⁇ 0)-CrC ⁇ ailcylene-N(R. 3 ⁇ 4 )(R 7 ) where R T is hydrogen and R 3 ⁇ 4 and R ' ⁇ are independently hydrogen, alky!, aniino lkyk. aikytemmoalkyl, or
  • the Compound of Formula 11 is a compound of formula II A.
  • R ! is alkyi,. cyeloalkyl, eycloalky!alkyl, aryl, arylalkyl, heterocycloalkyl,
  • R" is hydrogen or a!kyl
  • R is alkyl
  • R ' is hydrogen
  • R" is enyl, acyl or heteroaryl wherein the phenyl and heteroaryl arc is optionally substituted with 1 , 2, 3. 4, or 5 R groups;
  • each R when present, is independently halo, alfcyl, !ialoaikyh alkoxy, haioaikoxy. cyano, -amino, aikylanilao, dialkylaraino, aikoxyaikyl, earboxyalkyl, alkoxycarborryi, aminoalkyk c cioalkyl .aryl, .arylalkyl,. arylpx-y, heterocycloalkyk or heteroaryl and where the
  • 1.0 group un K " ' are independently optionally substituted with 1 , 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, ha!oalkoxy, amino, alkylamsno, and diaSk lamino,
  • Compound B is known by its name 2-an:iim)-8-ethyl-4-inediy!-6- ⁇ 1 /-pyi3 ⁇ 43 ⁇ 4K>l-3- yl)pyrido
  • the cancer is Type I or Type II .endometrial carcinoma (
  • the cancer is advanced or recurrent endometrial carcinoma
  • ie compound or " Formula I or Formula 11 is administered as a tablet or capsule pharmaceutical composition.
  • the compound of Formula I or Formula II is administered as a tablet pharmaceutical composition.
  • the compound of Formula 1 or !.l is fidniinistered in an effective amount, wherein the effecti ve amount produces at least one therapeutic effect selected from the group . consisting of reduction in sixe of a tumor, reduction in metastasis, complete.. remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response,
  • methods are provided herein for treating breast cancer comprising administering to a patient in need thereof a therapeutically effecti ve amount of letr Koie in combination with a Compound ' of Fonnula 1, la, or Compound A as described herein;: or letrosiqie in combinatio with Compound it, 11A, or Compoun B as described herein.
  • the compound of ⁇ Formula I or Formula 11 is administered orally as a tablet or capsule pharmaceutical composition
  • the compound of Fonnula 1 or Fonnula II is administered as a t bl t pharmaceutical composition
  • the -effective amount produces at least one therapeutic effect selected from the group consisting of redaction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response,
  • Figure 1 shows a plot of individual and mean SD (Bold, horizontal lines with error bars) for Compound ⁇ AUCiQ-24), ss after doses of 200 and 400 mg tablets in Arm 1 compared to historical data (TEDS 1433 & A D I 1439) ibr Compound A.
  • Figure 2 shows a plot individual and mean/SD (Bold, horizontal lines with error bars) for Compound B AUC ⁇ 0- 12), ss alter doses of 30 and ' 50 mg capsules BIO in Ann 2 compared to historical data (TED U 440) for Compound B (above).
  • Figure 3 depicts preliminary results from a Phase I results from a breast cancer clinical trial.
  • Figure 4 depicts preliminary results from a Phase I results from, a breast cancer clinical trial.
  • Figure 5 depicts preliminary results from a Phase I results from a breast cancer clinical trial.
  • a substituent "R.” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly deiined hydrogen from one of the ring atoms * , so long as a stable structure is. formed..
  • a substituent R" - may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the - ⁇ - in the formula above), implied hydrogen (for example as is the formula above, where the .hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, U " equals -CH-) from one of the ring atoms, s long as a stable ⁇ -structure is formed.
  • the group may reside on either the 5-memhered or the 6-merabered ring of the fused ring system.
  • the two "RV may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied. Or expressly defined hydrogen on the ring,
  • -Ac r means a -C(0)R radical where R is optionally substituted alkyl, optionally substituted aikenyl, cycioalkyL cyeloalkySaikyl, ary!, atalkyi, heteroaryl, heferoan kyl, hereroc cloalkyl, or h terocyeioaikylalkyl, as defined herein, e.g., acetyl,
  • Aeylaramo means a -NRR " radical where R is hydrogen, hydroxy, alkyl, or aikoxy and R ' is aeyl, as defined herein.
  • Acyloxy means an -OR radical where R is aeyl, as defined herein, e.g.
  • administering * ' a compound in reference to a compound of the invention means mfrodue ing 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.
  • AlkenyP means a means a linear monovalent hydrocarbon radical of one to si 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, propeny!, i -but-3-enyl, and l -pc t-3-enyI, and the like.
  • Aikoxy ** means an -OR group where R is alkyl group as defined herein.
  • Examples include methoxy, ethoxy, propoxy, isop opoxy, and the like.
  • AlkoxyalkyP means an alkyl group, as defined .herein, substituted with at least one, preferably one, two, or three, aikoxy groups- as defined herein. Representative examples include metho.xymethyl and the tike.
  • Alkoxyalk lammo means an - RR' group where R is hydrogen, alkyl, or alkoxyalkyl and R' is aikoxyalky), as defined herein. specifically one or two, alkoxyalkylamino groupis), as defined herein.
  • Alkoxyq-ar oayF means a -C(0) group where R is alfcoxy, as defined herein.
  • Alkyl means a linear saturated monovalent hydrocarbon radieal 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-propyi, butyl (including all isomeric forms), or peniyS (including all isomeric forms), and the like.
  • I0048 ⁇ i Aikytamino means an -HH group where 11 is aikyi, as defined herein.
  • 'Alfcyiaminna!kyn means an alky! group substituted with one or two aiky!amino groups, as defined herein.
  • ⁇ OOSOj 'V ky!a inoaikyloxy means an O gr up where R is alkyiaminoaikyk as defined herein.
  • Si Aikyiearbonyr means a -CfO)R group where R is aikyi. as defined herein.
  • Alkynyt means a linear mono valent 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., eihynyl, prepynyl, buty yl, pewiyN-2-yl and the like.
  • Alkyr means an alky! group substituted with at least one, specifically one, two Or three,, amino groups,
  • 'Aminoaiky!oxy means an -OR group whereR is aminoaikyt,. as defined herein, 100663 "AryP means a monovalent six- to tburteen- embered,. 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 tides permitting. Representative examples include phenyl, riaphthy.l, and indany!, and die like,
  • Arylalky means an alkyl radical, as defined herein, substituted with one or two aryl groups, a defined herein, e.g., ben3 ⁇ 4yl and phenethyl, and the like.
  • Aryloxy means an -OR group where R is and, as. defined herein.
  • Carboxyalkyl means an alky! group, as .defined herein, substituted with at least one, specifically one or two, ⁇ C(0)OH ,grbtjp(s).
  • eycltialkyl includes, bu is not limited to, cyclopropyl, cyelobutyi, cycloperityl, cyclohexyl, cyclohexyl, or eyclohex ⁇ 3 ⁇ enyl, and die like.
  • Cycloaikylalkyl means an aikyl group substituted with at least one, specifically one or two, eyeloalky! group(s) as defined herein.
  • Dialkylaraino means a -NRR' radical where R and * are aikyl as defined herein, or an -oxide derivative, or a protected derivative thereof, e.g., dunethylami V, dJethylamiao, A V-methylpropylamino or iV-raetJiylethylamino, and the like.
  • Dia!kylaminoa!liyl means an aikyl group substituted with One or two
  • ⁇ Dialkylaminoalkyloxy means an -OR group where R is dialkySamirioalky as defined herein. Representative examples include 2-(A' N-diethy1amrao)-eihyloxy, and the like.
  • ⁇ 0065 "Fused-polycyelie ⁇ or "fused ring system” means a poiycyclic ring system that contains bridged or fused rings; that is, where too rings have more than one shared atom in their ring structures, in this. application, iused-polycyclies and fused ring systems are not necessarily ail aromatic ring systems.
  • fiised-poiycycltcs share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydtO-naphtlia!ene.
  • a spiro ring sys ' tein is not a fused-polyeyciie by this definition, but fused; poiycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polyeyciie. in some examples, as appreciated by on of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to forxn-.a ring- structure.
  • the fused ring structure may contain heieroatoms 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 haloaikyl as defined herein, e.g.. trifluoromet oxy or 2,2,2-tri ' fluoroethoxy, find the like,
  • Haloalk ⁇ mean an aikyl grou substituted with one or snore halogens
  • halo atoms e.g., trifluororaethyL 2-chloroethyl, and 2,2-difiuoroetiiyl, and the like,
  • 0069j ''ReteroaryF' means a pionoeyclic.
  • One or two ring carbon atoms of any nonaromatic . rings comprising a bieyclic -or tricyclic radical may be replaced by a -C(0)-, -C(S , or ⁇ C( ⁇ NH)- group.
  • R x is hydrogen, alkyl, hydroxy, alfcoxy, acyl, or alkylsu!foiiyi, Fused hicyclic radical inerutles bridged ring systems.
  • the valency may be located on any atom of any ring of the heteroaryi group, valency rules penm ' tting. When the point of valency is located on the nitrogen, R' s Is absent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyi. 1.3,5-triazolyi.
  • phthalimidyl pyridinyl, pyrrolyl, imidazoiyL thienyl, ftiranyi, kdoly " 2,3-dihydro-1 H-iodoIyl (including, for example, 2,3 ⁇ dthydro- l/:/-mcloi ⁇ 2-yl or and the like), ispirtdolylJndolinyl, isoindolinyi.
  • benzothienyl and the derivatives ⁇ thereof, or N-oxide or a protected derivative thereof.
  • 'ileteroary iaik ' means an alkyl group, as defined herein, substituted with at least one, specifically one or two heteroaiyi group(s), as defined herein,
  • HeierQcycloalkyl means a saturated or partially unsaturated (but net aromatic) monovalent monocyclic group of to 8 ring, atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bieyclic group- of 5 to 12 ring atoms krwiheh one or more, specifically one, two, three, or- four ring heteroatoms independently selected from 0, S(0 ⁇ « (n is 0, 1, or 2), N, (R y ) (where R y is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkyteulfonyi ⁇ , the remaining ring atoms being carbon. One- or two.
  • rin carbon atoms may- be replaced b -G(QH ⁇ €(SK 0r ⁇ C( ⁇ NH)- group.
  • Fused bieyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group ma be loca ted on any ato m of any ring within the radical, valency rales permitting. When .”the point of valenc is located on a nitrogen atom, R J: is absent More specifically the term he erocycloalkyl includes, but is not limited to.
  • azetidkr l pyrrolidinyi 2-osopyrrolidinyl, 2,5-dthydro- iH-pyrrolyl, pipertditryl, 2-oxopiperidmyi, thiamorpholinyk auaraorphoiinyl, perhydroazepinyl, pyrazolidmyl, imidazolmyl, imidazolldiny ⁇ .
  • an alky! radical as defined herein, substituted with one or two heterocycloalkyl groups, -as defined herein, e,g., morpholinyirneihyl, jY-pyxrolidinylethyl, . and ' 3- ⁇ N>azeudtny!propyl, and the like.
  • Heierocycloalkylaikylo . xy means an -OR group where R is heterocycloaikytidkyi, as defined herein,
  • saturated bridged ring syst m ** refers to a bieyciie or polycystic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturatwn, but not aromatic or heteroaroruatie rings in its core structure ⁇ but may have aromatic substitution thereon). For example, hexahydro-i3 ⁇ 4roji3.2-b]furan, ⁇
  • Spirocyelyr or “spirocyelic ring” refers to a ring originatin 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 foe a shared, atom between the saturated bridged ring system and a spiroeyelyl (ring A) attached thereto.
  • a spiroeyelyl can he carbocyclic.or heteroalieyelic.
  • Optionally substituted aSkyP means an alkyi radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or five groups, .independently selected from, alkylcarboiiyk aikenyiearbonyl, eycloalkyIeart>onyl, alk lcarbonyioxy, alkcnykarbony xy, amino, alkylamiao, diaikylamino, -aminocarbonyl, aikytominocarhonyl. dialkylaminoearhonyl, eyano, cyanoalkylaminoearbonyl., alkoxy.
  • alky!3 ⁇ 4ulfonyl-NR e ⁇ (where R c is hydrogen, alkyi, optionally substituted alkenyl hydroxy, aikoxy, alkenyloxy, or eyaaoalkyl)* alkylaminocarboayloxy, dialkylatninocarbonyloxy, alkykrainoalkyibxy, dia!ky!anunDalkyloxy, alkoxyearbony!, lkenyloxycarbonyl,
  • alkoxycarbojjylamino alkylamiiiocarbonyiamirio, dia!kylaminoe-arbonylamuio,
  • R a and R b are independently hydrogen, alkyi,. optionally stibstituted alkeivyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyi
  • Optionally substituted alkenyf * means an alkyi -.radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or five groups, independently selected from alk tearbonyi , a-1 kenylearbonyl, eye loa Ikylcarbonyl, alkylearbonykTxy, : aikenyiearbonyloxy, ami * alkylamino, dialkyianiino, aminocarbonyl, alkylaminocarbonyi, dialkylaminoearhonyl, eyano, eyanoalkylaminoearbonyl, alkoxy, alkenyloxy, hydroxy,, hydrosyalkoxy, halo, earboxy,- alky!earbonylainino, alkylearbonyloxy, aik i-SfO);),!-, alfcenyl-S(0) ⁇ >:r
  • R i and R fe are independently hydrogen, alkyi, optionally .substituted alkeoyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyi).
  • Optionally substituted amino refers to the group -N(H)R or-N(R)R where each R is independently selected irom the grotspt optionally substituted alkyi.,.
  • Optionally substituted alkoxy optionally substituted aryl, optionally substituted heteroeycloalkyl. substituted alkyS
  • ⁇ S(0).2-optioria11y substituted ary-l optionally substituted ary-l
  • substituted heteroaryi includes- dietlvylaraino, methyisulfonyianrmo, and furanyl-oxy-suUbnanirao.
  • [ 0821 ' 'Optionally substitute ' aminoalkyr means an aikyl group, as defined herein, substituted with at least one, specifically one or two. optionally substituted amino group(s), as defined herein,
  • Optionally substituted ary! ' ' means an and group, as defined herein, optionally substituted with one, two, or three subatituents independently selected from aeyl, aeylamino, aeyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, a!kcny!oxy, halo, hydroxy, afkoxycarbonyl, alkenyloxycarbonyl, amino, alkyiaraino, diaikylamino, nitro, aminoearboayl, alkylaminocarbonyS, dialkylaminocarhooyl, earboxy, cyanq, alkyl.th.io, alkylsultuiyl, alkyisulionyl, ammosuifbnyi, alkylaminosuli myL dtalkylarainosul fonyl , alkylsulfonylamino,
  • aryiai.kyin means an alky I group, as defined herein, substituted with optionally substituted aryl, as defined herein.
  • Optionally substituted cycloaiky means a cycloalkyi group, as defined herein, substituted with one, two, of three groups independently selected from acyl, aeyloxy, acylaraino, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxyearbonyl, alkeny!oxycarhpnyl, alkyl thio, alkyisoitmyi, lkylsulfonyl, arainosuUonyl, slkyiarainostdibnyl, diaikyianiinosulr nyl, a!kylsulfonylamino, halo, hydroxy, amino, aikylamino, diaikylamino.
  • alkyl and alkenyl are independently optionally substituted with one, two, three, four, or five halo, e.g. ba!oalkyi, haioaikoxy, haioalkenyloky, or haloaikylsultbnyL
  • cyeloafkylalkyF means an -alkyl grou substituted ' with at least one, specifically one or two, optionally substituted cycloalkyi groups, as defined herein.
  • Optionally substituted heteroarylalky 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 heieroc eloalkyr' means a heterocycloalkyl group, s defined herein, optionall ' substituted with one, two, or three sabstituents independently selected .from acyl, acyiarnmo, acyioxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyioxy, halo, hydroxy, alkoxycarbonyl, .
  • alkenyfoxyearbonyl amino, alkylamtno., dialkyiarnino, niiro, aminocarbonyl, alkyiammocarbpnyl, ialkylaminoearhonyi carboxy, cyano, alkylthio, alkyisulfmyl, aikyisu!fonyk aminostdfouyL alkylaminosuU nyl, dialkylaminosullbny alkylsulfonylamino. aminoalkoxy, or r l is pentafiuorophenyl. Within the optional substituents on .
  • heterocycloa ' lkyi the alkyl and alkenyl, sitter alone or as part of another group . including, for example ' , the- lkyl itv alkoxycarbonyl),. are independently optionally substituted with one, two, three, lour, or five halo.
  • Optionally substituted heteroeyclpalkylalkyF' means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted
  • "Pharmaeeuticai composition” comprises 1) a Compound of Formula ! or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable sal t and .additionally optionally as a hydrate and additionally optionally as a solvate thereof; and 2) a • pharmaceutical ly acceptable carrier, exeipient, or diluent.
  • Formula la, lia the following structure .
  • Compound A is known by its chemical name N 3- ⁇ [(3 ⁇ [2-ehloro-5 ⁇ methoxy)pIv ⁇
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • I009S1 "Patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms-. Thus the methods are applicable to both human therapy and ' veterinary applications, In a preferred embodiment the patient is a mammal, and in: most preferred embodiment the patient is human.
  • an effective amount refers to a sufficient amount of an agent to pro vide the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more o f the signs, syinpioms, or. causes of a disease, or any other desired alteration of biological system, hi reference to cancer, 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, in some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence.
  • An effective amount can be composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retards skrtV t some extent, and preferably stop cancer cell mfiltratkm into peripheral organs; (iv) inhibit (i.e., slow: to some extent and preferably. stop) tumor metastasis; (y) 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 may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retards skrtV t some extent, and preferably stop cancer cell mfiltratkm into peripheral organs; (iv) inhibit (i.e., slow: to some extent and preferably
  • !3 ⁇ 4i3 ⁇ 4ctive amount for therapeutic use is the amount of Compound A or a metabolite thereof a pharmaceutically , acceptable salt Or solvate thereof, or a composition comprising Compound A or a metabolite thereof or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in the progression of EC,
  • At least one therapeutic effect is obtained.
  • the therapeutic effect may be a decrease in. the progression of EC as measured by the reduction in tumor size, reduction in metastasis, complete remission, partial remission,, pathologic complete response, increase in overall response rate, or stable disease.
  • the improvement of clinical benefit rate is at least about 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, or more,
  • a "pharmaceutically acceptable salt" of a .compound means -a salt that is
  • Examples of pharmaceutically, acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromie acid, sulfuric acid, nitric acid, phosphoric acid, and Ihe like; as well as organic aeids such as acetic acid, trifiuoroaeetsc acid, propionie acid, hesanoie acid, cyelopentanepropiomc acid, glyeoiip acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fiiraarie acid, tartaric acid, citrie acid, ' benzoic, acid, ei iamic acid, 3r(4-hydroxybenzoyl)ben2o.fc acid, niandelic acid,
  • a pharmaceutically acceptable base addition salts include those formed when aa 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 sot limited to, salts of primary, secondary, and terrfiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic sort exchange resins. Examples of organic bases include isopropy!amme, trimethylamme, diethyiamine, trklhylaniine, tripropylarame, ethanola ine,
  • tromethamme A-me iylglucam e, poiyanune resins, and the like- Exemplary organic bases are isopropylarairse, diethyiamine, ethanola rae, trimethyiamin.e, dicyclohexylamine.
  • Prodrug "1 refers to compounds that are transformed (typicall rapidly) is vivo to y ield the parent compound of the above formulae, for example, by hydrolysis in blood. Common, examples include, but are not limited to, ester and amide forms of a compound having an active form bearing -a carboxylic acid moiety.
  • pharmaceutically acceptable -esters of the compounds of this invention include, but are not limited to, alky! esters (for example with between about one and about six carbons) the alky! group is a
  • Acceptable esters als include eycloalkyi esters and aryialky i esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, bat are not limited to, primary amides, arid secondary ami tertiary aSk l 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, ⁇ thorough discussion of prodrugs is provided in T, Higachi 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 la the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, redaction, or- hydrolysis, or to a conjugate (see Goodman and Oilman, "The Pharmacological Basis of Therapeutics” S.sup.th Ed., Pergaiiion Press. Gilman et a-L (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, hi one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • 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; ami relieving the disease, disorder, or syndrome, that is, causing regression of the -disease, disorder, or syndrome.
  • adjustments 3 ⁇ 4r 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 preventin the disease, disorder, or syndrome from occurring hi 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 syiidrome.
  • the embodiment includes both the recited compounds as well as individual isomers and mixtures of isomers,
  • the embodimen includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof, comprises admroistering to a patient: an effective amount o.
  • Compound of Formula f or fa or a pharmaceutical, composition comprising a Compound of Formula ⁇ or la,
  • methods for treating cancer which method comprises administering to a patient an effective amount of a Compound of Formula 1 or pharmaceutical composition comprising a Compound of Formula 1 where the cancer is EC, in some embodiments, the cancer is T pe 1 EC, In -other embodiments, the cancer is Type IT EC. .
  • the Compound of Formula 1 is selected from any of the loUowirig emb diments, including from the Representative Compounds in Table ! .
  • W ⁇ W ⁇ , W ⁇ and w are -C(R ) ⁇ where each R 1 is independently hydrogen or alkyl
  • R ! is hydrogen.
  • R 3 ⁇ 4t> is hydrogen, alkyl, aikenyl, halo, ha!oaikyl, haloaikenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitrp, amino, alkyiamino, dialkylamino, -HC ⁇ CCOJ-Cs-C ⁇ -alk lene-HiR ' ⁇ 33 ⁇ alky!carbonyL alkenyl.carboayl, carboxy, alkpxycarbonyl. cyano, a!kylthio, -SCOhNR ⁇ 53 , or
  • R 5 " and R" ' are iadependentlt hydrogen, alkyl, or aikenyl and R 55a is hydrogen, alkyl, aikenyl, hydroxy, or alkoxy; and all other groups are as defined in the Summary of die Invention, in another ' embodiment, R "li is hydrogen.
  • [ 0112) Another embodiment (Q of a -Compound of Formula ⁇ is where 5 ' is hydrogen or alkyl; and all other groups are as defined in. the Summary of the Invention.
  • R 3 ⁇ 4 i is alkyl.
  • R 5! is methyl, or halo; and ail other groups are as defined in the Summary of the Invention, in another embodiment 32 is hydrogen or fluoro.
  • J ⁇ is hydrogen.
  • FIG. 1 Another embodiment (E) of a Compound of Formula 1 is where ' 3 is hydrogen, alkyl alkenyl, halo, haloalk l, ludoaSkenyi, hydroxy, aikoxy, alkenyloxy, haloalkoxy, nitro, amino, alkykmino, diaikylamino, ⁇ (3 ⁇ 4 '5 ⁇ )0(0) » ⁇ -0 & -3 ⁇ 6 ⁇ > ⁇ ( ⁇ 33 *) ⁇ * ⁇ ⁇ ⁇ 3 ⁇ 4 ⁇ ⁇ alkenyicctrbonyl, cai'boxy, alkoxycarbemyl, cyano, alkylthio, -S(Q ⁇ NR S5 R 35 * . or
  • alkylcarbonyiaffiino where M and R'" b are independent!* hydrogen, alkyl, or alkenyl and R ?3 ⁇ 41 is hydrogen, alkyl, alkenyl, hydroxy, or aikoxy; and all other groups are as defined in the .Summary of the Invention, in another embodiment, is. hydrogen, a!koxy, nitro, amino, or - ⁇ R >s )C ⁇ 0)-C -C ⁇ iky!ene ⁇ ⁇ R >3 )R 3 ⁇ 4iis >.
  • si is hydrogen, methox , nitro, amino, or -NHC(0)CH2 ( H.?)2» in another embodiment, is hydrogen or tnethoxy,
  • R' is hydrogen, alkyl, alkenyl, halo, haloaikyi, hatoaikenyi, hydroxy, aikoxy, alkenyloxy, haloalkoxy, -nitro, amino, aikylamino, dialkyiamino, -HCR ⁇ C-CQ ⁇ Ci-C alk lene-NiR ⁇ 5 ⁇ , alkylcarbonyl, a!kenylcarhonyl, carbo y, aikoxycarbony), cyano, alkylthio, -SfOja ⁇ 51 ' 2 , or
  • R* * is hydrogen, alkyl, aikoxy, or halo.
  • R 54 is hydrogen, methyl, meihoxy. bfomo, or chloro.
  • K * is hydrogen,, meihoxy, or chloro.
  • R Mi , " 2 , and '3 are hydrogen and R t i chloro or meihoxy;
  • R 30 , "y and R 3' ' are hydrogen and s '' is m.ethoxy; or
  • R 3t ' and R J ' are hydrogen and R " 3 and R >! together with the carbons to which they are attached form
  • B is heteroaryi optionally substituted with one, two, or three R 3 .
  • B is thico-J-yl, pyrid.ittyi. pyrtm.tdi.nyl, pyridazinyk optionally substituted with one or t o R".
  • B is ih.ien-3 ⁇ yi pyrkiin-2- yl, pyridm-3-yi, pyridm- -yl, oxazol-2-yh oxa?.ol ⁇ 4 ⁇ yl ?
  • oxaxoi-5-yk isoxazol-3-yI, isoxazol-4 ⁇ yl, isoxazol-5-yL i ida3 ⁇ 4oi-2-yl.
  • B ' is thien-3-yl, pyridtn-3-yk pyridm-4-yL isoxazol ⁇ 4 ⁇ yL or pyrazoM-yh each of which is optionally substituted with one or two R " ⁇
  • B is pyrid -3-yS, 2-hydroxy-pyri.diri-5-yl, fcoxazo -yl, ⁇ rpyrazoM-yl, each of which is optionally substituted with one r two R ⁇
  • 1 ⁇ 4 is cyano; hydroxya ino; carboxy; alkyisui forsyl, ammoalkylo : xy ' ; alkylatttihoalkyloxy; dia!k lamindaikyfoxy; ⁇ N(R 7 jC(0 ⁇ --C.rCiraSkyIene- N(R 7a )R3 ⁇ 4 -C(0)NR3 ⁇ 4 3 ⁇ 43 ; - R3 ⁇ 4fO)R 9il ; :(0)N(R l!) )-C 1 .C i> -aikyie«e. ( ua )R ,i3 ⁇ 4 ;
  • 3 ⁇ 4 is:
  • R ki is hydroxyamino, -N(R v )C(0 ⁇ -C ⁇ -C ⁇ a!kylene- (R 3 ⁇ 4 )(R 73 ⁇ 4 ) t -C(0)NRR & ⁇ - R"C(0)R 1 ⁇ 2 , *C(O) ⁇ ! ⁇ ')-Cr -aikyieae- (R K,a )R l0b , ⁇ NR- ⁇ (C 11 ⁇ ib , - (R 22 ⁇ e(0)-C C alkyten ⁇ -.NR°C(O)0R S'3 ⁇ 4 ( -N(R !
  • each of the alkylene in R 3 ⁇ 4 is independently optionally further substituted with 1 , 2.3, 4, of 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the . Summary of the Invention.
  • R ia is -!s
  • Embodiment (N) provides a compound of Formula I where each R s> is independently halo; eyaao; aiky!; alkenyl; a!koxy; hydroxyamino; carboxy; aikylsulfonyk.
  • heter ary! optionally su stituted with one or two ammoatkyk alkylaminoatkyl, or
  • each of "the alkylene in 3 is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkykmino; and all other groups are as defined in the Saaunary of the Invention,
  • R J is independently halo, a!kyi, hydrox zine,
  • each R" is independently methyl, ehioro,
  • R 3 is aikyl qr-N(.R ? )C(0)-Ci-C 6 -alky!ene- N(R' 's ) ⁇ R' -b ); and R' is hydrogen or alkyl and R '*a and R 0 are independently hydrogen, a!kyl, aminoa!kyi, a!kylaminoaikyi. or dialfcyianiino alkyl; and all other .groups are as defined in the Summary of the Invention.
  • each R -> is independently methyl - HC(0)CH 2 NH(C13 ⁇ 4 - HC(0)CH(CH.v) H 2 , - HC(0)C(CH 3 ) 2 NH2, -NHC(O)- -NHC(Q)CH 2 N(CH -)C3 ⁇ 4CH: fCH3) 3 ⁇ 4 or -NHC ⁇ 0)CI3 ⁇ 4CHj)NH(CH s ).
  • R 1 of embodiment R, R 51 ', R ' ⁇ , and R ! are hydrogen and R i:! is halo or alkoxy; R 5l! ,.
  • R > % and R'* ' are hydrogen and R s ⁇ is aikoxy: or R > ⁇ ! and R* are hydrogen and R ? ! and R J " together with the carbons to which they are attached lorn* a 6 ⁇ meinbered heteroaryl; and all other groups are as defined in the Summary of the .Invention.
  • R ', R* 2 , and iV " * are hydrogen and R is halo or alkoxy; or R ? ⁇ R J ⁇ and R'" are hydrogen and R ? A is alkoxy.
  • the compound of Formula I is a compound of Formula la;
  • R is methyl
  • R ⁇ ⁇ is hyd ogen
  • R" is hydroge or alkoxy
  • R '"4 is hydrogen, alky i, alkoxy, or halo; or R > and R* 4 together ' with th carbons to which they are ⁇ attached form a 6-memimred heteroaryl; and
  • IV is hal or methyl
  • 3 ⁇ 4 is -NC ⁇ yCfOi-C C ⁇ alk i . ert ⁇ NiR. ⁇ KR 51 ') .
  • R. 7 is hydrogen and R 7a and d it Iky ⁇ am moa I ky l .
  • R >! is methyl; and R >( ⁇ R " , and R. > arc hydrogen and R ' is halo or alkoxy or R : ⁇ i > R ' ⁇ and R 3 ⁇ 4i are hydrogen and 3 ⁇ 4 - is aikoxy; or a single stereoisomer or mixture of stereoisomers thereof.
  • R "iS is - HC(0)CH 2 NH£G%k -NHC(0)CH(CH>)NH 2> - HC.(G)C ⁇ C3 ⁇ 4)2NH2, -NW €(0)-CHlN ⁇ CH3) 2 ,-NHC(e)CM 2 N ⁇ CH5)CH 2 CH 2 ⁇ CH 3 )2,-- HC(0)eH(NH2)GH 2 €H 3s - HC ⁇ 0)C3 ⁇ 4 (CH3 . )CH 2 CH 2 N ⁇ CH3)2 5 or - HC ⁇ 0)eHC3 ⁇ 4)NHfC3 ⁇ 4).
  • the compound of formula la is:
  • R ! in the compound of formul II is hydrogen, optionally substituted alkyl, optionally substituted eycloaikyl, optionally substituted eycioalkylaiky optionally " substituted aryi, optionally substituted arylalkyl, optionally substituted
  • heteroeycloalkyl optionally substituted heteroeyeloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroaryialkyi.
  • R f is ydrogen, optionally substituted alkyl, optionally substituted eycloaikyl, optionally substituted arylalkyl, or optionally ⁇ .substituted heteroeycloalkylalkyl.
  • R l is hydrogen, alkyl alkyl substituted with one or two hydroxy, alky! substituted with alkoxy, eycloaikyl, arylalkyl, or heterocydoaikylalkyi.
  • R 1 is hydrogen, methyl, ethyl, propyl isopropyL ' 2-hydroxypr pyl, 3-hydtoxypropyl, 2-ethoxyethyL S-rneihoxypropyi,
  • R ! is ethyl, ssopropyi, eyclopentyi, or cycSohexyl
  • ! is ethyl
  • R is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R 3 ⁇ 4 groups.
  • R 2 is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three groups, More specifically, R " is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three * groups; and each R ⁇ when present, is independently selected. tem amino, alkylamino, dialkylainino, and halo.
  • R* is hydrogen, methyl, ethyl, propyl, isopropyl, ierr-butyi, -aniiiio propyl -( ' A' ' ⁇ met!rj'lamlno)-propyL 3- ⁇ N,/V- ⁇ li8ieihybmmo)-pr0pyl y 2 iluoroethyl, or 2,2,2 -triOuoroetliyl
  • R' is hydrogen or ethyl. Yet even more preferably.. R ' is ethyl
  • R " is hydrogen .
  • R is optionally substituted alkyl.
  • R 4 is methyl or ethyl. More specifically, is methyl. more specifically, R i; is acetyl
  • R i! is phenyl optionally substituted with 1 , 2, 3, , or 5 R v groups.
  • R° is: phenyl optionally substituted with one or two R ' groups; and each R: ⁇ when present, is independently selected from aryL halo, alkoxy, aryloxy, and hakralkyl. More specifically, .
  • R* 1 is phenyl optionally substituted with one or two R 9 groups; and each R !> , when present, is independently selected rom phenyl, iluoro, chloro, meihoxy, pheny!oxy, and mfiuo.romelhyl Eveu more specifically, R' f is phenyl, phenyl substituted with phenyl,, fluorophenyl, difluorophenyl, c orophenyS, diehlorophenyl, phenyl substituted with chloro and fluoro, terrorismhoxyphenyhdiuiethoxyphenyL phetiyloxypheoyi, or triflupro.raethylphenyl.
  • W is hctere>ary! optionally su stituted with I, 2, 3, 4, or 5 R v groups.
  • 6 is a ⁇ -membered .heteroaryi optionally substituted with one or two R ⁇ . More specifically, R* is pyridlnyl, pyrazinyl, pyrirnidinyl, or pyridaxmyi each, of which is optionally substituted vvith one R wherein R when present, is halo.
  • R° is pyridm-2-yl, pyridin-3-yl, pyridiB-4-yl 3-0aoropyiidm-4-y!, pyraziii-2-yl, pyrazm-3-yl, pyri.raidin-2-y!, pyrimidra-4-yl pyrimidin-5-yL pyridazin-3-yL or pyridazm-4 ⁇ yl, each of which is optionally substituted with one or two R .
  • R* is pyrazmyl, pyrirnidinyl, or pyridazirryl, each of which is optionally substituted with one wherein R ⁇ when present, is halo. Even more specifically, . R is pyrazin-2-y!, pyrazin-3-yi, pyi'iniidin-2-yi, pyrimidra-4-yL pyrimidm-S-yl, pyrklazin-3 -yl, o p ridazin-4-y 1.
  • R* is a 5-membered heteroaryi optionally substituted with one or two R '? .
  • R f! is pynm>lyl y imidszolyl, thien l, ihiaxolyl, oxazoiyl,
  • R (> is pyrazpH-yL pyriszol-3-yl, pyraza1-4-yS, pyrazol-S-yi, U idazol- I-yL irnidazol-2-yi, imit!azol-4-yi, imidazoi-S-yl, thieti»2 ⁇ yl, thien-3- yl, tbiazol-2-yl, thiazoM-yb thiazol ⁇ 5-yL oxazo!-2-yI, oxazoM-yl, oxazol-5-yi, isoxazol-3- yi, isoxazoM-yi, ispxazoi-S-yi, UJ ⁇ xa iazoM- L J-oxadiazoi-S-yi I 3 t 4-oxadiazol-2- yi, 1 ,2,4-oxadiazol-3-yL l ,2,4-
  • R y when present, i methyl, benzyl, cyano, phenyl, A ⁇ eri-hutoxycarbonyl, or chloro. Even more specifically, is pyrazoi-3-yb pyraxol- 4-yl, pyrazol ⁇ 5 ⁇ yl, iniidazol-2-yl, imidazol-4-yi, imidazol-5-yl, ihien-2-yl, . ihien-3-yl,. iliiazoi-
  • R ' ' when present, is methyl, benzyl, cyano, phenyl, ⁇ '-fert-butoxycarbonyl, or ehioro.
  • R (> is tlueayl, pyrroiyl, luranyl, pyrazoiyl, thiazoiyi, isoxazolyVimidazolyi, triazoiyS, or tetrazoiyi, each of which is optionally substituted with one R ' wherein K 5 ', when present, is methyl, benzyl, cyano, phenyl, A ? -ieri-buioxyearbonyl, or e mindo.
  • R" is thien-2-yi, thicn ⁇ 3-yl, pyrrol-2 ⁇ yi, 3 ⁇ 4ran-2-yl, rurasi-3 ⁇ yl, pyrazoi-3- vL pyraZol-4-yL pyrazol-5-yl, tliiazol-2-yL tbiazol-S-yl isoxazoi ⁇ 4-yl, sniidazohS-yi, tria3 ⁇ 4ol-
  • R" is thieri-2-yl thien-3-yl, .
  • 5-cyano-thien-2-yl s 4-meihvl-Chien-2-yi, 4-methyl- tliien ⁇ 3-yl, 5-chloro-thien-5-yb 5-phenyi-ihien-2-yI, pyrrol-2-yl- A-ie/ -butoxycarbonyl- pyrrol-S ⁇ yl, N-methyl-pyo3 ⁇ 4l ⁇ 2-yi, furan-2-yi, iuran-3-yl, pyrazol-a-yi, pyra ol-4-yi, ⁇ V- benzyl-pyrazol-4-yi, pyrazol-5-y.l, thiazol-2-yI, thiazoi-5-yl, isoxazol-4-y!, imidazol-5-yl, iriazol-5-yi, or tetrazo
  • R* is ihien-2-yl, ihi ii-3-yl, pyrrol ⁇ 2-yl s . furan-2-yi , furan-
  • R b is indoi-2-yl, mdoi-3-yl, indol-4-y!, indoI-5-yl, mdol-6-yl indoi- 7-yl, benzirnidazol-2-yl, benximidazol- -yl, benzimidazol-5-yL ben3 ⁇ 4imidazol-6-yi, henzsmtdazol-T-yi, henzo teri-l-yl, benzoitmm-3-yi
  • R s is hydrogen, optionally substituted alkyl, optionally substituted cycloailcyi,- optionally substi uted ' heferoeycloalkylalkyl, or optionally substituted aryialky!;
  • X is -NH- ' R 2 is hydrogen or alky), where the alkyl is optionally substituted with one or two R* groups;
  • R '! is alkyl;
  • R* is hydrogen: R* is phenyl or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with one.
  • each R ⁇ when present is independently amino, alfcylami.no, dialkylamtno, or halo; and each R ⁇ when present, is independentl alkyL arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
  • R* is pyrazol-3-yl, pyra3 ⁇ 4ol- -yl, pyrazo! ⁇ 5-yl, iinidazoi-2- yi, kn.idazol-4-yS, imidaz(il-5-yL thien-2-yl, thien-3 ⁇ yi, thiazoi-i-yi, thiazpl-4-yI, thiazoi-S-yl, oxazol-2-yl, oxazol-4-yt.
  • oxazoi-5-yi isoxazo!-S-yL isoxaxo -yl, isoxazol-5-yi, 1 ,2,3- oxadiazol-4-yl, 1 : 2,3 ⁇ oxadiazo!-5-yi 1 ! .3,4-o. adiazol-2-yi, .1 ,2,4-oxadiazoi-3-yl, 1 ,2,4- oxadiazol ⁇ 5-yi, aran-2-yl, iiiran-3-yl, pyrro! ⁇ 2-yi, pyiTol-3-y . triazo!-4-yi, triazol-5-yl, or tetraxol-S-yl; each of which is optionally substituted with .1, 2, 3, 4, or 5 R. 9 groups,
  • R 1 is alkyl or eycioalky!; R 4 is methyl; and R" is heteroaryl optionally substituted with one or two R* groups.
  • each R* when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxyearbon l, or halo.
  • pyrazol-3-yl is pyrazol-4-yJ, pyrazol-5-yk inmiazo.l-2-yl, imidazol-4-yl, imidazol-5-yl, thieu-2-yi, thien-3-yl, thiazol-2-yl, thiazo -yl, thiazol-5-y.l, oxazol-2-yi, oxazol-4-yl, oxazol- S-yi isoxazoi-3-yL isaxazol- -yl, ssoxazoi-S-yl, i ,2,3-oxadiazol-4-yi, l ,2,3-0.xadia20l-5-y!, l,3.4-'Oxadiazoi"2-yL 1 ,2, -oxadia2oi ⁇ 3 ⁇ y[, l,2,4-0xadiazo1-5-yl, furan-2-yl, furaa-3
  • R" is hydrogen
  • R ⁇ is methyl or ethyl. optionally substitut d with, one or two 11 ' groups. Specifically each R ⁇ when, present,, is: independently h.aio, alkoxy, or haloalkyl.
  • R ! is alkyl or eye!oaiky!; ⁇ is methyl; and R is hydrogen.
  • R 1 is alky! or c cloalkyl
  • R 4 is methyl
  • R * is optionally substituted alkyl
  • the compound of formula 1 is a compound of formula ⁇ A .
  • R ! is alkyl, cycloalkyl, cyeloaikylaikyl, aryl. arylalkyl, heterocycloalkyl,
  • R" is hydrogen or alkyl
  • R " * is alkyl
  • R '" is hydrogen
  • R 3 ⁇ 4 is phenyl, acyi or heieroaryi the phenyl and h teroaryl are is optionally substituted with L 2, 3 ⁇ , 4, or 5 R ' * groups;
  • each R ' ⁇ when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy* eyano, atatpp, aikylamino,. dialkylamino., alkoxyalky!, earhoxyalkyl, aikoxycarbotiyl, aminoa!kyl, cycloalkyl, aryl, arylalkyl, aryloxy.
  • heieroeycloalkyl or lieteroaryl and where the cycloalkyl, aryl heteroeyclo Sky],, and heieroaryi, each either alone or as part of another group within R" are independently optionally substituted with 1 , , 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloaikbxy, amiao, alkyiami.no, and
  • R ! is alkyL cycloalkyl, heteraeycloalkylalkyL or arylalkyl;
  • R " is hydrogen or alkyl;
  • W is afky :
  • R* is hydrogen;
  • R*-' is phenyl or heteroaryl wherein the phenyl and heteroaryl are isjjptionally substituted with one, two, or three R groups;.
  • R is methyl.
  • ! is aikyl.
  • each R 9 when present, is independently a kyl arylalky!, cyano, aryj, alfcoxycarbonyl, .or halo.
  • R" is pynizoiyl, imidazolyt thienyi, thiaxoSyl, oxazolyl, tsoxazol l, oxadtazolyl, ftsranyl, pyrroiyi, iriamlyl, or tetraxoiyl; each of which is optionally substituted with i , 2, or 3 v groups,
  • R. 6 is pyi3 ⁇ 4zo]-3-yl t pytazot- ⁇ yl, pyrazoh5-yi, inikiazoj-2 ⁇ yl, i ida «0 4-yl, ii «idazo!-5- I, Uueft-2-yI, dvieu ⁇ 3 ⁇ vL thiaz0i ⁇ 2-yl, thiazoS-4-yl.
  • R fi is pyraziny pyrimidiayi or py idaziny! each of which is optionally substituted with 1, 2, or 3 R y groups and R' is methyl.
  • K is hydrogen
  • IV is methyl
  • R 1 is optionally -substituted alkyl, eycloalkyl or heteroeyeloaikyl
  • " is heteroaryl optionally substituted, with ⁇ . 2, or
  • the compound of formula Ha is selected form:
  • the compound of formula HA is Compound B, which is
  • the invention provides a method of treating endometrial carcinoma in a patient, comprising administering, to the patient an. dfeetive amount of Compound A, or Compound B.
  • Compound A or B is administered as a capsule or tablet pharmaceutical composition.
  • the amount Compound A or in the tablet or capsule formulation is sufficient to produce saturation of absorption administered once. daily.
  • about 10.0 mg to about 800 mg Compound A is administered as a capsule composition once daily.
  • composition once daily.
  • Compound A or B is administered as a capsule, composition once daily.
  • about 100 mg to about 800 mg Compound A or B is administered as a- tablet compbsi Hon once daily. administered as a tablet composition once daily.
  • Compound A or B is administered as a tablet composition once daily.
  • the endometrial cancer is ' advanced or recurrent.
  • Compound A or B is administered as a capsule consisting of Sua 0 capsules filled with drug substance only. There are no additional exespients 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 or B is administered as a 100, i 50, or 200 tog tablet.
  • the tablet strength will be distinguishable by shape and/or size.
  • the tablet formulation contains ' Compound A, silk fied. aiicracrystailme cellulose, partially
  • Ail three tablet strengths are manufactured from a • common blend with the composition listed in the 3 ⁇ 4 flowing Table.
  • the effective amount of Compound A ' or B that is administered in the metiiod produces at least one therapeutic effect selected fom 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 effec is an increase in overall response rate.
  • the increase in overall response r te is about 10 percent or more or higher.
  • CBR clinical benefit rate
  • the improvement of clinical benefit rate is a least about 20 percent or higher.
  • a comparable clinical benefit rate (CBR - CR (compiete remission) + PR (partial- remission) + SD (stable disease) > 6 months) ts obtained with treatment of Compound A or a pharmaceutically acceptable salt thereof .
  • the impro ement of clinical benefit rate is at least about .20 percent or higher.
  • the invention provides a method for treating breast cancer in a.. patient in need of such treatment* .comprising administering to the patient an effective amount of (A) ietroKole in combination with or a. pharmaceutically acceptable salt* ⁇ dutiom.ec,. hydrate, of solvate ' thereof; or (B) !etrozofe in combination with
  • th method comprises at least one cycle, wherein die cycle is a period of 4 weeks, wherein for each cycle in (A) the ietrozole is administered at a daily dose of about 2.5 mg and the Compound A is administered at. a daily dose in tablet form -of 400 rag; and
  • the breast cancer is hormone receptor-positive (ER- and/or POR ⁇ .
  • HER2-negaisve (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor.
  • the breast cancer is hormone receptor-positive (ER ⁇ and/or PGR ⁇ , RER2-negative (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor and the . effective amount comprises a combination of leirozoie . and
  • the breas cancer is hormone receptor-positive (ER+ and/or PGR+), HE3 ⁇ 42 -negative. (HER2--) breast cancer which is refractory to n nonsteroidal aromatase inhibitor and the effective amount eornprises a combination of letrozo!e and Compound B. therapeutic effect selected from the group consisting of reduction in size of a tumor,
  • the effective amount produces an improved clinical benefit rate (CBR) according to the equation CBR ⁇ CR (complete
  • the improvement of clinical benefit rate is one or ail of (i) about 20 percent or higher; (ii) the: therapeutic effect is an increase in overall response rate;
  • the invention provides a composition for use in treating breast cancer in a human patient., t e composition comprising a clinically proven safe and efiee live amount of letrozoie and either Compound A or a pharmaceutically acceptable salt thereof, o Compound B or a pharmaceutically acceptable salt thereof.
  • the leirozole is formulated for a daily dose of 2,5 nig.
  • the letrozoie is formulated for a daily dose of 2.5 nig and the Compound A is formulated as a tablet for a daily dose o 00 mg.
  • the letrozoie is formulated for a daily dose of .2.5 mg and the Compound B as a table for a dose of 50 mg twice daily.
  • the invention provides a kit comprising a dose of (A) letrozoie and a. dose of either Compound A, or a pharmaceutically -acceptable salt thereof, or Compound B or a pharmaceutically acceptable salt thereof
  • the kit comprises instructions for using the letrozoie, as well as the Compound A or
  • the invention provides a method of treating breast cancer in a patient in need of such treatment, comprising administering to the patient an effective amount of !etroxole in combination with Compound A.
  • the Compound A is administered as a capsule or tablet pharmaceutical composition.
  • tire amount of Compound A is sufficient to produce
  • about 200 mg to about 700 mg Compound A is administered as a capsule composition once daily.
  • Compound A is administered as a tablet composition onee daily.
  • Compound A is -administered as a capsule consisting of Size capsules filled with drag substance only. There are no additional excip&nls other than the capsule gelatin and coioring agents.
  • the composition of the hard gelatin capsule shell and color demarcation are presented in the table below.
  • Compound A is administered a a 100, I SO, or 200 mg tablet.
  • the tablet strength will be distinguishable b shape and/or size.
  • the tablet formulation contains Compound A, siiieified macrocrystalline cellulose, partially pregeiatinized maize starch, sodium starch glyco te, hypromcUose, colloidal silicon dioxid stearic acid, and magnesium stearatc. All three tablet strengths are manufactured from: a common blend with die composition listed in the following Table.
  • the invention provides a method of treating breast cancer in a patient in need of such treatment, comprising . .administering to the patient an effective amount of letroxole in combination with Compound..8 ⁇ ,
  • the Compound B as a capsule or tablet pharmaceutical composition.
  • the ' amount of Compound Bin th tablet or capsule formulation is sufficient to produce saturation of absorption when administered once daily.
  • f.O02 i ⁇ jij the amount of Compound B in the tablet or capsule formulation is sufficient to produce saturation of -absorption when administered twice daily.
  • 00217 j about 10 mg to. about 100 mg Compound B is administered as a capsule composition twice daily.
  • Compound 8 is administered as a capsule composition twice daily.
  • Compound B is administered as a capsule composition twice daily.
  • composition twice daily in another embodiment, about 30 mg Compound B is administered as a capsule composition twice daily. composition twice daily.
  • Compound B is administered as a capsule composition twice daily,
  • Compound 8 is administered as a capsule composition twice daily.
  • Compound A is administered as a capsule consisting of Size-0 ca sules filled with 10. 30 or 40 m 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 invention provides pharmaceutical compositions comprising an inhibitor of the PDRs of Formula I or II and a pharmaceutically acceptable carrier, exeipiem, or diluent.
  • administration is by site oral route.
  • Administration cau be, for example, orally, .nasally, parenteral ly (intravenous, intramuscular, or subcutaneous), topically, transderoaliy, mtravaginaiiy, iiitravesicaliy, intracistemaliy, or reetaliy, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and har -geiada 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 carrie or exeipient and a Compound of Formula I or If as the/an. ac tive agent.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, arid, dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and -antifungal agents, for example, pant bens, ehforobmanoi, phenol, sorbie 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 ean 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 subs tances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorts-tan uioiioUuiraie, triethanolamine oleate, butylaled hydroxytoluene, etc.
  • auxiliary subs tances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorts-tan uioiioUuiraie, triethanolamine oleate, butylaled hydroxytoluene, etc.
  • the choice of formulation depends on various factors such as the mode of dru administration (e.g., for oral administration, formulations in the form of tablets, pills or capsiil.es) and the bioavailability of the dru substance.
  • pharmaceutical formulations have been developed especially for -drugs that show poor bioavailability based upon the principle thai bioavailability can be increased b -increasing the surface area i.e., decreasing panicle size.
  • U.S. Pat. No.. 4, 107,288 describes ⁇ . pharmaceutical formulation having particles in the size range from 10 to 1 ,000 ran in which the active material is supported on a crossl inked matrix of macromoleeuies. li.S.
  • Pat, No, 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 am) in the presence of a surface modi bomb and then dispersed hra liquid medium; to give pharniaceutical ibnmiiation that exhibits remarkably high bioavailability, acceptable sterile aqueous. r nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitute ri into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers examples include water, etlianol,. polyols ipropylenegiyeol, poiyethyie.neglyeol., glycerol, and the like), suitable mixtures thereof, vegetable oils (such s olive oil) and injectable organic esters such as ethyl oleate.
  • etlianol etlianol
  • suitable mixtures thereof examples include vegetable oils (such s olive oil) and injectable organic esters such as ethyl oleate.
  • vegetable oils such s olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as leci thin, by. the maintenance of the required particle
  • One specific route of administration is oral, using a convenient daily dosag 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, pill ' s, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sotf ium. citrate or dicaieium phosphate or (a) .fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol.
  • binders as for example, cellulose derivatives, starch, aiignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia,
  • hismeetants as for e ample ; , glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca tarch, alginie acid, erosearme ' Hose sodium, complex silicates, and sodium carbonate, (e).
  • solution retarders as for example paraffin
  • accelerators as for example, quaternary ammonium compounds
  • wetting agents as fo example, cetyl alcohol, and glycerol monostearaie.
  • magnesium stearate and the like adsorbents, as for example, kaolin and beuionite, and lubricants, as for example, tale, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium laaryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • Solid dosage forms as described above can be prepared with coatings ami shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, nd can also be of suc /composition thai -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- orm, if appropriate, with one or more of the above-mentioned exeipients, 002381
  • Liqu id dosage forms ib ' r oral • administration include pharmaceutically acceptable emulsions, solutions,, suspensions, syrups, and elixirs.;
  • Such dosage orms are prepared, for pharmaceutically acceptable, salt thereof,. and optional, pharmaceutical adjuvants in a carrier, such as, for example, wate , .saline, -aqueous dextrose,- glycerol, ethanol and the like;
  • solubilizmg agents and emulsifiers as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benfc l alcohol, -.benzyl benxoate, propylenegiyeoL
  • .oils in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrot rftayl alcohol,
  • Suspensions in addition to the active compounds, may cont in suspending agents, as for example, ethoxyiated isostearyl alcohol s3 ⁇ 4 pojyoxyethy e sorbitol and sotbiian esters, krocrystallme cellulose, aluminum metahydroxide». bentonite, agar-agar and tragaca th, -or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxyiated isostearyl alcohol s3 ⁇ 4 pojyoxyethy e sorbitol and sotbiian esters, krocrystallme cellulose, aluminum metahydroxide». bentonite, agar-agar and tragaca th, -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 exeipients or carriers such as cocoa butter, poiyetbyleneglycoi or a suppository wax, which are solid at ordinary temperatures but liquid at. body .temperature and therefore, melt while in a suitable- bod cavity and release the active component therein.
  • suitable non- irritating exeipients or carriers such as cocoa butter, poiyetbyleneglycoi or a suppository wax, which are solid at ordinary temperatures but liquid at. body .temperature and therefore, melt while in a suitable- bod 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 propelkmts a ⁇ may be required.
  • Ophthalmic ibnnulations, eye ointments, .powders, and isolations 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% b weight of a compound(s) of the invention, or a phannaceutically acceptable salt thereo f, and 99% to .1% by weight of a suitable pharmaceutical exeipient.
  • the composition will be between about 5% and about 75% by weight of a eonipound(s) of the invention, or a
  • the compounds of Formula ⁇ or la, or their pharmaceutically acceptable salts or solvates are administered in art .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, drag combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of Formula i or 0. can be administered to a patient at dosage levels in the range of about ( ) , 1 to about 1 ,000 mg per day, or i the range. of 100 mg to SCO mg per day, orin the range of 200 to 700 mg per day, or in the range of 300 t 600 mg per day,
  • a dosage in the range of about 0.01 to about 1.00 rng 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 o f the condition being treated, and- the pharmacological activity of the compound being used.
  • the determination of optimum dosages fo a particular patient is well known to one of ordinary skill in the art. If formulated as a fixed dose, such combination products emplo the compounds, of this invention within the dosage range described above and the Other
  • Compounds of Formula i or H may alternatively be used sequentially with known.pharraaceutically acceptable agent(s) when a "combination formulation is inappropriate.
  • the effective amount 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 effec tive amount produces an improved clinical benefit rate (CBR ⁇ CR (complete ' remission) PR (partial remission) * SD (stable disease) > 6 months), in some embodiments, the improvement ' of clinical benefit rate is about 20% or higher. In some embodiments, the improvement of clinical benefit rate is at least about " 20%, 30%, 40%, 50%, 60%, 70%, S0%, or more.
  • the therapeutic effect is an increase in overall response rate. In some 70%, 803 ⁇ 4 or more,
  • the improvement of clinical benefit rate is at least about 20%, .In some embodiments, the improvement of clinical benefit rate is at least, about 30%. in some embodiments, the improvement of clinical benefit rate is at least about 40%. in some embodiments, the improvement of clinical benefit rate is at- least about 50%. in some embodiments, the i pr v ment of clinical benefit rate is at least about 60%, in some embodiments, the improvement of clinical benefit- rate is at least.abo ' ut 70%. In some embodiments, the improvement of clinical benefit rate is at. least- bout 80%,
  • a comparable clinical benefit rate (CBR— CR (complete remission) + PR (partial remission) 4 ⁇ SD (stable disease) :6 months) is obtained with treatment of a) Co poun A or B or a pharmaeeuticaily acceptable salt thereof.
  • the improvement of clinical benefit rate is at least about 20%.
  • the improvement of clinical benefit rate is at least about 30%.
  • the improvement of clinical benefit, rate is at least about 40%,
  • the improvement, of clinical benefit rate is at least about 50%.
  • the improvement of clinical benefit rate is at least about 60%.
  • die improvement of clinical benefit ate is at least about 70%.
  • the improvement of clinical benefit rate is at least about 80%.
  • the starting -materials and she intermediates of the reaction- may be isolated and purified: if desired .using conventional techniques, including but not. limited to filtration, distillation, erystailiz3 ⁇ 4ti6r-,. chromatogra hy and the like. Such materials may he characterized using conventional means, including physical constants and spectral data.
  • the compounds of the invention may have asymmetric carbon atoms o quatermzed nitrogen atoms in thei 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 dtastereoniers.
  • the compounds may also exist as geometric- isomers. Ail such single stereoisomers, raeemates find mixtures the eof, and geometric isomers are intended to be within, the scope of this invention.
  • om of the compounds of the.- invention may exist as tautomers.
  • the molecule may exist in the ' euol form; where an amide is present, the molecule may exist as the iuiidle acid; and where an enamine is present, the molecule ma offers a inline. 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
  • ring-B in can be 2- hydroxy-pyridmyi, also described as its structure:
  • Compound A-2 is named N-(3 ⁇ i[(2Z) ⁇ 3 ⁇
  • iaiitomeric forms can mt rconvett
  • mterconverskm can also exist between the uncharged tautomeric forms and the xwitterionic forms.
  • each taiiiomcr or KwittcrioTJ is included withi herein, the structure
  • the present invention also includes -oxide derivatives and protected derivatives of compounds of Formula f.
  • the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • compounds of Formula I contain groups such as hydroxy, earboxy, thiol, or any grou -.containing a - nitrogen aiomfs), these groups can be protected with a suitable "protecting group” or "protective group," A comprehensive list of suitable protective Softs, I nc. 19 1 , the disclosure o f which is incorporated herein -by reference in its entirety.
  • the protected derivatives of compounds of Formula I can be prepared b methods well known in the art.
  • stereoisomers f rom raeemic mixtures or son-raeemie mixtures of stereoisomers are well, known in the art.
  • -optically active (R.) ⁇ and (S)- isom r may be prepared usin chirai sytuhons or chirai reagents, or resolved using conventional techniques
  • Enantiomers (R- and S-isome t s ⁇ may be resolved by methods known, to one of ordinary skill in. the art.
  • i niz ti n ofdiastereoisorrierie salts or complexes which may be separated, for example, by-crystallization; via formation of diastereoisomenc derivatives which may be separated, for example, by crystallisation, selective reaction of one enantiomer with an enautiomef" specific reagent, for example enzymatic oxidation or reduction, followed, by separation of the modified and unmodified enantiomers; or gas-liquid or liquid
  • enantiomeric form Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomers enriched in particular enantiomer, the major component enautiorner may be further enriched (with concomitant loss in yield) by reerystei!ization.
  • the compounds of the present invention can exist in unsolvated a well as solvates.) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the soivated 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 !ieating an appropriateiy substituted quinoxalmc (for example, commercially available 2,3-diehioroq:uino aliiie) and an appropriately substituted sulfonamide of formula 2 are -c mmereiaUy available or can be prepared by one of ordinary skill in the art), a base sueh as K2CO5, in a solvent, such as DMF or DM SO. Upon completion (about 2 hour ' s), the reaction mixture is then poure into water and followed by 2 N HCI.
  • an appropriateiy substituted quinoxalmc for example, commercially available 2,3-diehioroq:uino aliiie
  • an appropriately substituted sulfonamide of formula 2 are -c mmereiaUy available or can be prepared by one of ordinary skill in the art
  • a base sueh as K2CO5 in a solvent, such as DMF or DM SO.
  • the product is then extracted into a solvent such as ethyl acetate nd washed with water and brine.
  • a solvent such as ethyl acetate nd washed with water and brine.
  • the organic layers are combi ed and dried over a drying agent sueh as sodium, sulfate, filtered, and concentrated under -vacuum to provide a compound of formula 3.
  • LG is a leaving group such as ehloro.
  • Compound 5 is reacted with NH J ' or where R 8 and R° are independently hydrogen or alkyi. The reaction, is carried out in die presence of a base, such as KMCO3, in a solvent such, as DMF.
  • reaction is carried out in the presence of a base such as Naff in a solvent such as DMF.
  • R' is as defined in the Summary of the Invention:
  • R SSa where R i8 , K ⁇ and R , are as
  • HOC(0)-CrC is -aik ⁇ lene.N(R !S3 ⁇ 4! )C(O)R i * a ;
  • NiR ' ⁇ R* The reaction, is carried oui under standard- amide coupling conditions known to one of ordinary skill in the art. In particular, die reaction is earned out in the presence of a coupling ageat such as I!ATU. a base such as DFEA, and in a solvent such as 0MV. Where applicable, the -proieciing 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 wit H ⁇ R ' h )R presence of a base, such as DIEA, in a solvent such . as ACN.
  • LG in Scheme 6 is a leaving group such as chloro.
  • the reaction can be earned out by irradiating in a -solvent such, as DMA.
  • the reaction can be carried out in the presence of acetic add in a solvent such as DMA and by heating.
  • Preparative reverse-phase HPLC was used to isolate die desired, product directly from th crude reaction mixture.
  • a Waters Fracti miynx preparative reverse-phase HPLC equipped with a Waters SunFire Prep C IS, OCD 5 iiM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 m . ammonium acetate in watemveetorikrile; was used- to carry out the purification.
  • a CB microwave reaction vessel was charged with N ⁇ ( ⁇ N-Q- cidoroquinoxalin-2- l)siiSfa.moyl)phenyl)-2 ⁇ (30 mg, 0.071 mmoi), prepared -using procedures similar to those described in Example 374, the desired aniline ( 36 mg. 0.14. mraol, 2 eq), and 0.5 mL of dimethylacetamide.
  • the vessel was sealed and the Discover mierowave instrument. The solvent was then removed by roiary-evaporatiori. Purification of the filial product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NR+OAe ACN to the desired product.
  • Example 374 prepared usin procedure similar to those ia Example 374.
  • the desired aniline (0.56? mmol, 4 e3 ⁇ 4),-and 1.0 mL of toluene * '
  • the vessel was sealed and the reaction mixture wa heated under microwave .radiation for 60 mm at I SO *C hi a CEM Discover mierowave instrument.
  • the solvent was removed on a rotary-evaporator. Purification of the final product was done, by preparatory HPLC with. NM OAC/ACN as eluem to yield the desired produet.
  • Fractionlynx preparative reverse-phase HPLC equipped with, a Waters SunFire Prep CI 8, OCD 5 ⁇ , 30 X 70 mm column and running .a 5-1.00 % gradient with a binary solvent system of 25 raM ammonium acetate in waten'acetomtnle; W used to cany out the purification.
  • Compounds of Formula ⁇ 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 Chemieai.Go, (Milwaukee, Wis,) or Sachem (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 1-1.7 (John.
  • the starting materials and the ' intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterised using- conventional means, .including physical constants and spectral, data.
  • the reactions described herein take place at atmospheric pressure- nd o ver a temperature range, from about. -78 C to -about S 5() '! C, more specifieally from about ( j C to about 125 " C and more specifically at about room (or ambient) temperature, e.g., about 20 °C. Unless othe ' wise stated (as in. the case of an hydrogeaation),, all reactions are performed under an atmosphere of nitrogen.
  • Prodrugs can be pre ared 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 i?? viva. Amides and es ters of the compounds of the present invention may he ' prepared according to conventional methods. A thorough discussion of prodrugs is pro vided in T Higuehi and V. Stella, "Pro-drugs as Novel Delivery Systems, *5 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 ⁇ that may be prepared, through the syntheses described herein may exist as single stereoisomers, raeemates, and as mixtures of enantiomers and dsastereotuers.
  • the compounds may also exist as geometric isomers. Ail such single stereoisomers, mcemaies and. mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • Some of the compounds of the invention ma exist as lautome ' rs.
  • the molecule may exist in the enol form; where an amide is present, the molecule may exist as the iraidic acid; and where an enamine is present, the molecule may exist as an iraine.
  • All such tautoraers are within the scope of the invention, in particular, hnidazoI-3-yl and pyrazol-S-yi each can also exist in their respective tautomeric forms t .i a;ioi-4-yl and pyrazol-3-yL Regardless of which structure or which terminology is used, each automer is included within the scope of the invention,
  • the present invention also includes -oxide derivatives and protected derivatives of compounds of formula 11,
  • compounds of formula 1 when compounds of formula 1 contain an oxidtzable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the ar
  • compounds of formula I when compounds of formula I contain groups such as hydroxy, earhoxy, 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 TvW. Greene, Protective Groups in Organic Synth ix,. John Wiley ⁇ 3 ⁇ 4 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 knewn i.n the art.
  • stereoisomers from racemic mi xtures or non-racemie mixtures of stereoisomers are well known, in the art.
  • optically active (!3 ⁇ 4 ⁇ )- and (Sj- isomers raay be prepared using ehiral synthons or ehiral reagents, or resolved using conventional techniques.
  • ⁇ -isomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of d iastereo isomeric salts or complexes which raay be separated, for example, by crystallization; via formation of diastereoisomerie derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantlomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantioniers; 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 con verting one enantiomer to the other by asymmetric transformation.
  • the major component enantiomer may be further enriched (with concomitant loss in yield ⁇ by reerystaUization.
  • the compounds of the present invention can exist in unsolvated as well as soi.vated forms with pharmaceutically acceptable solvents such -as water, cthanol, and the like, in general, the solvated forms are c nside ed equivalent to the ⁇ unsolvated forms for the purposes of the present invention,
  • An intermediate of formula 2 is prepared by reacting -tut intermediate of formula i. with .a; primary amine R ! i ⁇ ki a solvent such as water and with heating, 2 is then treated with iodine moaoehioride in a solvent such as methanol at around 0 "C and allowed to react for approxim tely overnight or less as needed for the reaction to o to completion to form 3, Alter completion the residue is triturated with acetone.
  • the intermediate 3 is then reacted in solvent, such as DMA, with ethyl actyiate in the presence of a ba e, such as triethyi amine, and in the presenc of a catalyst, such as Pd(OAc); s . and ( ⁇ )BINA P.
  • solvent such as DMA
  • ethyl actyiate in the presence of a ba e, such as triethyi amine
  • a catalyst such as Pd(OAc); s . and ( ⁇ )BINA P.
  • the reaction i 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.
  • 1 . 00307 ⁇ 5 is prepared b 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
  • 10030$ 6 is prepared by reacting 5 with a .brom mating agent such as Br3 ⁇ 4 in a solvent such as .OCM. 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 ' aftd treated with a ase suclias irieth lainine. The mixture is then washed with water and dried over a drying, agent such as NajSCk to yield 6.
  • a .brom mating agent such as Br3 ⁇ 4 in a solvent such as .OCM.
  • a Suzuki, coupling is then ' .performed usin 6 and a boronie acid (or ester) of formula R (1 B(C)H); in a solvent(s) such as a DMB-3 ⁇ 40 mixture in the presence of a catalyst such as Pdidppp ) and a base such as trie thy lanaine at room temperature.
  • the reaction mixture is ..heated to reflux for approximately 4 hours-. After cooling to room, temperature, the reaction mixture is- artitioned with, water and ethyl acetate. After separation, the organic layer is dried over a drying agent such as r1 ⁇ 2S ⁇ 1 ⁇ 4 to yield 7.
  • An intermediate of formula is prepared fay reacting an intermediate of formula 8 with neat FOCI 3 and heating. 9 is then treated with a primary amin R ! NH ; > in a solvent such as water or THF and. trieihylamine at 0 U 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 iltrthor purification.
  • An intermediate of t rmisia 14 is prepared by reacting an intermediate of formula 13 with a primary amine 'NHj* in a solvent such as water and with heating. 14 is then treated with iodine monoehloride 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 tp 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 acryiate in the presence of a base, such as triethyi amine, and in the presence of a catalyst, such as PDFOAc) ⁇ . and (+)Bi AP.
  • a solvent such as DMA
  • An intermediate of formula 20 is prepared by reacting an intermediate of formula 19 with neat PQt3 ⁇ 4 and heating. 20 is then treated with a primary -amine ' R'Nj3 ⁇ 4 in a solvent such as water or THF and tnethyiminne at 0 "C to form 21. After removal of the solvent under reduced pressure, the intermediate 21 is then reacted wit lithium-aluminum hydride hi a solvent such as THF at 0 "C, Alter quenching and aqueous workup, solvent removal provides crystalline 22 without, further purification. Treatment of 22 with, manganese (H) dioxide in a solvent such as methylene chloride or chloroform at room temperature provides aldehyde- 23 -upon filtration and solvent removal.
  • H manganese
  • a Knovenegal-type 'Con ensation with 23 and an arylaceio trile in the presence of a base such as ⁇ potassium carbonate or sodium hydroxide in a pro tic solvent provides the eyefeed trains 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 ' ' corres ondin suIJ ' one with »i-CPBA at room temperature and displaced with ammonium to provide 1.
  • stage 2 A two-stage Phase 2 study is conducted to evaluate the safety and efficacy of Compound A in subjects: with endometrial carcinoma.
  • stage 2 a tablet ibrmulat n- will be used, A 400-mg tablet was chosen as the phase 2 dose based on the observation that the exposure at this dose level was similar to the MTD of capsules at 600 mg.
  • the primar objectives of this .study are to evaluate the co-primary efficacy endpoinis; of ( t ) objective tumor re.spon.se nvte (ORR) (co finn d complete response [CR] or confirmed partial response PR)); and 2) rate of 6-month (183 days) progression-free survival (PFS6), in subjects receiving Compound A Tor ad vanced or recurrent EC aad to evaluate the safety and tokrabllity of Compound A in this population.
  • ORR objective tumor re.spon.se nvte
  • PFS6 progression-free survival
  • PB /PTEN patiiway cosnponents/modolators eg, P1K3CA inutation ampSifieation, PTEN deficiency
  • P1K3CA inutation ampSifieation, PTEN deficiency eg, P1K3CA inutation ampSifieation, PTEN deficiency
  • the study was initially designed as. a two-stage Phase 2 study to evaluate safety and efficacy of Compound A with co-primary efficacy endpoints of ORE and PFS6.
  • Part 1 approximately 80 subjects were to be enrolled to obtain 71 evaktabSe subjects per protocol.
  • Stage I enrolled 3? evaiuable subjects. If at least four subjects had achieved an objective response (a confirmed PR or a confirmed CR) or at least seven subjects were- alive and progression free for at least 6 months, then the study would have continued to Stage 2 until 71 evaiuable subjects (including both stages) " have been, enrolled.
  • Part 2 As of amendment 3 (Part 2), approximatel 45 additional patients will be enrolled to obtain a total of approximately 75 per protocol evaiuable patients (including those enrolled in Part 1 ⁇ .
  • the primary interest of Part 2 is the estimation of ORR and PFS6 for all patients meeting the Amendment.3 .mciusion/ ' exciuskm criteria.
  • biomarkers thai may predict increased frequency of response or longer disease stabilization. If molecular profiling data obtained during the course of the stud -suggests a predictive .markers] for response or disease stabilization, up to 15 additional subjects; with this tunior-j ioraarker'"sigtta$ui3 ⁇ 4" will be enrolled.
  • Qualifying screening assessments must occur wi thin 21 days before the first administration of stud drug; a subset of screening assessments may also be considered the Study Da I pre-trcatment evaluations if done within 4 days before ini ial dosing.
  • Treatment Period Subjects are treated and monitored for safety ⁇ ncluding laboratory assessments), signs of toxicity, progressive disease (PD), and
  • Tumor assessment visits for each subject will be after Week 8, Week in, and Week 26 following the first dose of study drug, and every JO -weeks thereafter. During Week 9 and beyond subjects mast return to the study site for tumor -assessment visits that may not coincide with- equired, elude visits,
  • Post-Treatment Period Subjects return to the study site between 30- nd
  • radiographic PD death, or the initiation of subsequent anticance therapy.
  • an additional 15 subjects whose tumors exhibit this- biomarker signature may be enrolled.
  • the subject has a histologically continued diagnosis of EC (endometrioid, serous, clear cell adenocarcinoma, adenosquamous carcinoma, or mixed histology, any grade ⁇ that is advanced (ie, persistent, locally advanced) or recurrent and is incurable- by standard therapies, and ha received one platinum-based chemotherap regimen for EC.
  • EC endometrioid, serous, clear cell adenocarcinoma, adenosquamous carcinoma, or mixed histology, any grade ⁇ that is advanced (ie, persistent, locally advanced) or recurrent and is incurable- by standard therapies, and ha received one platinum-based chemotherap regimen for EC.
  • the subject is at least 18 years old,
  • the subject has an Eastern Cooperative: Qneology Grou f ECOG) performance; status of 0 or 1 ,
  • the subject has at least one lesion that is measurable on computerized tomography (CT) or magnetic resonance- -imaging (M.RTJ scan determined by investigator per RECIST
  • CT computerized tomography
  • M.RTJ scan magnetic resonance- -imaging
  • a lesion within a previously radiated field is only considered measurable if there has been demonstrated progression in the lesion and documented by:
  • the subject has organ and marrow function as follows:
  • Serum creatinine ⁇ 1 ,5 x ULN calculated creatinine clearance > 60 aiL niin, or glomerular .filtration rate > 40 ml./min
  • ALT Alanine atnwptn sfetase
  • AST aspartate aminotransferase
  • the subject is capable of understanding the informed consent and complying with the protocol and lias signed the informed consent document before any study-specific screening procedures or evaluations are performed.
  • -Sexually active subjects must agree t use a medically accepted barrier method of contraception (i.e., male condom or female condom ⁇ during the, course of the ⁇ study and for 3 months following discontinuation of study treatments.
  • a barrier ' method and a second method of contraception must be used.
  • Horm al contraceptives are discouraged because of. a possible decrease in effectiveness due to a possible drug-dru interaction,
  • Subjects of chiidbeanng potential must have a negative pregnancy test at screening.
  • Subjects of chiidbeanng potential are defined as premenopausal subjects capable of becoming pregnant (i.e.. subjects who have had any evidence of menses in the past
  • the subject has previously been treated with a PB inhibitor, mTOR inhibitor, or AKT inhibitor.
  • the subject has uterine sarcomas (leiomyosarcoma),, mixed uUerian tumors, squamous carcinoma of the uterus, and/or adenosarcomas of the uterus.
  • uterine sarcomas leiomyosarcoma
  • mixed uUerian tumors squamous carcinoma of the uterus
  • adenosarcomas of the uterus adenosarcomas of the uterus.
  • Cytotoxic chemotherapy including investigational cytotoxic agents
  • biologic agents antibodies, immune modulators, cytokines
  • nitrosoureas or mitomycin C within 6 weeks, before the iirst dose of Compound
  • a small-molecule kinase inhibitor (including investigational small-molecule ' kinase inhibitors) within 2 -weeks, , or five half-lives of the drug or active metabolites, whichever is longer, before the first dose of Compound A:
  • the subject has a known primary brain tumor or brain metastasis.
  • the subject has any other diagnosis of malignancy or evidence -of malignancy (except noiwmdanoma skin cancer or in situ carcinoma of the cervix) within 2 years before screenin for this study.
  • the subject has a diagnosis of uncontrolled diabetes mellitus (glycosylated hemoglobin AIC > 8%) or has a fasting plasma glucose > 160 nig dL,
  • The- subject is currently receiving anticoagulation with therapeutics doses of warfarin (low-dose warfarin ⁇ 1 nig/day is permitted).
  • the .subject has prothrombin time (:PT ⁇ interaa tionid normalized ratio f l Il ⁇ or partial thromboplastin time (FIT) test results at screening that are above 1.3 ⁇ the laboratory ULN.
  • prothrombin time :PT ⁇ interaa tionid normalized ratio f l Il ⁇ or partial thromboplastin time (FIT) test results at screening that are above 1.3 ⁇ the laboratory ULN.
  • the subject has uncontrolled, significant intercurrent illness including, but not limited to:
  • the subject has a baseline corrected QT interval 470 ms
  • the subject is known to be positive for the human iromwiodefrcieney virus (HIV).
  • HAV human iromwiodefrcieney virus
  • the subject is pregnant or breastfeeding:.
  • the subject has a previously identified allergy or hypersensitivity to components of the study treatment f rmulatioE.
  • Compound A will be supplied as 100 mg capsules or 100, I SO, and 200 mg tablets. Compound A will be administered at a dose of 600 mg once daily ⁇ capsule) or 400 mg once daily (tablet).
  • Tumor assessments will be performed within 28 days before the first dose o study drag , and after Week 8, Week 16, and Week 26 following the first dose of study drag, and every 10 weeks thereafter until the earlier oi documented radiographic P , death, or the initiation of subsequent anti-cancer therapy. Response and progression will be determined per ECiST Version 1.1. Responses will be; confirmed by repeat assessments that should be performed 28-35 days after the response criteria are met.
  • Evaluation of baseline disease will include a physical examination, a screening chest x-ray and/or a chest CT scan, an abdominal-pelvic CT or MR! scan, and a tumor .marker CA125 assessment. All tumor lesions must be assessed by GT or MRI scan and physical examination (if appiieable) at each evaluation during the study.
  • IRC Independent Review Committee
  • Safety will be assessed by evaluation ' of adverse events (AEs), vital signs, electrocardiogram, laboratory 1 tests, and concomitant medications. Adverse event seriousness, severity grade, and relationship to study treatment will be assessed by the investigator.
  • CCAE Criteria for Adverse Events v3,0
  • Blood samples will be obtained at predetermined time points for Compound A plasma conce trati n assessments.
  • PK. samples will also be . collected, if possible, at the 30-day visit during the Post-Treatment Period and whenever a subject has study drug-related SAE(s) (e.g., skin, rash) and or is withdrawn from the study. [00335. ⁇ Detailed instructions for sample preparation and shipping will be provided, in a separate Pharmacokinetic- Laboratory Manual
  • Blood, tiunor tissue, and non-lurnor tissue (collected at. the same time as tu or tissue) will -be obtained from consented subjects for analysis of a variety of established and exploratory phaniiacodynamic markers- on. a defined schedule throughout the study.
  • Pharmacodynamic studies may include investigation of the impact of target mutations (PI3K. catalytic -and/or regulator;-' subunits) pre-existing in the subject's tumor on response, fluctuation of plasma levels of pathway-relevant proteins (e.g.. vascular endothelial growth factor A fVEGF-A], glucose, and insulin), drag-induced changes in phosphorylation of signal -transduction proteins and lipids (e.g... pEGFR, pAKT. pPRK, pGS . and P1.P3 as well as assess ment of the contribution of complementin genet ic changes in targe t modulators (e.g commencing PTEK RAS, c- ET, HER2, and L B- ' l) on efficacy
  • the co-primary efficacy cudpoints are: 1) ORE, defined as the proportion of subjects for whom the beat response is a confirmed CR or confirmed PR, and 2) PfS defined as- the proportion of subjects who survive and are- progression free at least 83 days after the date of the first dose of study ding, Delermmation of response and progression will be- based on -evaluation per RECiST Version 1.1 ,
  • AEs will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred terms. Laboratory test results will be evaluated with respect to changes from baseline
  • letrozole and of t he combination of Compound B with ktrozole Phase 1 and Phase 2.
  • CB clinical benefit rate
  • PBR/ mTOR inhibitor (Ami .2) in combination, with, ietrozoie based on. molecular pro tiling of tumor tissue (Phase" 1 a d Phase 2).
  • Phase L subsequent subjects will be enrolled in Phase 2, As of Amendment 3, the doses for Phase 2 are 400 mg qd of Compound A (Arm 1) .and 50 mg bid . ' of Compound B, both in conibii stioo with letrozole 2.5 rag qd.

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