EP2755654A1 - Phosphatidylinositol 3-kinase inhibitors for the treatment of cancer - Google Patents
Phosphatidylinositol 3-kinase inhibitors for the treatment of cancerInfo
- 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- Withdrawn
Links
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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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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Abstract
The invention provides a method for treating endometrial carcinoma comprising administering a Compound of Formula (I) or (II). Also provided is a method for treating breast cancer, comprising administering letrozole in combination with either a Compound of Formula (I) or Formula (II).
Description
CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
{Θ0Ο!} This application claims the benefi t of priority of U.S. Provisional Application No. 61 33 3$, filed September 14. 201 1, U.S. Provisional Application No..όΤ/543:,5 9-, filed October 5, 201 1 , and U.S. Provisional Application No. 61/562,670, November 22, 201 1 , ail. of which are incorporated herein: by reference.
BACKGROUND
(0002) 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.
(American Cancer Society 2008).
(0003| 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. 2005; Doll et al, 2008: Gadducci et al, 2008), Type Π 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).
|0() 4| Standard therapy tor newly diagnosed patients includes Surgery, radiation, hormone therapy, and chemotherapy. There has not been any treatment approved in the
United States or in Europe ibr adjuvant treatment of advanced or recurrent EC. Cispiatim
combination for the treatment of primary advanced and recurrent disease. Overall response rates were higher in combination studies than with single agent studies, Paeiitasel in combination with carboplatin is increasingly being used as the preferred regimen in advanced and refractory EC based on a favora le toxicity profile and on relative treatment convenience (Akram etal. 2005; Scudder e ill. 2005). However, toxicity associated with chemotherapy remains problematic and challenging in the therapeutic field of EC
{0005} Clinical studies ha ve suggested that response to chemotherapy in EC varies from 17 to 78% in recurrent and advanced disease and is not associated with histologic subtypes. In general,, higher response rates to chemotherapy did not correlate with improved survival benefit in EC. However, a randomized controlled trial, comparing the addition of paclitaxel to doxorubicin and cisplatm with, doxorubicin an eisplatin has demonstrated an improved survival benefit (median survival of 5.3 versus 12,$ months) associated with an improved response rate (57% versus 34%). Data on progression-free: survival (PFS) and overall survival have been reported in multiple clinical studies comparing chemotherap regimens in advanced or recurrent EG. The median overall survival varied from 7 to 15 months, and the median PFS varied from 2.5 to S months (Carey et al 2006; Humher et !. 2007; McMeekin et al. 2007),
10006] Approximatel two-thirds of breast cancers exhibit hormone-dependent growth, primarily involving estrogen, and inhibition of estrogen activity is an important treatment strategy for patients with estrogen receptor -positive (ER+) breast cancer (demons et al. 2001). Adjuvant .therapy for S years with tamoxifen, which blocks ER activat ion, has been standard therapy after primary' treatment Aromatase inhibitors prevent estrogen-mediated breast cancer stimulation through suppression of estrogen biosynthesis rather than by blocking activation of the ER and effectively reduce total estrogen synthesis after menopause (Geisler et al. 2002). 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.
}0007J Letrosiole specitically blocks production of estrogens by competitive, reversible binding to the heme of the cytochrome P450 subunit of the enzyme aromatase. Letrozole has been shown to be more effective in die treatment of metastatic breast cancer and in neoadjuvant and adjuvant 'settings than tamoxifen (Ellis et al. 2001; Mouridsen et al. 2003;. The Breast International Group [BIG] -9S Collaborative Group 2005). Lelrozole is indicated
early breast cancer, for the extended adjuv nt treatment of earl breast, cancer in
postmenopausal omen who have received 5 years of adjuvant■■tamoxifen therapy, for first- line treatment of posnnenopausal women wit hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer, and for the treatment: of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. Aromatase inhibitors such as lejrozole are effective in treatment o hormone receptor-positive breast cancer; ho wever, many minors become resistant t aromatase inhibitors. As a result,, a need remains for new therapeutic options for the treatment of breast cancer, paniciilariy hormone receptor-positi ve (ER+ and/or progesteron receptor positive (PGR*)} or HERl-negative (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor.
|OO08J As -a result, despite the generally favorable prognosis of early stage EC, there remain unmet medical needs for less toxic and more effective therapies in patients with advanced or recurrent disease,- A need also remains for new 'therapeutic options for the treatment of breast cancer, particularly honnonc receptor-positive (ER- and/or progesterone receptor positive (PGR+)) or RER2-negative (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor.
SUMMARY
10009] Accordingly, methods are provided 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:
where the Compound of
wherein:
~N= an .the remaining are -C(Rf }:;:;; 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;
" is hydrogen or halo;
Rii!, R55, and RS i are independently hydrogen, a!kyi, alkenyl halo, haioa!kyl, ha!oaikenyl hydroxy, alkoxy, alkenyioxy, haloalkoxy, niiro, amino, alkyiarnmo, dialkylamino, -N(R55}C(0)-CrC6-alkyleac- (R )R5¾ } alkylc'srfomyl, alkenykarhonyl, earboxy, aikoxyearbonyi, cyano, a!kyifhio,
and R>>B are independentit hydrogen, atkyl, or alkenyl and ^ is hydrogen, alkyl alkenyl hydroxy, or alkoxy; or Rs" 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 R3;
R'3 is cyano; hydroxyamino; carboxy; aikoxyearbonyi; alkylaraino; dialkylamino;
alkylearhonyk haloalkoxy: alkylsulfonyl; aminoaikyloxy; alfcylaminoa!kyloxy;
dialkyiaminoaikylOxy; or
a) - (R7}C(0)-CrG aikyiene-N(R¾)(R?¾ where R7 is hydrogen, alkyl, or alkenyl and R'a and R'* are independently hydrogen, alkyl, alkenyl, hydroxyalkyl hatoaikyl, alkoxy, alkoxyalkyl,. aminoalkyl alkylaminoaikyl, dialkylaminoalkyl, eycloalkyl, cycloalkylalkyl, heterocycloalkyi, he!erocycloalkylalkyl, heteroaryl, heteroarylalkyl aryl, arylalkyl or aryialkyloxy and where the.ar l, eycloalkyl, heterocycloalkyi and heteroaryl rings in 'a and R:,H (either alone or as part of arylalkyl, cycloalkylalkyl, heterocyc'loalfcy kyi and heieroaryiaikyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, amino, alky!aniino, dialkylamino, hydroxy, halo, alkoxy, aikyHino, and. oxo):
b> ~C(0)NRsRS;! where R5 is hydrogen, hydroxy, alkoxy. alkyl, alkenyl, haloalkyl,. or haloalkoxy and ^ is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl,
alkoxyalkyl, alkyithioalkyl, heterocycloalkyi heieraeydoaikylaikyl, eycloalkyl., eycioalfcylalkyl heteroaryl, heteroarylalkyl, aryl,- or arylalkyl and where the aryl, eycloalkyl, heteroaryl, and heterocycloalkvl rings in R¾* (either 'alone: or as part of arylalkyl. cycloalkylalkyl. 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;
e) - R9C(0)R^ w ere R? hydrogen, hydroxy, alkoxy, alky}, alkenyi, haioalkyl, «r haloalkoxy and R'!;1 is hydrogen, Cr Valkyl, alkenyi, hydroxyalkyL alkoxyalkyl, eyeSoalkyk oycloaikylaikyl, heterocyeloaikyl heteroeycloalkylalkyl, heteroaryl, heieroarylalkyh ary or aryla!kylr where the-aryJ, cycioaSkvl heteroaryl, and
heterocyeloaikyl rings in R¾ (either alone or as part of atylalkyl, eycloalkylaikyl, heteroeycloalkylalkyl ^ nd heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alky]., alkenyi, alkoxy, hydroxy, hydroxyalkyl, halo, haioalkyl, haloalkoxy, oxo, amino, aikylaniitio, dlalkylammo, alkylearbosiyi alkoxycarbonyl, ~C{0)H, aryf (optionally subsiiteied with one or two halo), ary!alkyi, heidfoaryl. hereroaryialkyl, heterocyeloaikyl. heterocyploalkylalkyl, eyloalkyl, cyloalkylalkyl, and eycloalkylearboiiyi;
d) -C(0)Nf '^-Cr r ik ien -NiR'^R'* where 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
e) -NRs iC{0) RmRi Sii where Rl is hydrogen, alkyl, aSkenyi, hydroxy, or alkoxy and Ru and R' ! ¾> are independently hydrogen, alky I, alkenyi, amitioaikyl, alkylaminpalkyl, or dialkylaminoalkyl;
f) -C(0)R12 where u is heterocyeloaikyl optionally substituted with 1 , 2, or 3 groups selected from alkyl, oxo, amino, alkylanSino, and he.teroeycloalkylal.kyl;
g) -NR^CCOJO 1 8 where R| J is hydrogen, alkyl, or alkenyi and R! ¾ is aminoalkyl, .alkylaminoalkyl, diaikylammoalkyk aryl, or arylalkyl;
h} ^C(0)N(Ri¾,) (R!'5;i)(Rs ib where R54. R! s, and Ri4b are independently hydrogen, alkyL or alkenyi;
0 -SfQ^ CR^I-C; -C<i-a}kylene- CRi 5a)R,$e where: Rlk\ R' ft, and R!ib are independently hydrogen, alkyl, or alkenyi;
j)
Rl" is hydrogen, aikyl, or alkenyi and
R! i i is alkyl or aikenyi;
k) heteroaryl optionally substituted with one -or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl:
independently hydrogen, aikyl, of alkenyi;
nil -N{Ri S)C(Q)-C| idkylene-N(Ri; l,)C(0) i&a where Rt Sn is hydrogen, a!kyt, alkenyi, or alkoxy and R5 and R1 b are' iadepeiideijtly -hydrogen, -alkyl, or alkenyi;
«} -C(0}N( iii)~CrC(ralkyle«e-C(D)Ri¾ where R,f> is hydrogen, aikyl or alkenyi and
R '3 is amino, alfcylamino. dialkylamino, or heterocycloaikyl;
) - C -^CCOj^Ci-a-alkyiene-CCdj ^ where R-26 is hydrogen, -aikyl, or alkenyi and
R¾la is cycteiky!. or heterocyei alkyl;
p) - R21S(0)rCrCV^Ikykne-N{R2,fe}R2 where R2S is hydrogen, aikyl or alkenyi and 2fa and R2i¾ are independently hydrogen, alkyl, or alkenyi;
q) -N{R~)C(Q>C,^-s k lene. (R32VW22cKR22a where R22, R22a and R 2t> are independently hydrogen, aikyl, or alkenyi;
r) - ^-alkyiene-N(Ri}}-CrO-alkyi:ene- (R22i,)RJia: where R2\ R2Sa and R23b 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 R¾ is - independently Optionally further substituted with 1, 2, 3,
4, or 5 groups selected from halo, hydroxy, amino, alkyUwnina, and dialkylamino; and each R"' (when R1 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; or
a) -NfR^CfO^^rC alkylene- lR^ii 7^ where R7 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!a!kyi, eye-loatkyialkyl, beteroc-yeloalkyialkyl and heteroarylalkyl) are■independently optionally substituted with I, 2, or 3 groups independently selected from alkyl, amino., alkylamina, dialkyi.anii.no, hydroxy, halo, alkoxy, a!kyiihio, and oxo);
b) -C(G}NR¾* where * is hydrogen, hydroxy, alkoxy, alkyl, alkenyi, haioalkyl, or hakiaifcoxy and Rsa 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
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)R¾ 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 aikyl, alkenyl, alkoxy, hydroxy, hydroxyalkyi, halo, haloalkyl haioalkoxy, oxo, amino, alkyiamino, diaikylamino, aikyicarbonyl, alkoxycarbonyl, ~C(0)H, aryl (optionally substituted with one or two halo), arylalkyi, heteroaryl heteroarylalkyl, heterocyeloalkyl, heteroeyeloaikylalkyk cyloalkyi, cyloalkylaiky!, and eycloalkylearbonyi;
d) -C(0> (Ri¾)'Oi^-a^ylen.e- (RK¾ Ruib where Km is hydrogen, hydroxy, alkoxy, alky I, alkenyl, haloalkyl, or .hydroxyalkyi and Rf 0 and Rm are independently hydrogen, alkyl alkenyl, haloalkyl, or hydroxyalkyi;
e)
where R! ] :i is hydrogen, aikyl, alkenyl, hydroxy, or alkoxy and R! i and Rui> are independently hydrogen, aikyl alkenyl, aminoalkyl,
a!kylanunooalkyi, dialkylaminoalkyl;
f) -C(Q)R!2 where R;2 is heteroeycioaikyl optionally substituted with 1, 2, or 3 groups selected ftom alkyl, oxo, amino, alkylanuno, and heteroeyeloalkyialkyl;
g) -NRuC(0)OR! ¾ where is hydrogen, alkyl, or alkenyl and !*! is aminoalkyl •alkylaminoalkyl, .dialkylaminoalkyl, aryl, or arylalkyi);
h) -C{0)N{Ri ) {Ri d)(R ti) where RH, Rm, and R5 b are independently hydrogen, alkyl, or alkenyl;
i) ~S(D}2N(Rs i)-CrG6-a!kylene-N(R:i s*)R where R13, RiS and RJ 5h are independently hydrogen, alkyl, or alkenyl;
j) -C{0)N(Ri:i Ci -C6-aikylene-C(0)ORs¾ where RtS is hydrogen, alkyl or alkenyl and R;<¾i is alky! or alkenyl;
dialkylaminoalkyl;
!) -N{Ri7)-C(-N(R!7 ,)(Ri 7¾(NRi¾R17iJ) where Ri7, Rm, Rl ¾, R!¾, and Ri 7d are
independently hydrogen, alkyl, or alkem'l:
m) - (Ri8)C(0)-CrQ aikylcne-N(R}8l C{Q)SLiSii' here R!*a is hydrogen, alkyi, alkenyi.
or alkoxy and Ri?> and Rm< are independently hydrogen, alkyl, or alkenyi;
n) -C(Q)N(R! ''i-C Q-alkylen -qOiR5^ where R5 is hydrogen, .alkyl, or alkenyi md
15 8 is amino, aikylammi dialkvlaramo, or heiereeyeloalkyl;
o) -N(R?9)C{0).CrC^alkylene-C(0)R2C3 where: R¾) is hydrogen, alkyk or alkenyi and
R"¾> is eycioalkyl or fieteroeycloalky!;
p) -NR2!SfO)ret-Qra!kylene. (R3 ib)R la where R21 is hydrogen, alkyl or alkenyi and
R" i!i and Rm are independently hydrogen, alkyk or alkenyi;
q) -N( 22}CiO)-C Cfral^^ where R22, R22a and R"¾ are independently hydrogen, alkyk or alkeayl;
r) -C^Q-aik !en^Ni ^^ where R 3 R25a and ft2* are independently hydrogen, alkyl, or alkenyi; or
s)
or alkenyi and R24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl;
wherein each of the alkyl ene in R' is independently optionally i'urther substituted with i . 2, 3,
4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and diaikylamino; and provided that when R > and R^ are hydrogen, R3i 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-γΙ, o thien-2~yi substituted, with one R' where R is halo
where the Compound of 'Formula 0 is
Formula II
wherein:
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 -NR3-;
K~ is hydrogen;
R* optionally substituted alkyl:
* is hydrogen; and
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 Rs, when present, is independently hydroxy, halo, aikoxy, haloaikoxy, amino, alkyiaroino, dialky!ammoalkyl, or alkoxyalky!amino; and
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
dtalkylaiiiino,
{0010} In one embodiment, the compound of Formula I is a compound of .Formula la
la,
or a single tereoisomer or mixture of stereoisomers thereof and optionally as a
pharmaceutically -acceptable salt, iaaurmer, hydrate, or solvate thereof, wherein;
R ' is hydrogen:
A is methyl;
R''~ is hydrogen;
Ri"< is hydrogen or 'aikoxy; and
which they are attached form a ό-membered heteroaryl; arid
R" is hal or meihy!.; and
R3* is -N(R?)C{0)-CrC^ailcylene-N(R.¾)(R7 ) where RT is hydrogen and R¾ and R '^are independently hydrogen, alky!, aniino lkyk. aikytemmoalkyl, or
draikylaininoalkyL
(00.1 Ij In one embodTment, the compound of Formula S. and of Formula, la is Compound A:
Compound A
or a (autoraer, zwitterioa, or pharmaceutically salt thereof.
{0012} Compound A is known by its chemical name -(3~ {[(3-{ 2-ch1,oro~5~
(meihos j heny j tn^
In one embodiment, the Compound of Formula 11 is a compound of formula II A.
HA
or a pharmaceutically acceptable salt thereof, wherein:
R! is alkyi,. cyeloalkyl, eycloalky!alkyl, aryl, arylalkyl, heterocycloalkyl,
heteroeycloalky!alkyl, heteroaryl, or heteroaryialkyl;
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; and
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,
(00141 In another embodim 0 is Compound B
(0015 j Compound B is known by its name 2-an:iim)-8-ethyl-4-inediy!-6-{ 1 /-pyi¾¾K>l-3- yl)pyrido|2 -ii pyriinidsn-?( /)-oiie, Com oun 8 is disclosed in. WO 07/044813». the entire contents of which are incorporated herein by reference,
(0016{ hi one eniboditneni, the cancer is Type I or Type II .endometrial carcinoma (
|O0i 7] In auotlier embodiment, the cancer is advanced or recurrent endometrial carcinoma,
00I8] In another embodiment, ie compound or" Formula I or Formula 11 is administered as a tablet or capsule pharmaceutical composition.
(O01 J In another embodiment, the compound of Formula I or Formula II is administered as a tablet pharmaceutical composition.
[0020] In another embodiment, 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,
1.0021J In another aspect, 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.
[0023{ In one embodiment, the compound of■Formula I or Formula 11 is administered orally as a tablet or capsule pharmaceutical composition,
{'00231 hi another embodiment, the compound of Fonnula 1 or Fonnula II is administered as a t bl t pharmaceutical composition,
i i
effective -amount, wherein 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,
BRIEF DESCRIPTION OF THE FIGURES
j¾025f Figure 1 shows a plot of individual and mean SD (Bold, horizontal lines with error bars) for Compound Λ 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).
(002?) ' Figure 3 depicts preliminary results from a Phase I results from a breast cancer clinical trial.
\QH2$) Figure 4 depicts preliminary results from a Phase I results from, a breast cancer clinical trial.
j-0029) Figure 5 depicts preliminary results from a Phase I results from a breast cancer clinical trial.
|0030| Figure 6 depicts preliminary results from a Phase I results: from a breast cancer clinical trial
DETAILED DESCRIPTION
Abbreviations and Definitions
100311 The following abbreviations and terms have the indicated meanings throughout;
Abbreviation Meaning
! Ac j acetyl
j br j broad
Γ';:;ο 1 degrees Celsius
i c- } cycio
1 C Z I CarboSeuZoxy benzyloxvearbonyi
! d j 'doublet
! dd j doublet of doublet
j dt 1 doublet of iripiet
DCM ! diohlororneiiiane
DMA i Dimethyiacetamide
DME ■ ί ,2-dimethoxyethane
DMF j AQV-climethyllbmramide
1 032 The symbol ■ means it single bond, means a double hood, "Vv means a triple bond, means a single or double bond. The symbol. k ww" refers to a group on a double-bond as occupying either position on. the terminus of a double bond to which the symbol is attached: that, is, the geometry, E- or Z- of the double bond is ambiguous, When a group is depicted removed from its parent formula, the " * - " or I ''s mb l will he used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
[0033) When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform, to a valence of tour. For exampie, in the structure on the left-hand side of the schematic below (here are nine hydrogens implied. The nine hydrogens are depicted in die right-hand structure. Sometime a
hydrogen's as' substitution, (expressly defined hydrogen), tor example, -C¾C1¾-. It is understood by one of ordinary skill in the art thai the aforementioned descriptive techniques are co mon ia the chemical art to provide brevity and simplicity to .description of otherwise complex .structures,
0034. if a ..group " " is depicted as "floating" on a ring system, as for example in, the formula;
then, unless otherwise defined, 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..
}0835j If a. roup "R." is depicted as floating cm a fused ring system, as for example in the formulae;
then, unless otherwise-defined, a substituent R" -may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the -ΝΉ- 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. In the example depicted, the group may reside on either the 5-memhered or the 6-merabered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then 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,
|0036| When a grou "R" is depic ted as existing on a ring system containing, saturated carbons, as- for example in the formula::'
depicted, implied, or expressly defined hydrogen on the ring; then, imi.-e.ss otherwise defined, where the resulting structure is stable, two "RY" ma reside ©a the same carbon. A simple example is when R is a methyl group; there can exist geminal dimethyl, on a carbon of the depicted ring (an ^annular" carbon). In another example, two R's on the same carbon, including that carbon, may form a ring, thus creatin a spirocyelie ring (a "spirocyclyT group) structure with the depicted ring as for example in the formula;
|0037| -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,
MfiuoromethyScafbonyi, or 2-niethosyethykarbony and the like,
|0038| "Aeylaramo" means a -NRR" radical where R is hydrogen, hydroxy, alkyl, or aikoxy and R' is aeyl, as defined herein.
[0039] "Acyloxy" means an -OR radical where R is aeyl, as defined herein, e.g.
c-yanoxnethy earbonyloxy, and the like,
[0040] "Administration" and variants thereof (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. When- a compound of the invention or proding thereof is provided in combination with one or more other aciive agents, "administration*' and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
[0041] "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.
{0042} " Aikoxy** means an -OR group where R is alkyl group as defined herein.
Examples include methoxy, ethoxy, propoxy, isop opoxy, and the like.
[0043] "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.
10044] "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.
|0046] "Alkoxyq-ar oayF means a -C(0) group where R is alfcoxy, as defined herein. 10047} "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.
[0049] '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.
10051] SiAikyiearbonyr means a -CfO)R group where R is aikyi. as defined herein. J0052] "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.
[00531 "Amino" means
{00541 "Aniinoaikyr means an alky! group substituted with at least one, specifically one, two Or three,, amino groups,
1 055) '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,
(0057] "Arylalky!" means an alkyl radical, as defined herein, substituted with one or two aryl groups, a defined herein, e.g., ben¾yl and phenethyl, and the like.
J00S8] "Aryloxy" means an -OR group where R is and, as. defined herein.
IO059J "Carboxyalkyl" means an alky! group, as .defined herein, substituted with at least one, specifically one or two, ~C(0)OH ,grbtjp(s).
(0060] "Cycloaikyl" means a monocyciic or fused bicyclic, saturated or partially unsaturated (but not aromatic), . monovalent hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. 'Unless stated
radical, valency 'rules pennitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. More specifically, the term eycltialkyl includes, bu is not limited to, cyclopropyl, cyelobutyi, cycloperityl, cyclohexyl, cyclohexyl, or eyclohex~3~enyl, and die like.
[0061] '"Cycloaikylalkyl" means an aikyl group substituted with at least one, specifically one or two, eyeloalky! group(s) as defined herein.
100621 "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.
(0063| "Dia!kylaminoa!liyl" means an aikyl group substituted with One or two
diaikylamino groups, as defined herein.
|0064] ^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. Typically, but not necessarily, 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.
|0066| "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
|0067| "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,
|0068] "Haloalk Γ mean an aikyl grou substituted with one or snore halogens,
specifically one to five halo atoms, e.g., trifluororaethyL 2-chloroethyl, and 2,2-difiuoroetiiyl, and the like,
|0069j ''ReteroaryF' means a pionoeyclic. Fused bicyclie, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, specifically one, two, three, or four ring
remaining ring atoms being carbon, wherein the rin comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bieyclic or tricyclic radical is aromatic. 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. Rx is hydrogen, alkyl, hydroxy, alfcoxy, acyl, or alkylsu!foiiyi, Fused hicyclic radical inerutles bridged ring systems. Unless stated odrer ise, 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. bctEa Vldaxolyl, benzodioxol-4-yl, benzo&raoyl, cmnoiitty!, ndoii¾inyl, naphthyridin~3-yl plnhalaxm-3-yi. ph.thalazia-4-yi, pteridmyi, purinyl, quinazolinyl, quinoxalisiyl, tetrazoyi, pyrazolyl, pymzinyl, pyrimidinyi, pyridazmyi oxazoiyl, isooxazolyl, oxadiazolyl, benzoxazo!yi,.
qumolinyl, isoquinolmyl, tetrdhydroisoquinoliny! (including, for example,.
ietrahydroisoqoinoliti-4-yl or tet}¾hyd >is<>qinnolin--6-yt, and the like), pyrrolo[3,2- c]py.ridmyl . including, for example, p rrp3ops2Hs3 yridm~2~ l or pytToio[3.2-e pyTidin»7-yI. and the like), benzopyranyl, thlazolyl, isothiazolyl, thiadiaxolyl, 'benzothiazolyi,
benzothienyl, and the derivatives · thereof, or N-oxide or a protected derivative thereof.
[0070} 'ileteroary iaik ' means an alkyl group, as defined herein, substituted with at least one, specifically one or two heteroaiyi group(s), as defined herein,
{0071 ) "Meieroatom" refers to Q, S, , or P.
{0072) "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, (Ry) (where Ry 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, RJ: 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^ . dihydropyridiiiyh teifaliydropyridbiyL oxazoHnyJ, oxaxoiidinyl, isaxazolidinyl, thiazolinyl, thiazoliduivi, quinuclidmyl, Isothiaxolidinyl, oeiahydroine!olyl, OGtahydroisoittdoiyl, deca. ydross i|ui«oiyl, leimhydrofuryf, and tetrahydropytanyl, and the derivatives thereof and N-oxide or a protected derivative thereof,
[0073]
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.
{0074} "Heierocycloalkylaikylo.xy means an -OR group where R is heterocycloaikytidkyi, as defined herein,
('©075] "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-i¾roji3.2-b]furan,^
?-aza-bicyeiof2.2. I]hepiane, and l ,2,3!4,4a,5,8i¾< cudiydro~naphthaleue are ail included in the class "saturated bridged ring system,
[0076] "Spirocyelyr or "spirocyelic ring" refers to a ring originatin from a particular annular carbon of another ring. For example, as depicted below, 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.
(0077} "Optional** or ''optionally" means that the subsequently described event or circumstance may or may not oeeor, and that, the description includes instances where said event or circumstance -occurs and instances in which it does not, One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional subsiiiuents, only sterically practical ami/or synthetically feasible Compounds are meant to be included. "Optionally-substituted*"' refers- to all subsequent modifiers in a term. So, for example, in the term "optionally
optional substitution may
he substituted,- A list of exem lar optional substitutions is presente below in the definjtion of "substituted."
10078} 'Optionall substituted ai.ke.xy" means an -O group where RJ.S optionally substituted alky), as defined here n.
|'0079J "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.
alkenyloxy, hydroxy, hydroxyalkoxy, .halo, earboxy,■■alkylearbonyiamrao, alfcylcarbonyjoxy, alkyi-S(0)(i.:-, a]keayi-S(0 it).;-, arotnosulfonyt, alkylaminosulfonyl, dtalkylam asulfonyi. alky!¾ulfonyl-NRe~ (where Rc is hydrogen, alkyi, optionally substituted alkenyl hydroxy, aikoxy, alkenyloxy, or eyaaoalkyl)* alkylaminocarboayloxy, dialkylatninocarbonyloxy, alkykrainoalkyibxy, dia!ky!anunDalkyloxy, alkoxyearbony!, lkenyloxycarbonyl,
alkoxycarbojjylamino, alkylamiiiocarbonyiamirio, dia!kylaminoe-arbonylamuio,
alkoxyalkyloxy, and -€(0)Ν¾¾!'' (where Ra and Rb are independently hydrogen, alkyi,. optionally stibstituted alkeivyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyi),
J0080) "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, ammosulionyl, alkylaminbsult i l, dia!kylaminosulfbnyi, alkyisul bnyl-N'R11- (where Rt: is hydrogen, alkyi, optionally substituted alkenyi, hydroxy, alkoxy, alkenyloxy, oreyanoalkyi), alkyi aminoearhonyio y, dialkylaminoearbonyloxy, a!kylauomoalkytoxy, dialkyiammoaikyioxy, alkoxyearbonyl, alkenyloxy arbonyi, alkoxycarl myl m o, alkylam noearbonylamtno, diaikylamiiiocarbonylamino,
aifcoxyalicytoxy, and ~C(0}NR¾!> (where Ri and Rfe are independently hydrogen, alkyi, optionally .substituted alkeoyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyi).
{0081] "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), -S(0)a-(optioiiaUy substituted
hetero ycloallcyl), -S(0)r (optionally substituted h'eietfearyl), and -S(0}2-{opi!0!ialiy
substituted heteroaryi). For example, "optionally substituted amino'' 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,
06831 "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, aimrioalkoxy, o aryi is pentailuorophenyL Within the optional substituents on "aryl". the alkyl and alkenyl, either alone or as part of another group
(including,, for example, the alky! in alkoxyearbonyl), are independently optionally
substituted: with one, two, three, four, or five halo.
i.SQ§4j "Optionally substituted aryiai.kyin means an alky I group, as defined herein, substituted with optionally substituted aryl, as defined herein.
(0085) "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. aminoearbonyl, alk iaminoearbonyl, dialkylaminoearhonyl, nitro, alkoxyalkylaxy, ami.noaikoxy,' ikylanitni3alkoxy, dialk {aminQaIkoxy, carboxy, an cyano. Within the above optional substituents on eyeloalkyl", the alkyl and alkenyl, either alone or as part of another substituem on the cycloalkyi ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. ba!oalkyi, haioaikoxy, haioalkenyloky, or haloaikylsultbnyL
[0086] '"Optionally substituted cyeloafkylalkyF means an -alkyl grou substituted' with at least one, specifically one or two, optionally substituted cycloalkyi groups, as defined herein.
substituted with one, two, or three substituents independently selected' irom acyl, acylamino* acyioxy, optionally substituted alkyl, optionally substituted alkenyl, alfcoxy, alkenyloxy, halo, hydroxy, alkoxycarhem , alkenyloxyearbonyl, amino, aikylami.no, dialkyiarnino, nitro, aniinoearhonyl, alkylammocarbonyk dialkytaminoearbonyi, earboxy, eyano, alkylthio, aikyisu!finyS, alkyisulfon j, amiiiosul&nyl, alkylam'inosuHonyl, dialky'laminosultenyl, alky!sul onylamino, aminoalkoxy, aikykiininoalkoxy, and dtalkylaminoalkoxy: Within the optional substitnents on "hdieroaryl", the alkyl and alkenyl, either alone or as part of another group (including, tor example, the alkyl in aikoxycarbony!), are independently optionally substituted with one, two, three, four, or five halo.
}0088] "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,
(0089) "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.
[0090J "Optionally substituted heteroeyclpalkylalkyF' means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted
.heterocycloalkyl group(s) as defined herein,
{§091) "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, lias the following structure . Compound A is known by its chemical name N 3-{[(3~{[2-ehloro-5^methoxy)pIv^
yi)amino]suifbnyl}p eny l}-2-:raetky As- discussed in more detail below, the com ound may exist in several tautomeric forms. Accordingly, as used herein the terms "Compound A" and " H {{(3-![2 hlor 5«(m
yljfammo]sulibny!}phenyl)-2-medryIaianinamide>* encompass all possible tautomeric and •zwiiterionic. forms of the compound.
|<K)93 | As used herein, is a Compound of Formula II and of
Formula Ha, has the structu
Compound 8 is known by its name 2- araino-8-emyl -me:^ Compound B is disclosed in WO 07/G44813, the entire contents of which a e incorporated herein by reference,
10094] "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.
(0096} The terms "effective amount" or "pharmaceutically effective amount" or ^therapeutically effective amount" refer 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. In some embodiments, 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. For example, an
!¾i¾ctive 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,
J0097J In some embodiments, 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. In some embodiments, a comparable clinical .benefit rate (CBR = CR + PR 4- SO >: 6 months) is obtained by administering Compound A or a eiabolite or phannaeeuiieaily acceptable salt thereof as compared to treatment with a» antitumor agent.. In some embodiments, 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,
(0098) A "pharmaceutically acceptable salt" of a .compound means -a salt that is
.pharmaceutically acceptably and that possesses the desired pharmacological, activity of the parent-compound. It is understood that the phannaceuiicaity acceptable salts are non-toxic. Additional information on suitable -pharmaceutically acceptable salts can be found in
mingian 's Ph rm e iic l Sciences, 17* ed,t Mack Publishing Company, Eastern, PA, which is incorporated herein by reference or S. M. Berge, et a!., "Pharmaceutical
Sails, '' J. Pharrn, Sci,, 1 77;{¾6: 1 - 1 both of which are incorporated herein by reference, |0 99j 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, inetiianesuliom'c acid, ethanesuifoiuc acid, l,2~ethaaedisui.fonic acid,
2-hydroxyethanesulf nic acid, he«zenesutlonic acid, 4-ehloro'benzenesullome acid,
acid, 4,4'-methylene is*(3-bydroxy-2-ene-'l -carboxylic acid), 3-phenyipro kraic acid, tmnethylacetic acid, tertiary butyiaeetie ackivlaury.l sulfuric acid, gluconic acid, glutamic acid, hydroxynaphmoie acid, salicylic acid, stearic acid, mueoaie acid, p-io!uenesulfonic acid, ami salicylic acid and the like,
{00100] -Examples of 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,
2-dime¾hylaminoetJiaoo 2-diethylammaethano!, dieyciobesylamine, lysine, arginine, histidme, caffeine, procaine, hydrabamine, choliae, betaine, ethyienediamine, glucosamine, methylgHieamlne, theobromine, purines, piperazine, piperidme, N-ethylpiperidine,
tromethamme, A-me iylglucam e, poiyanune resins, and the like- Exemplary organic bases are isopropylarairse, diethyiamine, ethanola rae, trimethyiamin.e, dicyclohexylamine.
choline, and caffeine,
|0Θ10ί[ "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. Examples of 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
-straight- or branched chain. 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, Λ 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.
Symposium Series, and in Bioreversib!e Carriers in Drug Design, ed. Edward B. Roche,
incorporated herein by reference for all purposes.
(00102} "Metabolite" 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
biotransformation).. .As used herein, the metabolite of a 'Compound of the invention or its salt may be the biologically active form of the compound in the body, hi one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite.. s discovered seremUpitously, thai is. no prodrug design pe se was undertaken, An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure. (00103) Unless otherwise indicated, "treating" or "treatment" of a disease* disorder, or syndrome, as used herein, 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. As is known in the art, in the context of treatment, adjustments ¾r 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.
[001041 "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.
Embodiments
[00105] The 'following paragraphs present a number of embodiments that can be used to practice the invention. In each instance, the embodiment includes both the recited compounds as well as individual isomers and mixtures of isomers, In addition, in each instance, 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 ί or la,
f 00107 J In another embodiment, methods are provided 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. .
tOOlOSj Any of the following embodiments, including the representative compounds described belo w, may be used to practice any of the methods disclosed herein.
Compounds of Formula I
(001091 The Compound of Formula 1 is selected from any of the loUowirig emb diments, including from the Representative Compounds in Table ! .
|C.t011 J One embodiment (A) of the -compound of Formula ί is where w w W', and W* are ~C(R!)~; or one or two of w', W*, and W are independently ~N= and the remaining are -C(R!)":; where each R1 is independently hydrogen, alkyl, hajoalkyl, uitro. alkoxy, haloalkoxy, halo, hydroxy, cyauo, amino, alkyiamino. or dialkylamino; and ail other groups are as defined in the Summary of the invention. In another embodiment, W!, W", W'\ and W are -CfRs}:;- and each R! is independently hydrogen or alkyl; or one of W and W5 is ~Ν~ and the other is -C(H)=. I.n another embodiment, W\ W~, W\ and w are -C(R )~ where each R1 is independently hydrogen or alkyl In another embodiment, R! is hydrogen.
jflOl ί I] Another embodiment ( B) of Compound of Formula Ϊ is where R¾t> 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
aikylcarbfmylanuno; where R5" and R"': are iadependentlt hydrogen, alkyl, or aikenyl and R55a 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 Ϊ is where 5 ' is hydrogen or alkyl; and all other groups are as defined in. the Summary of the Invention. In -another embodiment, R¾ i is alkyl. In another embodiment, R5! 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. In -another embodiment, J~ is hydrogen.
(00114 j 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, ^ (¾'5^)0(0)»Οί-0&-3ΐ^ΐ6ηο>Ν(Κ33*)Κ*δ ^ ε¾ι^^^ alkenyicctrbonyl, cai'boxy, alkoxycarbemyl, cyano, alkylthio, -S(Q} NRS5R35* . or
alkylcarbonyiaffiino; where M and R'"b are independent!* hydrogen, alkyl, or alkenyl and R?¾1 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)R¾iis>. In another embodiment, si is hydrogen, methox , nitro, amino, or -NHC(0)CH2 ( H.?)2» in another embodiment, is hydrogen or tnethoxy, (QUI 15j Another embodiment (F) of a Compound -of Formula I is where 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
alkyicarbonyiamino; where " ' and R5>* are independentlt hydrogen, alkyl, or alkenyl and R¾5a is hydrogen, alkyl, alkenyl, hydroxy, or aikoxy; and ail. other groups are as defined in. the Summary of the Invention. In another embodiment, R** is hydrogen, alkyl, aikoxy, or halo. In another embodiment R54 is hydrogen, methyl, meihoxy. bfomo, or chloro. In another embodiment, K * is hydrogen,, meihoxy, or chloro.
jOOI Ify Another enihodirnent (G) is directed to a compound of Formula I wher R - R'~, and are hydrogen and . 3* is halo or aikoxy; RH!, ^, and R'4 are hydrogen ami R ? is aikoxy; or R'v,) and 5* are hydrogen and R5<* and R" ? together with the carbons to which- they are attached form a 6-membered heteroaryi; and all other groups are as defined in the Summary of the invention, in another embodiment, RMi, "2, and '3 are hydrogen and R t i chloro or meihoxy; R30, "y and R3'' are hydrogen and s'' is m.ethoxy; or R3t' and RJ ' are hydrogen and R" 3 and R>! together with the carbons to which they are attached form
is chloro or
pt>l 17} in another embodime t (G l ) of embodiment G is -a compound of Formula 1 where R' ' is methyl.
|0 118). Another embodiment (J), B is heteroaryi optionally substituted with one, two, or three R3. hi another embodiment B is thico-J-yl, pyrid.ittyi. pyrtm.tdi.nyl, pyridazinyk
optionally substituted with one or t o R". In another embodiment, 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 ida¾oi-2-yl. pyrr0l-.2-yi, pyrroi-3-yl, imidazol-4-yl» imidazo!-S-yl, pyrazel-3-yl, pyrazoM-yi, or pyraeoi-S-yl, each of which is optionally substituted with one or two R'. In another erabodiraent, 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"\ In another embo iment^ 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\
[00119} Another embodiment < ), ¼ is cyano; hydroxya ino; carboxy; alkyisui forsyl, ammoalkylo:xy'; alkylatttihoalkyloxy; dia!k lamindaikyfoxy; ~N(R7jC(0}--C.rCiraSkyIene- N(R7a)R¾ -C(0)NR¾¾3; - R¾fO)R9il; :(0)N(Rl!))-C1.Ci>-aikyie«e. ( ua)R,i¾;
- RuCfO)NRu*R!, vhere R!!:f; -C(0)Rn; - R!iefO)ORi¼; .G(O R! ) (R5 i,){R ^; -S{0) (Rls)-CrCV8lkylene> (R!-¾)Ri'5b: -CiO)N{Rh Cf-Q-alky1ene-C(0)OR! a;
heteroaryl -optionally substituted with ne or two ammoaikylvitiky4:araino iky'L or dialkyJamthOiUkyl; -N(R'?)-C.(« (Ri?fc)(R,¾))( R'!7cRl7¾; -N(Rl8)C(0.)-C,-Q-<ilkyleBe- N(R!Sb)C{0)R5¾; .C(0)N(Ri'5)-C1-C6-alkykne-C(0)R,¼; >N(R22)C{0)-Ct-C alkyiene- (R"h)-- ( R"¾ ""*}; ^¾-alkyk¾e- {R;3)^-^ or~ R¾:{0)~ Ci-Cft-alkylesie-O 2*; where each of the alkylene-m R'?a is independently optionally further, substituted with I» % 3,4, or 5 groups' selected from halo, hydroxy, amino, alk laroino, and dialkylamino; and ail other groups are defined in the Summary of the Invention,.
{0 f 20] hi another embodiment, ¾ is:
-NHC(©)C¾NH(C¾), -NHC(O)Ci¾ H(C¾CHj), ^HC(0)CH(CH3)NH2>
-NHCip)C(CHj};NH3i5 -NHC(0}C¾N(C .;)2, -NH€iO)CH;N(CHj)CH:CH; (CHj)2,
-NHC(0)CH(CHi) H(CHj), - HC(0)Ce; H3, -M4C(0)H, -NHC{0)CH2(azeiid.ra« 1 -yl), 'NHC(0)(pyrrolidjn-aryl)5 - HC(0)Cll( H2)CH2OH,.'.NHC(0)(a¾etidin-4-yl),.
-NHC(D)C(CB3)2NH(C¾), - H2, -NHC(G}CH2NH(CI¾CH2CH¾), -NHC{0)CMjCH2 Hz,. -NHOH, - HC(0){piperid'in.3 -yl), - llC(0)CH2(4-methyl-! ,4-diazepan-l-yl),
-NHC(D)CH{NH;3)(C¾CHi), >NHC(0)CH2NH{CH;CH{OH)(CHj)),
-MliC(0)C¾NHCHjCH?F , -NHC(O)CH2NH(OCH2CH(Ci-i. ), - HC(0){ \ - aminocyclopi-op-l-yl), - FlC{0}CK2Nti(eH2cyelopTOpyi), . -NHC{0)CH2(3~
(dimethylammo)-azeiidin-l -y!), -NHt QXpiperidin-2-yl), >NHC(0)(morphol'in-4-yl), -NI-iCfO)CH2fpyrroi!din- l-yi), - HC{0)CK(NH2)CH2Cl 2C:iI2CH2NiC¾)2,
1 -yl). - HC(0)CH3 H(CH2CH(CH}2X ~ HC(Q)CH2 (CHj.)(CH:CH3},
-NHC(0)(A-(in3{daxoH-ylniet!wi)-azeudH^
- HC¾ (CHj)CH2C¾N(CH5)2,-NHC(0)CH2N(
-N HC(0)CH2N(GHi)'(CH2CH2N(C¾)2}, - HC(0)CH2{3-hydroxy-pynOlidjn- -yl ),
-NMC{0)( i-amino-cyc buH -yi), ~ Ηα )ΟΗ2ΝΗ(€Η2)3€Η , -NHC(Q)C¾(3 peridm~l- yiazetidin-lyl), - HC(0)NH2, - .BC{0)(l-hydroxycyclopropyl), - HC(0)CH2NHN(CH3 , - HC{0)NH(CH2)2N(CH5. , -NHG(Q)CM2OH, -NHC<0)(pynda23ii-4-yl)t -NHC(0){ - meihyi-pijieridtti-4-yl), -NHCiO}a¼NHCH(CH3)?i -NflC(0}CH2{3-dimeihySamitio- pyiToHdin- 1 i), - HC(0)CH2NH(CH2)2N(CHs)2i -NHC0)( I -cyclopropylmet yl-aze(idi!i-3- yi), -NHC(0)C¾NH(CH3)3> -NHC(0)(imidazo.-2-yi), -N C(O)(imidazoS-4-y ,
-NHC(0)(1 ,2-oxa¾pH-yl), -NBG{0)CH2NHCH2CF¾ - HC(0)Ci¾C¾fpiperids»-l -yl), -NHC(0)f 3-oxo-cyeiopent- Ϊ -yl), - HC(0)(2-liydroxy-p rid!ii-6-yl)? - HC(0}CH:NH(3- fiuoro-4-hydaixypbeayl), -Nl-JC(OKCH2)iN(CHj)2, - HC(0){ I -(iitran-l-ylmet ylj-az ttdiii- 3-yl), .NHC(0}(p>Timtdm-5-yl), - HC(0){pyrroi-2-y{}; - HC(0)CH3N(CHj)CI S(CI Jj}2> - 'MHC(0)C¾^'CH2t¾3)^
-MHC(0)C1¾NHC¾(3.^
amino- teirahydropyran.-2-yl), -Ni-iC{0)CH2(4-met¾>%m!no-piperid{n-l-yl),
- HC{0)(piperidin-l -yl), - HG{O}(<V-ra thyi-pyrroiidm-2yl), -NHC(0X<iuen-3yi),
- HCCOiiA^Ceyclopo lcai-bO v azetiditi-S-yO, -MHCf 0)CH2( -methylpi em2m- I -yl),
NHG(0)CH2NH(b.enzyi), ~NHG(Q)CH2OCH3>
«NHC(Q)(pyrktin-3-y$), - HC(O)CH2NHCH2CH20CH3,> HC(0)(l-CC(0)CH^iperidm-4-yl), - HG(0)CM2(2- rae l-pyrmlsdin- ! -yl), - HC(0)({¾ran-3-yl), -NHC(0)CHjN(C!ij)2; -NHG0)(2-chioro- •pyridi 5«yl)5.-NHC{02-chloK>pbenyl), -NHCfO)CH2(pyridm-2-yl}; «NHC{0)CH2{3- dimet ylnmiiTO-iizetidiQ- 1 -yl), - MC(0)CH2(pyridin-3-yl}, «Nf lC(0)C ijfS-chiorophenyl), -NHC(0)Gi¾N(CHj)CH?GH2CH2N(Ci-i})2, -NHC{Q)GH2H(CH2GHj)CH2CH2OH,
- HG(0)Ci½(2-benzy!--pyiToiid!H;-!~yi)( -NHC(O)(.ft«un-2-yl, -NHG(0)(2-chloro-pyridm-4« yl), -NHC(0)CH2MHCC0)GH3, -NHO0)C¾GH2CH3t -NHC(0)("4-chtojOpbenyl),
-NHC(0)(4-m f yI-phenyi). ~ EC(0)CH2 FlC(O)O{CH: ?t -NHCCO}(beo2ofdl[ i jdiox l- 5-yl), - HC{0>CH2NHOCl¾(2-ineilioxypbeiiyl), ~NHC(0}( yridm-4-yi}, . -MHCf0)CH3[4- (3,4~dicbloropb«.nyi)-piperas.in- 1 -yl], -NHCCO)CH2CH2Cpyridiii-3-yS),
-NHC(0)CH2NHCH:i(2^melhylphenyl),
- iIC(0)(2--nie l-cyclepr p-!-yl), - HC(0)( >metbyl-4M«etli x^henyl)- - HC(0)(2- methylpyridm^3~yi); -NHC(0}(4-merJ»xyphetjy¾ -NHCCG)CH2(4-et ylpiperazin- 1 -y!), ~NHC{0){thien-2-yl) -NH (0){3-fluoro-2-mcthyiphenyi>, - l- (0){2-bronM-ihien-3-y{), - HC(0)(4~il ropheviy!), - HC(0)C¾(3-mc iyipipcridin-l-yl), -NHC(G)CH(CH5)2, - NHCCQXCH CH -HHC(G}CH2OCHsCH?,- HC(0)Ci¾NH(2«fluorophenyi)?
- HC(0)C¾NH(2- propyiphenyi)! - MCfOjplienyL -NHC{D)(|>yrazin2-yl), -NHC(0){3- i1uQra-4-methoxypheiwi)!- HC(0)C(CHi^C¾CHi. - HC(0)CH;0(4-fluorophenyl)! ^NHC(0¾!-me¾yicarb^ti.vl-a2eti m-3-yl>5- -NHC(0)C¾Nil(4~met y!p]¾enyf),
- HG(0)CH2{4-aIlyl-piperazm- 1 -yl), - HC(0)(2-metliylpheiiyl}( - MCCG}C¾C¾OCi¾ «N:HC(0}(3-rae{hyI-f\irat^2-yl)? - HCfOJCCCHj),, - NHC(0)CH2NHObenzy!? ^HC(0)CH2NI-l(3-chiorop enyl) --NHC(0)cyGlobutl
- HC(0)C¾(3-raethoxypheiiyl}! -NHQO'K l-meihylcycloprop-l -yl), - NHCCOXS-ta hen l), - HC(0)(4-dimethylai»m phenyI), -NBC(G)(3,4-dkhlo∞p enyi), - He(0)CH2NHCH2(2-ra^^^^ - Nl (G)CH2N(CH2CHrCH(CH3)2, NHC(O)(thiazo.l-4.yl), >NHC(G)CH2N(C¾)bei yi, - iliC( )CH2 HCI:l2(ti3ien.2~yi), ~NHC(0)C¾NHC¾{pynditi-2-yl}, -NH€(0)(3- methoxypheoyl),.-HHC(G)¾
NHC( )CH(C¾)CH?CH2C¾^ ^^^
mediylphenyl),« HC(0)CH2G(2-m<jthylpheijyi), -NHC(0)CH2(€Yclohcxyi}, - HC(G){2- phenyl-cycloprop-l -yi), - HC(0)(3-ch!orophenyl).5 -NHC(0)CH2(2-metbGxyphenyl),
- HC(0}eH2CH2(3-me? oxy^^
-NHC(0)CH2NHCH2(3-nuofo-pheoyl)i- HC(G)CH:(4-tneiJioxy-pbeny , -NH€(G)bcn yL -NlIC(G)(2!4-dich!ofoph nyi)! -NHC{0){3-oxo-cyclohex- 1 -yl), -NHC(0)CH2N«(3- fiuomphenyi), -NHC(0)CH2(3-cWo.ropheny:l)-
NHC(G)C¾NHCH2(2,4-dimeihylpheny!) -NHC(0)C¾(2-mchyl-pipericiin-l-yl);
- i:lC(0)CH2NH(2-meifloxyphiirty!}, - HG(0}CH2( 1 ,2 J,4-tet?ahydroi.soqu!3iolk--2-yi),
- HC(0.!CB2CH2 CH :H ^
piperkHa-l -yl), -HH€<0)(2-t¾oropheayl), ^ HC(G)CH.2NHCl.(CH5.)pheiiyl, -NHC{0}(2- fluoro-S-methoxyp enyl), -NHC(G)CH2N! (2-isopropy!phenyl)) -MHC{0)CH2C¾(2- meiboxypheny!.}, ~NHC(0}CH2CH2CHiCHj¾3 -NHC(G}CH2(2-pheny!-motpbol! -4-yl), -Nl-IC(0)CI¾C.H.2(4-merhpxypbenyl)« - ¾C(G)CH^(allyi)cyctopeatyl, - NHC(0)CH2N!(CH3)CI%CH20C¾5 - HC(0}CH2CH2C(O)c ciopjopyL NHC(0)CH:j li{3-
cyciopentyl), -NHC(0)CH2NH(4-chfou}phenyi), -NI iCiO)CH i4-piperidin- 1 -y!piperidi n- 1 - yl), - HC(i}}C¾{4-cyclopentyipiperazk-l-yl}! -NHCCO)CM2(2-met yIphenyl),
-NHCCO)C¾NeCH2^^
chioropbenyi), -NHC(0)(3-ilui:« 6~metJwlplienyl}, -Nf:iC O)(4~iluoro-3-iT.ieihylp ejiyl)i
dimethylpheiiyl), -NHC(0)(2-fluosx)-5-meiljylphenyl}> -NHC(0}CH2NBOCi¾i4-- ethylphenyl), - i-iC(0)Cfl2(4-isopropyipjp mzm-- i -yl), - HCCO)CH2(4~fiuoropheny}k - NHC(0)CH.jCH(C¾)2, ~ HCCO 2-me(hox -4^raethylpUenyl), - HC(0) H2(4-w- propylptperidin-l -yl}} -NH.C(0)CH-20(3-iHethylp enyl), -NHC(0)( etrahydrpfuran~2>yi), -NHC(0)CHa(3-hydr©xymetliyl.pipe.rkHa~l-yl), -N-HC(0)'( 1 -/«r/-butoxyiearbt>nyipiperi<ija-2- yl), -NHC(0)CH5N(CH3)C¾(pyndin-3-yl). -NHC{0)CH;N(CH2C!¾)pheayK
-NMC(O)C¾0CM2€H20^^
dic ior phenyi), «HHC(0)C¾(4>methyicar o»ylpipera¾in»i-yl)> -NHC(0)(5-fluorQ-2- roetfcoxyphenyl), -NHC(0)CHiNfCH2CHj:)cycloS½xyL -NMC OXS-meth M^xaz i-S- l), -NHG(0)(3-methyipy^^^ - HC(0)(3,S- dichloropheayl), NHC(0)CH2{tl«azolidm3-y! , - HC(O)C¾(4-[C{0)H]-piperazin- 1 -yi), -NH (0}CH;{2-pyndin-4-ylpip<iridm- 1 -yl), -NHC(0)(2-metlioxyphenyi). - NtlCi0)C¾N(CH CH2€^^
~NHC{0}( i -pheayleycioprop- I -yl). - HCiO}CH2(2,6^iOTe.iliytmotp.hoHn-4-ytK
NHC(Q)CH*<2-phenylpyrrolidm^^
C(0) HCH(CHj)C¾NfC¾)i, <C(D)NRCH2CH2N(CH?)2> ~C(0)NH(pym>iidin~3-yl), - C( )NHCH2CH2(pyn-olidm -yl)5 -C{Q) HCH3CH2NH2, -CfO)N{C¾)CH2CH2N(CH,)2, - C(0) MC¾(piperidin-2-yi), -C 0)NH(i-methyiazetidi:n~3~yi). -C{G) HCli2CJ¾{pipe.ridiri- 1 -yi), -C(G) HCH2CH: (CH2Ct¾)2, .e(0)NH(l-methylpiperidin»3-yl),
~C(0)KH(piperidjn»3*yl), -C(0)NHO W l-methy!piperidin-3-yl), - C(0)NHCH CH2N(CH2CH2OH)2, -C(0)NH( I -ethySpiperidm-3-yi), -C(0)NH2, -C(0)(3- aminopytrolidin- l-yl), -C(0)(3-raeihylaramopyrjrolidm-,l-yi), -C(O)0H, -
3-oxo-pyramiidin.-1.-yi}, -C(Q)MHCH-j, -C{0).(3-ammo.cyelobut- 1 -yl), -C(0)N CH (pyridtn~ 3-yi), -C{0) HC¾C¾OH, -C(0)NrH{3-oxo-pyrazoIidm-4<yl), -NWCH2CH2{irakteM-yi)( -C(0)(3-ditn8thylammopyrroHdt«- 1 -yl), -C(0) HCH2(pyridin-4-yl)? -C(Q)N(C¾)(1- iBethyl-pyrrolidSn-3-yl), -C(OX3-die.hykminppy-Toiklm- 1 -yi), -C(O)NH(pyiT0l-l -yl), - GfO)NilC¾CS¾CM2(pym>itdm~I-yl); -C(0) (CH5)C¾C¾CN, -G{0)NHO¾CH2OCH3i -
-CCO HCmorpholia^-yt), -C(0)NHN(CHj)3) -C(0} HCH2CK2CH2(iinidazol-l -yl), - C(0)NHCH2CH2CH2Sf(CH;.CH? s
-C(0)NHCH:GH2CN .C(0) HCH2CH2C(0)0C:H3, «C{0)NHCH2C¾SCH3,
-CO)NHCH2CH2SCH2CHJ. >C{0}H(CH2CH3)C.H2CH2N(Cf ¾t -CfO} HC¾CH;C¾(2- oxo~pyrroiidm -yi}? -C(0) HCH2CHj(pyridm-4-yl), -C(0)' HC¾ ¾CHsOC¾C¾,
C(0)H(CHj)C¾Cii2CH2N(CH5)2, -C(0)^HC¾CH3CH2OCH2Ci¾CH3,
.C(0)NHCH2CH2C( )OCHCH¾ -C(0)NHCH2CHCH2OCH(CH.^
• (0}NHC(CH)2C¾(piperidin- i-yl)
-qO)NHCH(CHj)C¾OCH , (O) HC(CH;2CH2(raon3boMn-4-yl -C{O.K'2- diniet ylaminometiiylpiperidin- 1 -yl), -C(Q)NM(CH2)30(CH2)3C¾
-C(0)NHCH(CH3)(C¾)?N(CH2CHj)2, -C(0}NHC(CI- }2C(0)(pipendin-l-yl), ~C(0}(4- methyipiperaz - 1 -yl), .'{0)(2-pipcrk!sn~ l-ylmethyl-piperid -1 -yl), eyano, -NHCHj, -CB(CH. HC¾CHj fCH: 3,-C(O)C¾; -S(0)2NHCHjCi¾ (Ci:I¾)2t
.S{0}.NH(C¾} (CH3)2s S-( A-dimeUiylamiHomethyl)- ! >3,4-oxad!a2ol-2-yL
-NHG%Ci¾ (Cr¾, -N(C%)2, -OCH2GH2N(CH3)2! -NHC[N(CH3fcKHN(eH3)d» -0CHF2, -S(0)2CH5, -OCF3, or -NHCiOX^H2(4rdimet a^opiperi<ii»-i-yO^
[0)121 j in another embodiment (L), Rki is hydroxyamino, -N(Rv)C(0}-C{-C^a!kylene- (R¾)(R7¾)t -C(0)NRR&\ - R"C(0)R½, *C(O) { !<')-Cr -aikyieae- (RK,a)Rl0b, ~NR- ^(C 11^ ib, - (R22}e(0)-C C alkyten^ -.NR°C(O)0RS'¾ ( -N(R! 8)C(0)-C C alkykne-NfRiiii:!)C(O)RiS8 , -NR24C(0)-Cj.C alkylen^OR24a ? or - i ^)C(0)-Gi-C§-8lkyieoe-<C(0) itiaA hefe each of the alkylene in R¾ 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. In another embodiment, Ria is -!s|HC(0)CH; H{CHj.), -NHC(0)CH(CR3)NM2, -NHC(0)C(C1¾)2NH2! -NHC{0)CH2 (CHj>, - HG(0)CH2N(CHi)CH2CH2N(CHi)2s -NHC(0)CH(N¾}CM2CHi, -N4C(D)CH2H(CHj)CH2CH2 (CH5)2i -NHC(0)GH{GH3)NH{Ci-i3), -NHG(0)H,
>NHC(0)CH2(szetidin- 1 -yl), -NHC(0)(pyrro!idm-2-yl), -NHCfO)CH(N¾)CH2OH, - HC(0)(azeiidin-4-yl), - HC(0)C(CH3 HH(CHs), -NH3, -NHC(0)C¾ i r(Cl CH2CBi), - iHC(0)CH2CH2 H2, -NHOH, or -N.HC(0)(piperidin-3-yl).
1001221 in: another embodiment (M), R3;l -N{;R?}C{0)-Gi-C^alkyi«ne-H(R¾)(K¾ and R7 is hydrogen or alky! and R;,i and R"i! are independently hydrogen, alkyh ammoaikyl.
alkyia inoaikyi, or dialkyisnsinoalkyi; find all other groups are a defined in the Summary of
-KHC(0)CH(a i5}NH2, -NHC(0)C{C¾)2NH;, -NI iC{0}CH;N(CH3}2, - NHC(0)CHj (C Ii)CH>CH2 (CHj)3, -NHC(0)CH(N¾)G¾C¾, - NHC{O)CHj (CH. C¾C¾ .(CH5}, or -NHC(0)CH(CH ) H(CH5).
fO023] Embodiment (N) provides a compound of Formula I where each Rs> is independently halo; eyaao; aiky!; alkenyl; a!koxy; hydroxyamino; carboxy; aikylsulfonyk. ammoalkylo y alkylaramoalkyloxyidialkykminoalkyloxy; -N(R')C{0)-CrCralkylene- (R7*)(R7i)); -€;ίΟ)ΝΙ¾Λΐώ; ~NR¾(G)R93; -C(0)N(Rift}-C rC^alk 'lene- iR^j '^ -Ν¾Γί€(Ό)ΝΚ ¾Ηί! where R,la; -C{0)RiJ; - ,3CfO)ORt¾; -C(0)N(RM)N(Ri¾)(R|iil ;- -S{02 'N(Rls)-Ct-C^alkylene. (R15a)Ri5¾; -C(0)N(R!i>)-Cl-Cfl-alkyiene-C(O)0 !6a;
heter ary! optionally su stituted with one or two ammoatkyk alkylaminoatkyl, or
4 lkyl^in alkyi -N Ri5 C(-N(R!7b}(R,¾))( R!?¾,¾i) - (Ris:)C(0}-Ct-C6raikykne~ N{ RISB}C(0}R5^; -C(0) (Rw)-Gi-e6-alkyiene (O)Rl¾; -N(R22)C(0)-C , -C alkyteiie- N{R-A)~ (R"^ -NR3''G(0)- CjX alkytene-OR"'1*;. where 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, |§0i24) hi another embodment, each R' is independently methyl, bronv^ cMoro, fluoro, - HC(0)C¾NH(CHj),
-NHC(0)CH(CHi)NH2,
-NMCfOjCfCl- NH^ -NHC(0}CH2N(C¾b, . -NHCCOJ'CI-fc iCHjJCHiCHiNiClIj)^ -NMCCO)CB( ^
-NHC(0){pyiTOlidm-2-yl),- HC{0)CH( H2)CH20H, -NHC(0)(aa.iidin-4-yi),
- HC(0)C(CH5}2N.H(CH5),- H2, - HC<0.)CMi H{CHjC.H2C.H3),
-NHe(Q]C¾C¾NB2! - HOH, -NHC(0)(piperidin-3-yl j, -HHC(0)C¾'(4-ntethyl- 1 A- diazepan-l-yl)t . HC(0)Ce{NH2)(C¾CHi), -NHC{0)C¾ H{CH2CH{OH)( Hj)),.
- HC(0)C¾NHCH2CBjFi -NIiC(0)Cl!2Nf'i{OClbCH(CH3)2}; - HC(0)( 1 - aminGcycloprop- 1 -yl), - H:C(Q)CH.2 l:i(Cri2cyelopropy!), ~NHC(0)CH2(3 - (dimethylaniinoHzetidin-l-yl), -NHC(0)(piperidm-2-yI), ~NI-lC{0)(morpholin-4-yl}, -NHC(0)CH2(pyrrc>iidin-i -y5}, - HC(0)CUi H2}CH2CH2CH2CH2 (CH3)25 - HC(0)C¾N(CHj)(CH;Cii3), ~NHC(O}CH2(mvidaz0l~5~yl), -NHC{0)(.Uamino yciopent- 1 -yl), -NBG(0)CM2NH( CHaCWCM^a), - H.C(0}CH2N{CH5KC¾GH3}, - Ή0(Ο)(Λ?~ (iraidazoi-4-y!tnediyi)-3zetidin-3-yi); - HefO)fiV-ethyi-azetidin~3-yi},
-K¾CH2N(C!¼)CH2CW
-NHC(0}CH2(3-piperidin-]- ylazetidm-tylj, - HC(0}Ni h, -NHC(0)( I -hydraxycyc!opropy!), -NHC(0)GH2NHN(C¾)2, -NHC(0}NHfCH;) (CMjt.h, -NTHC(0)CH;OH, -NHC(G}(pyrida2in-4~yl), ^ HC(0){N- pyrr»lidm-lyi); >NHC(O)C¾NH(CH2)2N{CH 2, - HC(0)t I -cyc!oprop lnietliyl-azetidin~3~ yl), -NHC(0)CHs^M(CH.?k -KHC(OJ{imidazol-2-yl>,. -NHC(0)(imidazol-4-yi),
-NHC(0)(L2~oxazoi-5-yl),-MHC(0)CH2 i:iCH;CF,, - HC(0)CH2C¾{piperidin-i-y!X -NHC(0)(3-o)co-cyclopeHi- 1 -yl), - HC{0)(2-liydroxy-pyridi«-6-yl), - HC(0)CHi H(3- fluoro-4-hydroxypiienyl}, -NHG0)(CH2)j (CH3)2, -NHC{0}Cl-(fi»ian-,2~yliftei yl)»az«¾diii- 3-yi), - H O){pyriimdm-5-yi)5 -NHG(OKpy^
-NMCiO)CHiN{CH2CI¾)3 -NHCiO)CH2i3-methyM,2-oxa¾ol->5-yl),
~NHC(0)CH2NHCH2(3½dmxyphenyl), -Nf lCiO)(A?~meihy^pynx)i-2^yl) -NBC(0)(2- amino-ietrahydropyran-2-yl), -NHCCC Ci¾i4-ra^
-NHC(0)(piperidi - 1 -yl), -NHC(0)iV-m.eihyl-pyrralidin-2yl), >MHC.(0)(thieti-3yi)5 -NHC(0)(^(cyc] prapylcarbonyI)a2etidin-3--y!)? -NHC(0)CH2(4-methyIpiperazin-l-y!)?
-NHC(0)CH2(pyridin--4- yl), -NHC(0)CH2M(CH?)iCi:fcCH-Cl½), - HClOiCHi Hfb riz l), - HCfO)C¾OCH, - MHC{0)[I-CC{0)CH;C^
-NHC(0)C¾ HeH2CH2OCH3, -NHC(0}(1
methyl-pyrrbliditi-l-yl), ~NHC(0)(tu«m-3-yl), - HC(0)eH2N( B?b,-MHC'(G)(2-ch ro> pyrkim^vl), -NHC{0)(2-chioro^^^ -N.HC(0)CH>(3- d½edrylamiiiQ-az tidm~i~yl). -MHC(0)CH3i pyridm-3-yl), -NHC{0)CH2(2-ehtoropheny!), -NHC{0)CH2 (CHi)CH2C¾C¾N{CH )2, -NHaOCI-fc iCHjCHiJCHjCHiOH, - NWC(0)CH2{2-beozy.l-pyrrolidiB- 1 -yl), -NHC(0)(furan-2-y^ -N HC(0)(2-c¾ ro-pyridin-4- yl), -NHC(0)CH2NHC(G)CH,t
-NHC(0)f4-chioropheny!), - NHC(0)(4-meihyii>henyl), - HC{0)CH2NHC(O)G(CHj)j, - HC(O)(benzod.H1.3)di0xol- S-y!J, ~NHC(G)CHjNHOCH>(2-methoxypheiiyl), -NHC{O)ipyridm-4-y}),■^ CiOjCH^A' (3,4-dich.loropbenyi)-piperazia-l -yl), HC(G)CH2CH2(pydditi-3-yl),.
-NHC(0)(tetrahydrof ran-3-yl), ^NHCfO)CH2NHCH3(2-methylphsnyl):
-NHC{0)CH(CH¾)C¾CH - HC(0)CH;{3-iuoroptoyi)? -NHC(0)C¾C{a¾):phenyL - NHC(0){2,methyl-cycloprop- l-yS), -NHC<G)(2-methyl-4-m thoxypfaeiiyl), - HC(0)(2- raethylpyridift-3-yl}, - HCiO)(4-ra:6ihoxyphe«yl), ~NHCfO)CH2{4-¾hylpipemxm- 1 -yl), -MMCXO)(«uen-2-yl), -NHC(.0)(3-.fl«oro-2-metiiylphe yI), -NHC(0)(2-bromorthien-3-yl),
- BCiOXCM^bCH^ - HCiOlCHjOCHiCHi, -NHC(0)CH, H(2-fluorop enyi),
-NHC(O)3-dime iammop¾e»y!),-KHC(0)^^
-NHCiO}CH2 H(2-/i-pt¾pyiphenyl), -NHC{0)phenyL -KHC(0)(pyrazm2-yl), - H€(0){3-
. HC(OX 1 -nteiliyicar oayi-iizeudin-S-y!), -N HC(0)CBNH(4-meihyIphe!iyl)?
-NHqO)CH2NB(phe«yI), -NHC(0)CH2{4-3ilyI-pipera7J.n-l-yl}? -NHe(0)(2-methylphenyl); -NHCCO)CH2CH2OC¾, -NHC(0)(3-raethyl-fi)raii-2>yl), .- HC{O)C(C¾)¾, - NHCiOjCHj-NHObeiizyl, - H¾0CH2NH<3-clilorophettyl), - BC(0}cyek)l:nriyl,
-NHC(0)C¾(3-methqxyph.enyl), -NHC(0)(1 -methylcy¾loprop-l-yl),
- HC(0)(3-«UiOphenyt),-NHC(0)(4rd«nethylsm.nopj l) -Ni-iC(0)(3,4-dichloropheayl), - HC(O)CK2NBCH2(2>raethylihJ0pl¾enyl), - HC(0)CH2(2«ilu rophei5yi)>
-NHG(O)CH2N(CH. beiizyL -NHC{ )CH2NHCH2(t¾ien.-2-yl), - HG(0)CH2NHCH2(pyridm-2»yi).-NHC{Q)(3-.
methoxyphenyl), -NH.C(0)C:H2NHCH2(3 .hlorv4-methyiphenyl),
-NHC(OK3-iluoro- -methylpheayl), -NfiC(0)CH20(2-methy!phenyl)5.
-NHCCOJCHsCcyclohexy!), -NMCiO)(2-p enyi-cyci prop- 1 -yl), -NHC{O)( cWoix>phenyl), -NHC(0)CH; 2-raetbDxyp t;ny!), ~NHC(D)CH2CH2p-methoxypheftyi), -NHC(D)CI¾NH(2- fluoro- -m¾thyl-plienyl), -NHqOJCBj HCHsiS-fiuem-phen i), -NHC(0)CH2(4~methoxy- phenylj*. - HC(0)benzyl, -Nl-lC(0)(2,4^iohlorophonyl), ~NBC(0){3-oxo-cyolohex~t-yl), - lC(0)C¾ H(3-fuorophenyi), -NHC(0)CH2{3-chl0rophenyl), - N¾QO)CH2NHCI¼CH¾
- HC(0}CH2( -m^^^^
- HCCO)CH2CH2CH-CH2>
«NHC(0)C:H. H(2-iT3ethyIplmny)}, ~NHC(0)CH2(4-oxo-piperidii l-yl}; -NMC(0)(2- D.uoropheayl)5 - HC(D}C¾NHCH(GBj)phenyL -NHC(0){2-«ui»ro-6-n3«thoxyph«myi)> -NHC(0}eH2 H{2-isopropy!p eiiyl)> - HC(0)CB2CM2C2-meihoxypheayi};
- 'HC(0)CH2CH2CH(CH3)2, - HC{0)CH2(2-phetiyf-morpholm-4-v1), « HC(0)CH2C¾(4« methoxyp nyl),; - HC0)CH2 (iillyi}eyclopeniyi, - ^ {0)CH2N(CH.?)CH>Ct;i¾DCBi, - Hlie(0)CH2Ci¾C(a)ey^^ -NBC(ttJCHN(»- propylHcyclopropyImethyl>< <NHC(Q)CH2(2-oxt-cyclop ntyl),-NHC(0)CBjNH(4- chloiophenyl). T HC(Q)CH2(4~pipt,ndift-l-ylpiperi(li««'l-y!), - HC(0)CH 4-'
eydopimiyipiperazin-i-yi), -NB (0)CI¾(2-meihy!p:heny!), -NKC(0)CHj HCH2(3-fiuero-
Ouoro-e-TOethylphenyl), -ftHC(0)( -ftueu¾^
«NHC(0)CH2OphenyI, <KHC{0)Ci¾ H{2 ^im6t¾1phen 1),- H {0)( ~fluoro>
5-methylphe:n l ^^
isopropylpiperazin-l-yl), >NHC(0)CH2(4-BuoRphenyl.), -NHC(0)CH2CH(CH5)2
-NHC O)(2-avetlHX\y-4-mei y.IpfieByi, - i-if'(0)CH2f4-ii~propylpiperkim-!~yl),
-NHC(0)CH20(3-methy!p eny!), -NHCCOXtetraliydroftinia-2-yl), -NHC(0)CH;(3- hydroxymethylpiperidm- i -ylj, -NHC(0)(J»?^b»oxy¾tl?p.oyipipefidi«'-2-iyl),
-NHC(0)CH2OCB2CH;OC¾, -NHC(0)CH3Gi¾(cyclopeKtyl), ~NHC{0}(2
di iterdphem-i), -NHC(0)CH¾(4-methykarfSQnylpipecazm- i -yl), -NB€(0}(5-fiuoK>~2~ methoxyp enyl), -NHC(0}C¾ (C¾eH)eyelohexy -NH.C(0)(5-methyH,2-oxa2ol-3-yl)t - HC(0)(3-raetiwipyridin-3-yl)! -NHC(0)(2-i«eii\oxypyiIdjn-3-yI), - HC(Q)(3
dichtoropheoyl), - i-lCfOJCffciihiazolidu^-y!), ~ Ηαθ)€Η2(4-€(0)ί1]- 5 βΓ»ζίπ-1-νΙ), -NHC(0)CH2(2*p riditH
-mC( }CH2NH'CH5)CH2CH(CH3)∑> - HC(0)CH2.{4-C(O}H^om ipeR^i« l- i
-NeC(0)(l-p enylcycopmp-l-yl), - HCfGlCilii ^-dimethyimoip olm^-yi),
NHC(C5)CB2 -p enylpymUdin- 1 -yt), -^HC(0)CH2(itt rplioIin-4-yl),
-C(0) HCH2CH2 (CH3.)2- -C(O)NH(pytto «-3-y ,
-C(0) HCH3C¾(pyrroiidift-l-yl), -C(0)HHeii3,€¾N¾ -C( ) ( H)C¾CH2 {eH )2,■ C(0)NHeHi{p!peridin-2-yl), -C(0)NH( 1 -methylazetidin-3-yl), -C(D}NHC¾CB:(psperi.din- i-yl), -C(0)NHCH2C.¾N(Ct¾CH3)¾ -C(0)NH(l-rnetiiyip5peridin-3- l);,
~C(Q H(piperidin-3-yi), -€{0) HCH>{ 1 -meihylpiperidin-3-yi),
-C(0)NH H∑CM2H(CH2CH20H)2, 'C(0)HH(l.e ipipemU»-3-yl)5 -C(Q)NH2f -C(0)(3-
-C(0}(3~dimeihylaminopyiToiidtn-i-yl), .C(0)NHCH2(pyndin-4-y!), -C(0)N(CI¾}(I~ ractyi-pyrroiidsa-3-yi), ~C{0H3-djeihylaminopyrrofidla-!-yt), -C{0)NH(pyrrol-l-yl), -C0) HC!:l2CI:I2C¾pyiTOiidin-- 1 -yl), «C(0) (CH2)C¾CH2CN, -C{0)NHCB3CI¾OCH2, -C(0} (C%eH: C^
-C( )HHCH2CH2CH2N(C¾)¾ -C(0)NHimorpholin-4-yl), -C(0) H fCH3:)2, - C(0)NHCH2C¾CH2(imsdazo]- 1 -y!), -C(0) HCB2CH2CM2 (CH:jCH3)2s
-C(0)NHCH2CH2SCH2 H3,-C(0) <CH2CH5)CH2CH2 (CH3)2, ~C(0) HCH3CHnCH2(2- oxo-pyrsolidm- 1-yi), -C(0).NHCH2CHi(:pyridm-4-yl), -e(O)NHCH2C¾CH20C¾CH3, - CCOjNHCHiCH^CH^mor lwHii-- l), -C(0)NHCI¾CH2Ci¾OC¾,
,C(O)N{C¾)CH2CH2CH2N(CH. i -CiO)NHG¾CH H:OCH2C¾C! ,
-C(0) HGH2CH2CO)OCH2CHjf «€(Q)NHCi¾CH2eH20CH(C¾)2, - C(0)NHC{CH3)2C¾(pi ^ -C(0)NH(piperidin~l -y!),
-C(O)NHCH{CH?)CH2OCH55..C(0) iC(C¾)2.CH2(morpholin-4-yl),-.C{0)(2- dimet y!aramomediylpiperidm- l~yt)s -C(0}KH{Ci¾)jO(CH2)3C¾, - C(0) HCl¾(CH. CH2KN(CH2Cf^)2, -C(0)Ni ICf Ci¾)LC(OXpiperidii5- 1 -y!), -C(0)(4- •mediylpiperazin-l ~yi), ~C(0)(2-p jperidia- 1 -ylmethyl-piperidin- Ϊ -yl), eyano, -NHC¾, -CH(CHj) HG:H2CH2 (CH,)2, -C(0)GH3, -S(() NHGH2CI: !;Cl¾)2,
-S(0)2 :H{CH2);5N(CH3)2! 5-(Ar.N-d netliylanu«ometh i)- ϊ 53,4-oxadiazol-2-yi,
-NHCKjCH2N(CH5)2> -N(CH.j)2> -OCHC¾N(CI¾ , -NHC(N(CH3)2|(- (CH>fc], -0€i¾ -CFj, -S{0¾CH3, -OCF.5, ~NHC(0)C¾(4-diniediyianrinopiperkii.n-l~yl)> or .tnethpxy.
{90125} in another embodiment. (F), RJ is independently halo, a!kyi, hydrox zine,
-NiR')C(0)-Ci-C aikyIene-N( i:)(R¾), -C(0) R¾¾ , - 11¾0}Κ¾, -OOiH^yC Or alky!ene~N(R -!0a)Rlftb-NRl !C(0)NR! n ~ (&22)C(Q)-€i -C aikylene~N(R"h}- (R~ (E22a), - Rl3C(Q)0R!?i\ - fR'-jCCOi-CrC alkyiene- i ^^CiO)^8'1 , -NR2C(0)- Q.C¾-»ikyle.neOR\ r-NfR2i>. X )-CrC<i-alkyieiie-C(O)R20a; where each of the alkylene in R" is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from .halo, hydroxy, and amino; and all other gro tips are as defined in the Summary of the
In vention. In another embodiment each R" is independently methyl, ehioro,
- '!;{C(0)CH?N H(C¾), -NHC(0)CH(C¾.)N¾, -NHC(0)C(C¾)≥M¾,
-NHC(0)CH2 {CHjk, - HC(D)a¾ fCHj)CH:C¾N(CHi)2, -NHCiO)GH(N¾)CM.3C¾, - BC{0)CH2N(CHJ)CHJ<:H2.N{CH5)2..
- HG{0)H, - HCOCHiCa etidiii-l- ^NHCCajfp rrolidiji-a- l), -NH(¾0)CH(NH2)CH3OH,
- HC(0)(azetidm-4-yI), - HC(0)C(C¾)2 if(CHj), -NH2} - HC{0)CH2NH(CH2CH2CB3),: -NBG(G)C¾CH2 ¾ - HOH, or - HC(0}(p!pendin-3-yi).
100126) in another embodiment {Q% R3 is aikyl qr-N(.R?)C(0)-Ci-C6-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. In another embodiment, each R-> is independently methyl - HC(0)CH2NH(C1¾ - HC(0)CH(CH.v) H2, - HC(0)C(CH3)2NH2, -NHC(O)-
-NHC(Q)CH2N(CH -)C¾CH: fCH3)¾ or -NHC{0)CI¾CHj)NH(CHs).
optionally further substituted with 1 , 2, 3. 4, or 5 groups selected from halo, hydroxy, and amino; and ali other groups are as defined in the- Summary of the Invention.
100128! In another embodiment (R 1) of embodiment R, R51', R '~, and R ! are hydrogen and Ri:! is halo or alkoxy; R5l!,. R>% and R'*'are hydrogen and Rs~ is aikoxy: or R><! and R* are hydrogen and R? ! and RJ" 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. In another embodiment, R ', R*2, and iV"* are hydrogen and R is halo or alkoxy; or R? \ RJ\ and R'" are hydrogen and R? A is alkoxy.
1 129] In another embodiment of (R2) of embodiment R, R> ! is methyl. Compounds of Formula la
θ¾13θ·| In. another embodiment, the compound of Formula I is a compound of Formula la;
la
or a ' pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof wherein: i¾"* is hydrogen;
R is methyl;
R~~ is hyd ogen;
R" is hydroge or alkoxy; and
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; and
¾ is -NC ^yCfOi-C C^alk i.ert^NiR.^KR51'). where R.7 is hydrogen and R7a and
d it Iky ί am moa I ky l .
|0013Ι{ In one embodiment of the compound of Formula la, R>! is methyl; and R>(\ R", and R. > arc hydrogen and R' is halo or alkoxy or R:<i > R'\ and R¾i are hydrogen and ¾- is aikoxy; or a single stereoisomer or mixture of stereoisomers thereof.
[00132} In. another embodiment,. R"iS is - HC(0)CH2NH£G%k -NHC(0)CH(CH>)NH2> - HC.(G)C<C¾)2NH2, -NW€(0)-CHlN{CH3)2,-NHC(e)CM2N{CH5)CH2CH2 ^CH3)2,-- HC(0)eH(NH2)GH2€H3s - HC{0)C¾ (CH3.)CH2CH2N{CH3)25 or - HC{0)eHC¾)NHfC¾).
[00133]
embodiment, the compound of formula la is:
or a pharmaceutically acceptable salt thereof.
[0013 1 ϊη one embodiment, the eonipouitd of Formula ! and of Formula la is Compound
Compound A
or a pharmaceutically salt, taiitamer, hydrate, or solvate thereof. Compound of Formula H
[00135) In one embodiment, 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. Specifically, Rf is ydrogen, optionally substituted alkyl, optionally substituted eycloaikyl, optionally substituted arylalkyl, or optionally■.substituted heteroeycloalkylalkyl. More specifically, Rl is hydrogen, alkyl alkyl substituted with one or two hydroxy, alky! substituted with alkoxy, eycloaikyl, arylalkyl, or heterocydoaikylalkyi. Even, more specifically, R1 is hydrogen, methyl, ethyl, propyl isopropyL '2-hydroxypr pyl, 3-hydtoxypropyl, 2-ethoxyethyL S-rneihoxypropyi,
3-ethoxypropyl, 3-isopropoxypropyl, cyclopropyl, cydobutyl, eyclopentyi cyclohexyl, benzyl, or 2-ptperidin- 1 -ykthyl. Yet even more specifically, R! is ethyl, ssopropyi, eyclopentyi, or cycSohexyl Yet even more specifically, ! is ethyl,
1001361 i another embodiment, R is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R¾ groups. Specifically,. R2 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. Even more specifically, R* is hydrogen, methyl, ethyl, propyl, isopropyl, ierr-butyi, -aniiiio propyl -('A''~met!rj'lamlno)-propyL 3-{N,/V-<li8ieihybmmo)-pr0pyly 2 iluoroethyl, or 2,2,2 -triOuoroetliyl Yet even more specifically, R': is hydrogen or ethyl. Yet even more preferably.. R ' is ethyl
Ι'ββ.137 i In another embodiment, R" is hydrogen .
|00138| ¾ another embodiment, R is optionally substituted alkyl. Specifically, R4 is methyl or ethyl. More specifically, is methyl.
more specifically, Ri; is acetyl
106140} in another embodiment, Ri! is phenyl optionally substituted with 1 , 2, 3, , or 5 Rv groups. Specifically, 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 R9 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, nieihoxyphenyhdiuiethoxyphenyL phetiyloxypheoyi, or triflupro.raethylphenyl. Yet even more specifically, R" k phenyl, 2>¾>henyl-phenyl, 3-phe»yl-pheny 4-phenyl- pbertyL 2-iluorophenyi, 3-lluorophenyl, 4-f uorophenyl, 2,3~dinuorophenyl, 2,4- difluorophenyl, 2,5~diiiuor p.henyl, 2,6^diflu(>rophenyl, 34-diiJuorophenyi,
3.5- diil.«:oiOphenvL 2-eliloropheiiyl, 3-ctn¾ropoeiv j,: 4-chl'Qrophenyl, 3 J-dich rophenyL 2,4-dic o«>phenyl, 2,5-dichlorophenyi, 2,6-dichloraphenyl, 3,4-dichlorophenyl,
SjS-dichlo'ropheny '^'Ohl r ^fluorb-phehyl, 2~methoxyphenyl, 3~raeihoxyphenyl,
4-methoxyphimyl, 2,3-diihethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-diraethoxyphe.iwl,
2.6- dimetho:xyphenyl, 3,4-dime.thoxyphenyl, 3,5-di.methoxypoenyI, 4-phenyloxyphenyi, 2-uifluorqniethylphenyi, 3>tri0uot»methylphenyl, or 4-irifiuoronvethylphenyl,
{001411 In another eaibodiraent, W is hctere>ary! optionally su stituted with I, 2, 3, 4, or 5 Rv groups.
(001421 In another embodiment, 6 is a ό-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. Even more specifically, 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 .
S0f)143j In another embodiment. 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.
|0Q.1.44j In another embodiment, R* is a 5-membered heteroaryi optionally substituted with one or two R'?. Specifically Rf! is pynm>lyly imidszolyl, thien l, ihiaxolyl, oxazoiyl,
Isoxazolyi, oxadiazoiyi, ftiranyl, pyrroly.1, triazolyl, or tetrazoiyl. each of which is optionally
alkoxyearboiryl, or halo. More specifkally, 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 3t4-oxadiazol-2- yi, 1 ,2,4-oxadiazol-3-yL l ,2,4-oxadiazc)}-5~y}, furan-2-yl, i\mm~3-yl, pyrrol- 1-yl- pyrroi-2-yl, pyn¾1-3-yI, triazol-i-yl, triazol-4~yI, triaKoi-S-y!, tetr zoi-l-yb or tetrazoI-5-y each of which is optionally substituted with otic R wherein. Ry, 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-
2- yl, thia¾oM-yl, thiazol-5-yl, oxazol~2-yL oxazol- -yl, oxazol-S-yl, isoxazol-J-yl, isoxazol-
4- yl isoxaxoi-5-yb 1 ,2,3-oxadiazol-4-yi, l ,2,3-osadiazal-5-yl, l ,3,4-oxaiiiazol-2<-yi,
l,2,4^oxadiazoi-3-yl, l ^^-oxadiazoi-S-yi, &ran-2-yL ftiran-3-yl, pyrrol-2-yL pyrrol-3-yi, triazol-4-yl, triazol-5-yi , or tetrazoJ-5-yi; each of which is optionally substituted with one herein R'', when present, is methyl, benzyl, cyano, phenyl, Λ'-fert-butoxycarbonyl, or ehioro.
(001451 in another embodiment, R(> is tlueayl, pyrroiyl, luranyl, pyrazoiyl, thiazoiyi, isoxazolyVimidazolyi, triazoiyS, or tetrazoiyi, each of which is optionally substituted with one R ' wherein K5', when present, is methyl, benzyl, cyano, phenyl, A?-ieri-buioxyearbonyl, or eiiloro. Specifically* R" is thien-2-yi, thicn~3-yl, pyrrol-2~yi, ¾ran-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, tria¾ol-
5- yl, tetrazol-5-yl, each of which is- optionally substituted with one R wherein R'", when present, is methyl, benzyl, cyano, phenyl iV-feri-butoxyearbony!, or chloro. More
specifically, R" is thieri-2-yl thien-3-yl, . 5-cyano-thien-2-yls 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-pyo¾l~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 tetrazohS-yb
100146] In another embodiment, R* is ihien-2-yl, ihi ii-3-yl, pyrrol~2-yls. furan-2-yi , furan-
3- yh pyraxol-3-yL. pyraaol-4-ylv pyrazo!-S-yl, thu¾oh2-yl, thiazobS-yi, isoxazo -yl, imida ol-5-yi, triazol-5«yl, or tetrazoi-5~yi, each of which is optionall substituted- with one wherein R'5, when present, is methyl, benzyl, cyano, phenyl, v¾?t-butoxycarfaanyL or chloro.
benzoxazolyl. or benzoisoxazoiyl, each of which is optionally su stituted with 1. 2, 3, 4, or 5 y groups. Specifically, Rb 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 ben¾imidazol-6-yi, henzsmtdazol-T-yi, henzo teri-l-yl, benzoitmm-3-yi
be«z»fiiran-0-yl;, bea?;oiwan-7-yi, be«zoxa2ol-2-yl benzoxaxoM-yl, bettzoxasol^S-yl, beRzoxazol-6-yl, herm>xa¾ol-7-yl, benzoisoxaxol-3-yl, benzoisoxazol- -yl, benzoisoxazol-S- yi benzoisoxazoK yi or benzoisoxazoh?-y!; each of which is optionally -substituted with i, 2, 3, 4, or 5 ¾ groups. More specifically, * is indol-6-yl.
(00148) In another embodiment. Rs is hydrogen, optionally substituted alkyl, optionally substituted cycloailcyi,- optionally substi uted' heferoeycloalkylalkyl, or optionally substituted aryialky!; X is -NH- 'R2 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. two, or three R9 groups; 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.
[ 01 9! hi another embodiment, R* is pyrazol-3-yl, pyra¾ol- -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,
{00150} In another embodiment, R1 is alkyl or eycioalky!; R4 is methyl; and R" is heteroaryl optionally substituted with one or two R* groups. Specifically, each R*, when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxyearbon l, or halo. Specifically, Rt! is pyrazol-3-yl, 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-yl, pyriOl-2-yL pyrrol-3-yl, triazoi-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with one 'J wherein R9, when present, is methyl, benzyl, cyano, phenyl, or N-t&i- butoxyearbonyl.
(00151 j I another embodiment, R" is hydrogen.
(00152} In another embodiment, 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.
[00154] in another embodiment. R! is alkyl or eye!oaiky!; Τ is methyl; and R is hydrogen.
In another embodiment. R1 is alky! or c cloalkyl; R4 is methyl; and R* is optionally substituted alkyl.
Compounds of Formula ίΙΛ
[00.155} In another embodiment, the compound of formula 1 is a compound of formula Π A .
HA
or a pharmaceutically acceptabl 'salt .thereof, wherein:
R! is alkyl, cycloalkyl, cyeloaikylaikyl, aryl. arylalkyl, heterocycloalkyl,
heterpcyeloalkylalkyl, heteroary!, or heteroaryiaikyl:
R" is hydrogen or alkyl;
R"* is alkyl
R'" is hydrogen;
R¾ is phenyl, acyi or heieroaryi
the phenyl and h teroaryl are is optionally substituted with L 2, 3·, 4, or 5 R'* groups; and
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
dialkylamino,
100156] In one embodiment, 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;.
100157} In another embodiment, R is methyl.
[00159] In another embodiment, ! is aikyl.
[0016 j I» another Lwbodi eoL i is heteroaryt optionally substituted with 1 , 2, or 3 R' groups.
[001611 in another embodiment, each R9, when present, is independently a kyl arylalky!, cyano, aryj, alfcoxycarbonyl, .or halo.
1001621 In another embodiment, 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,
[00163] In. another embodiment, R.6 is pyi¾zo]-3-ylt 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. iinazeii-S-yi, oxazoi-2-yl, o azol-4-yl, oxazol-3-yl, isoxa¾o.l-3-yl, isoxazo!-4-yi, isoxazol-5-yl, 1 ,2,3- oxadia ol~4~y l ,3 iXiul.ia¾ol-5-yi 3»4-oxadraxoi-2-y 1 ,2,4-oxadiazol«3-yl5
i,2,4-oxa(iiazo!-5-yL l½ra»-2^yI l¾nui-3-yl,.pyrri l-2-> , pyrrol-3-yl, triaz0l~4*yi- triazol-5-yl, or tetrazoi-5-yl; each of which is optionally substituted with 1 , 2, or 3 R groups.
[00164] In another embodinieni, Rfi is pyraziny pyrimidiayi or py idaziny! each of which is optionally substituted with 1, 2, or 3 Ry groups and R' is methyl.
[00165] hi another em odiment, K" is hydrogen, IV is methyl, R1 is optionally -substituted alkyl, eycloalkyl or heteroeyeloaikyl, and " is heteroaryl optionally substituted, with ί. 2, or
3 R groups.
[00166] In another embodiment, the compound of formula Ha is selected form:
2~anvmo-8-cye1opentyi-4-me^
|"00167) In another embodiment, the compound of formula HA is Compound B, which is
■2-amino-8-tni¾yi-4- ei yI-^
B) or a piiarmaccuticaily acceptable salt thereof.
Additional Embodiments
Treatment of Endometrial Carcinoma
(001.68] In one embodiment, 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.
|00lo9J in another embodiment. Compound A or B is administered as a capsule or tablet pharmaceutical composition.
j80170} in another embodiment, the amount Compound A or in the tablet or capsule formulation is sufficient to produce saturation of absorption administered once. daily. |'00t71] In another embodiment, about 10.0 mg to about 800 mg Compound A is administered as a capsule composition once daily.
|00i 721 in another embodiment, about 200 mg to about 700 mg Compound A or B is administered as a capsule. composition once daily.
1 0173( In another embodiments about 500 rag to about 700 mg. Compound A or B is administered as a capsule, composition once daily.
[00174) In another embodiment, 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.
{001761 In another embodiment, about 300 m to about 500 mg Compound A or B is administered as a tablet composition once daily,
|'60177| in another embodiment, about 400 mg Compound A or B is administered as a tablet composition once daily.
{00.178} t o another- embodiment, the endometrial cancer is' advanced or recurrent.
{©0179} In another embodiment. 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.
Gelatin Capsule Composition
Swedish Orange Opaque Capsule
Component {for 100-mg strength)
FDA/El 71 titanium dioxide 0,4902%
FDA/El 72 red iron dioxide 1 ,4706%
Gelatin sp 100%
FDA, Food and Drug Administration; qsp, quantity sufficient for 100%,
100.180} in another embodiment, 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
pregekittnized maize sta:rch, sodium starch alveolate, iry romeiiose, colloidal silicon dioxide, stearic acid, and magnesium, stearaie. Ail three tablet strengths are manufactured from a •common blend with the composition listed in the ¾ flowing Table.
Composition of the Compound 100-, 150-, and 200-mg Tablets
Ingredient Batch Formula (% w/w)
Compound A or B 50.00
Si!icil d Mic'rocrystaUme Cellulose, 14,75
Partially Pregeiaimized Make Starch 20.00
Sodium Starch Glycolate 7,00
Hyproirteltose 2 1 6,00
Colloidal Silicon Dioxide 1.00
Stearic Aci 1.00
gnes um Steara te f U '! . ϋ J
Purified Water a
* Essential ly removed du in manufacture.
[90181 j in another embodirnenl, 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. 100182] in another embodiment, the effective amount produces an improved clinical benefit rate (GBR) according to the equation CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > : months) as compared to other treatments.
[001831 In another embodiment, the improvement of clinical benefit rate is about 20 percent or higher.
[00 (84] in another embodiment, the therapeutic effec is an increase in overall response rate.
jOOlSSj In another embodim n , the increase in overall response r te is about 10 percent or more or higher.
('00186 j In another embodiment, a comparable clinical benefit rate(CBR) according to the equation. CBR - Cfl (complete remission) t PR (partial remission) * SD (stable disease) > 6 dosing cycles) is obtained with Compound Λ or a pharmaceutically acceptable salt thereof.
[00187| In another embodiment, the improvement of clinical benefit rate is a least about 20 percent or higher.
100188] In another embodiment, 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 .
100189) in another embodiment, the impro ement of clinical benefit rate is at least about .20 percent or higher.
Treatment f Breast Cancer
[00.190] in another embodiment, 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
or a pharmaceutically acceptable salt thereof;
wherein 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
wherein for each cycle in (B) the SetrozoSe s administered at a daily dose of about 2.5 twg and Compound B 'is administered at dose in tablet form of 50 mg twice daily.
{001911 In one embodiment, the breast cancer is hormone receptor-positive (ER- and/or POR÷}. HER2-negaisve (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor.
10 1921 in another embodiment, 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
Compound A.
100193] In another embodiment, the breas cancer is hormone receptor-positive (ER+ and/or PGR+), HE¾2 -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,
reduction, in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, and a pathologic complete response.
1110195] Alternatively, in these and other embodiments, the effective amount produces an improved clinical benefit rate (CBR) according to the equation CBR ~ CR (complete
remission) + PR {partial remission) * SO {stable disease) > 6 months) as compared to other treatments. In this embodiment, 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;
(in) the increase in overall response rate is about !O percent o more.
1.00196} in another embodiment, 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.
10 197| in another embodiment, the leirozole is formulated for a daily dose of 2,5 nig.
100198] in another embodiment, 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.
j00199| In another embodiment, 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.
[0(1200] In another embodiment, 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 In this and other embodiments, the kit comprises instructions for using the letrozoie, as well as the Compound A or
Compound B in the method. as disclosed herein.
Letrozoie with Compound A
10 201 In one embodiment, 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.
[002021 i another embodiment, the Compound A is administered as a capsule or tablet pharmaceutical composition.
[00203] In another embodiment, tire amount of Compound A is sufficient to produce
-saturation, of absorption when admini stered once daily .
administered as a capsule composition onee daily,
[00205] in another embodiment, about 200 mg to about 700 mg Compound A is administered as a capsule composition once daily.
(002061 In another embodiment, about 500 mg So about 700 mg Compound A is
administered as a capsule composition once daily.
100207 j In another embodiment, about 100 mg its about 800 mg Compound A is
administered as a tablet composition once daily.
[00208] In another embodiment, about 200 mg to about 700 mg Compound A is
administered as a tablet composition onee daily.
(00209} la another embodiment, about 300 mg to about 500 mg Compound A is
administered as a tablet, composition once daily,
{00210] In another embodiment, about 400 mg Compound A is administered as a tablet composition onee daily.
(00211 j In another embodiment. 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.
Gelatin Capsule Composition
Swedish Orange Opaque Capsule
Component (for 100-rng strength)
FDA El.71 titanium dioxide 0.4902%
FDA/E172 red iron dioxide 1 .4706%
Gelatin qsp 100%
FDA, Food and Drug Administration: s , quantity sufficient for 1 0%.
[002 21 In another embodiment, 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.
Silieiiled Macrocrystalline Cel. lufose 14,75
Partially Pregeiatinized Maize Starch 20.00
Sodium Starch Giycoiate 7.00
Hypro ellose 29 ί 0 6.00
Colloidal Silicon Dioxide LOO
Stearic Ac id 1.00
Magnesium Stearate 0,25
Purified Water
Essentially removed during manufacture.
Letrozole with Compound B
[00213] in one embodiment, 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·,
[00214] i another embodiment, the Compound B as a capsule or tablet pharmaceutical composition.
|Ο0215} In another embodiment, 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 In another embodiment, the amount of Compound B in the tablet or capsule formulation is sufficient to produce saturation of -absorption when administered twice daily. 00217 j In another embodiment, about 10 mg to. about 100 mg Compound B is administered as a capsule composition twice daily.
[00218) in another embodiment, about 10 mg Compound B i administered as a capsule composition twice. daily.
[00219} In. another embodiment, about 20 mg Compound B is administe ed as a capsule composition twice daily,
[00220} In another embodiment, about 30 mg Compound 8 is administered as a capsule composition twice daily.
[002211 In another embodiment, about 40 mg Compound B is administered as a capsule composition twice daily.
[00222] in another embodiment, about 30 mg Compound B is administered as a capsule composition twice daily.
composition twice daily.
{002241 la another embodiment, about 70. mg Compound B is administered as a capsule composition twice daily,
[00225} in another embodiment, about 80 mg Com oun B is administered as a capsule composition twice daily.
{00226) in another embodiment, about S>0 mg C mpound B is adm nistered as a capsule composition twice daily.
{0 227 j In another embodiment, about 1.00 mg Compound 8 is administered as a capsule composition twice daily.
[00228j in another embodiment. 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.
Gelatin Capsule Composition of Compound B
G cnera! Ad ministration
[00229] in one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of the PDRs of Formula I or II and a pharmaceutically acceptable carrier, exeipiem, or diluent. In certain oilier specific embodiments, administration is by site oral route.
Administration of the compounds of Formula 1 or la. or their pbannaeeutiealiy acceptable
any of the accepted modes of achirinistrasion or agents for serv n similar utilities. Thus, the Compound of 'Formula I or II ean be. administered m " the same r separate vehicles.
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.
(00230} The compositions will include a conventional pharmaceutical carrie or exeipient and a Compound of Formula I or If as the/an. ac tive agent.
[00231 j 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.
1002321 If desired, 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.
(00233 j 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. Recently, 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. For example, 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 fier 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.
Examples of suitable aqueous and nonaqueous carriers, diluents, sol vents or vehicles 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. Proper fluidity can be maintained, for example, by the use of a coating such as leci thin, by. the maintenance of the required particle size in the ease of di spersions and by the use of surfactants.
(0 235 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.
(002361 Solid dosage forms for oral administration include capsules, tablets, pill's, powders, and granules. In such solid .dosage forms, 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. and silicic acid, (b) binders, as for example, cellulose derivatives, starch, aiignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) hismeetants, as for e ample;, glycerol, (d) 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, (f) absorption, accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as fo example, cetyl alcohol, and glycerol monostearaie. magnesium stearate and the like (h) adsorbents, as for example, kaolin and beuionite, and (i) lubricants, as for example, tale, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium laaryl sulfate, or mixtures thereof. In the ease of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
[0023?) 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
1 ,3-butylene lycol, dime thylfomiantide; .oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrot rftayl alcohol,
polvethyieneglycols and fatty acid esters of sorhitan; or mixtures' of these substances, and the like, to thereby form a solution, or suspension.
(002391 Suspensions, in addition to the active compounds, may cont in suspending agents, as for example, ethoxyiated isostearyl alcohol s¾ pojyoxyethy e sorbitol and sotbiian esters, krocrystallme cellulose, aluminum metahydroxide». bentonite, agar-agar and tragaca th, -or mixtures of these substances, and the like.
100240] 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.
((10241 j 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.
(00242] 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.
(002431 Gener ll , depending on the intended mode of administration, the
pharmaceutically acceptable 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. In one example, the composition will be between about 5% and about 75% by weight of a eonipound(s) of the invention, or a
phannaceuticall acceptable salt thereof, with the rest being suitable pharmaceutical exeipients,
(00244] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington 's Pharmaceutical Sciences, I Sth. Ed,,
any event, contain an. effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance- with the teachings of this invention.
[00245] In the pharmaceutical compositions disclosed herein, the compounds of Formula Ϊ 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,
100246) .For a normal human adult .having a- body weight of about 70 kilograms, 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, however, can vary. For example, 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
pharmaceutically active agent(s) within approved dosage ranges. Compounds of Formula i or H may alternatively be used sequentially with known.pharraaceutically acceptable agent(s) when a "combination formulation is inappropriate.
188247] In some embodiments, 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. In some embodiments, 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. In some embodiments, the therapeutic effect is an increase in overall response rate. In some
70%, 80¾ or more,
(00248] In some embodiments, a comparable clinical benefit rate (CBR = CR (complete remission). -f PR (partial remission) SD (stable disease) 6 cycles) is obtained with treatment of a) Compound A or B or a pharmaceutically - acceptable sail thereof. In some embodiments, 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%,
[00249] In some -embodiments, 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. In some embodiments, 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 improvement of clinical benefit rate is at least about 60%. In. some embodiments, die improvement of clinical benefit ate is at least about 70%. In some •embodiments, the improvement of clinical benefit rate is at least about 80%.
Ceneral S nthesis
Sy thesis of Compounds of Formula I
(00250} The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such a Aldrich Chemical Co. (Milwaukee. Wis.), or Bache (Torrance, Calif ), or are prepared by methods known to those skilled in the art following; procedures set forth in references such as Fisher and Fisher's Reagents for Organic Synthesis, Volumes 1 -17 (John Wiley and Sons, 1991 ); Rod's Chemistry of Carbon
Compounds, Volumes 1 -5 and Supplemental (Elsevier Science Publishers, 1089); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), rch's Advanced Organic Chemistry, (John Wiley and Sons, 4"1 Edition} and Larch' s Comprehensive Organic
Transformations (VICHY Publishers/me., 1 89.). These schemes are merely illustrative of
modifications to these schemes can be made
ar having referred to this disclosure. 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, erystailiz¾ti6r-,. chromatogra hy and the like. Such materials may he characterized using conventional means, including physical constants and spectral data.
{00251} Unless specified to the contrary, the reactions described herein take place at atmospheric pressure sod over a. temperature range from about -78 ¾ to about 150% in. another embodiment from about 0 ¾, to about 125 ¾ and most specifically at about room for ambient)- temperature, e.g., about 20°o:. Unless otherwise stated (as in the ease of a ydrogenatioii), all reactions are performed under an atmosphere of nitrogen
00252} Prodrugs -can be prepared by techniques know to one skilled in the art. These techniques' generally modify appropriate -fimctional groups in a gi ven compound,. These modified functional groups-regenerate original iimetlonal group by routine manipulation or in vivo. Amides' aod esters of the compounds of (he present inventio may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in. T, Higuchi and V. Stella, "Pro-drugs as Novel. Delivery Systems," Vol 14 of the A.C.S..
Symposium Series, and in Bioreversible Carriers-, in Drug 'Design, ed. Edward 8, Roche, American Pharmaceutical Association and Pergamon Press, 1-987, both of which are - incorporated herein by reference for all pus-poses.
{00253} The compounds of the invention, or their pharmaceutically acceptable salts, 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.
{00254] om of the compounds of the.- invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the' euol form; where an amide is present, the molecule may exist as the iuiidle acid; and where an enamine is present, the molecule ma existas 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
tautomeric forms..
100253] Thus, compounds of Formula 1
can exist as. tautomers. In particular,. ring-B in (he Coinptamd of Formula 1 or B can be 2- hydroxy-pyridmyi, also described as its structure:
14.
Both 2-hydroxy-pyridiayi find the above structure 14 include, and are equivalent to. pyridin- 2( iH)-or≤ and its structure JS:
15.
Regardless of which structure or which, terminology is used, each, tautomer is included within the scope of the Invention,
10()256j For example, one tautomer of Compound A is Compound Λ-1 :
Compound A-l
1 0257] Another tautomer of Compound Λ is Compound
Compound Λ-2
Compound A-2 is named N-(3~i[(2Z)~3~|{2-cl oro-5~metbo ypIienyi)aml
2( XHJ-ylklenejsuIfamoyl phenyil-I-nuitbyiaiauinasnide,
100258] As would be understood by a skilled practitioner,, tautomeric forms can mterconveit
•molecules, or eatioriic salts such a sodium or pb'tassium, depending on the substitutions on the B ring and on reaction conditions. All such zwitierk ic forms are within the scope of the invention, and to the extent that one structure i used to depict a zwitterionic compound, it includes all such xwiiteriomc forms,
160266] For example, o Compound A-3
Compound A-3
[06261] Another z itterionic depiction of Compound A is Compound A~
Compound A-4
|¾0262| pound
Compound AS
jj0 263j As would be understood by skilled practiiioner, iaiitomeric forms can mt rconvett,
{0026 ] Moreover, mterconverskm can also exist between the uncharged tautomeric forms and the xwitterionic forms.
(002651 Regardless of which .'structure or which ienninoiogy is used, each taiiiomcr or KwittcrioTJ is included withi herein, the structure
and the associated terms "Compound A" and < -(3- {[(3- ([2-cHoro-5- {.meth,o-xy)phen..y.]am^
encompass all possible tautomeric and x htcrkmic forms of the compound.
(00- 6 ) The present invention also includes -oxide derivatives and protected derivatives of compounds of Formula f. For exampli% when compounds of Formula i contain an oxk&ahie nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I contain groups such as hydroxy, 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.
I08267J Methods for the preparation and/or .separation and isolation of .si.ngie
stereoisomers f rom raeemic mixtures or son-raeemie mixtures of stereoisomers are well, known in the art. For example, -optically active (R.)~ and (S)- isom r (nay 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. for exanip!e by: 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
chromatography in a chirai. environment, for .example on chirai support, such as silica with a bound chirai ligand or in the presence of a chirai solvent, it will he appreciated that where a desired enantiomef.is converted into another chemical entity by one of the separation
'procedures described above, a further step may be required to: liberate the desired
enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a -mixture of enantiomers, enriched in particular enantiomer, the major component enautiorner may be further enriched (with concomitant loss in yield) by reerystei!ization.
[00268] In addition, 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.
[00269] In the examples that follow, unless otherwise specified, the final, form, of the compound was assumed to be the uncharged -molecule in the absence of analytical techniques that would have determined otherwise. Compounds of Formula I can be prepared using method known to one of ordinary skill in the art or starting from the Compound of formula 1 as depicted in Scheme, j. below. Compound of formula I can be prepared starting from compound 1 by fusion -of appropriate reagents at 180 <}C in the presence of a base such as
Dandegaonker and C, K, esta, , Med. Chem. 1965, <S\ 884),
Scheme 1
[00270} Refen ng again to Scheme t , 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. The product is then extracted into 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.
{002711 The intermediate of formula 3 is then treated with an intermediate of formula 4 in a solvent such as DMF or p-xylene at reflux temperature. Upon completion of the reaction (about 16 hours Or less), tire reaction is allowed to eoo!, extracted into DCM, washed with 2 N HCI and brine, dried over a drying agent soehas sodium sulfate or magnesium sulfate, filtered, and concentrated to give a compound of Formula I.
(00272) Alternatively, other methods to prepare uinoxaline derivatives are known to one skilled in the art and include, but are not limited. to S. V. Utvhien.ko, V. 1. Savich, D. D. Bpbrovmk, Chem.. Hetewe ti, Compd. fEngl. Transl), 1994, 5ft, 340 and W. C. Lamina, R D. iiaitmaft, Med Chem. 1981, 24, 93.
[00273] Compounds of Formula 1 where B is phenyl substituted with ~* where RJ8 is alkylamino or diaiky.lamino or B irheteroaryl substituted with R' where R* i s amino, alkylamino, or diaikylamino, and all other groups are as defined in the Summary of the
Invention can be prepared according to Scheme 2.
f n Scheme 2, LG is a leaving group such as ehloro. Compound 5 is reacted with NH J ' or
where R8 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.
[00274] Compounds of Formula ! where 'B is phenyl .substituted with Rja where R"13 is arrimoaikyioxy, alkylaminoalkyloxy, or dial'kylannnoatkyloxy orB is heteroaryl substituted with R' where _ is ammoalkyloxv, alkyia inoalkyloxy, or dsalkylamintialkyioxy, and all other groups are as defined in the Summary of the Invention can be prepared according to Scheme 3.
Scheme 3
002751 The reaction is carried out in the presence of a base such as Naff in a solvent such as DMF.
|6®276] Compounds of Formula 1 where' Bis phenyl substituted with R.ja or B is heteroaryl substituted with R! where R¾ and } are
L - (.R7)C{0)-C Valkyk^e-N'(R¾j(R^ where R\ R7\ and R7,! ar as defined the
Summary of ihc Invention;
ii. - R'C(0)R fi! wh re R' is as defined in the Summary of the Invention:
hi. -Nil' lC{0)NR{ (¾! ih where R' ia, R! u ? and R¾ are as defined in the Summary of the invention:
Invention;
v. -K{RJ¾)C(O rC aikyiene-N(Rl¾fc)C(0):RSSa where Ri8, K \ and R, are as
defined in the Summary, of the Invention;
vi, -Nf R^^jCiQJ-C C^-a!k ie!ie-CCOjR^'" where K <s and R~**a as defined m.ihe
Summary of the Invention;
vti. ^R2,S( )^, 6^lky!ene-M(R2ib)R"l¾' where R2\ R?¼, and R: u' are as defined in the Summary of the Invention;
■viii. -Ni 22}C(0) C^aIk iene- {R2a)-N(R2¾)(R&), where R22 R22* and R22 are as.
defined in the Summary of the invention;
lx. - R'"V.XO;}~Ct.Cfraikyieiie-OR"¾ where R""4 and R?4* are as defined in the Summary of the Invention; and where the alkytene in RJ and RJil are independently optionally substituted as described in the Summary of the invention can be prepared accordin to .Scheme 4 by reacting with an intermediate of formula 9(a), 9(b), 9(c), 9(d), 9(e), 9(1), or 9(g):
9(a) liOC(0)"C Cr4¾!.ky!ene- (RT;i)(R?¾) where Ra is R?a or a -protectimg group, such as Boe or Fnioe;
9(b) HOC(0)R¾;
9(c) HOC(03NRT ,sRS Jb;
9(d) I:iOC(0 ORi3¾;
9(e) HOC(0)-CrCis-aik¥lene.N(R!S¾!)C(O)Ri*a;
9(g) LO-$( ;fe:-C|.Q-aIkylerte- '(R1! b)Ra where R" is Rit;i or a N-protectmg group, such as Boc or Fraoe.
Scheme 4
8
C,-C6 >alicylene-N( -5 Sb)qO).R<$i\ -C{O}-CrC alkylene-C(O)R203 9 or -S(0)rOYtValkylene-
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.
('(MJ27SJ Proceeding as described for Scheme 4, compounds of the invention where B is phenyl substituted with R** or B is heteroarv! substituted with R5 where and R? are
i. -C(0)NR¾¾3;
i i . -C(Q) ( li,)-C I -Or alky lene-N{ R.s' '}Ri!¾;
tu. >C(©)R' " where R! " is an -substituted heterocycloaikyl
iv. "CCO}N(R.S } (Ri½) Rt ti);
v. -C(0}N(Ri6)-Ci--C1!-aikyieiie-C(0)OR5fe; or
vs. -C(0) (R; 1 Ci-C -aikyie!ie-C(O)Ri¾; or
can be prepared by exchanging the starting materials as accessary. In particular, the intermediate of formula ! 1 1
n
is used instead of 8,
100279} Compounds of Formula i where B is phenyl substituted with Rja or B is heteroaryl substituted with R3 where "¾ and R ' are - i !C(0)Ci¾NR,;iR; where R7a and R ' are as defined in the Summary of the Invention can be prepared according to Scheme 5.
12 Iff)
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.
iil()280| Compounds of Formula ί can be prepared according to Scheme 6.
Scheme 6
!fh}
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. Alternatively, the reaction can be carried out in the presence of acetic add in a solvent such as DMA and by heating.
cedure 1
{00281 j into a l-dram vial was placed 2 br mo-;V-(3-(AK3-('3,5-dimeihoxy- phen iamino)qumoxa1ia»2-»yl) &ulfaraoyl) phenyl) aceiami.de (86 mg, 0- 15 nunol), prepared using procedures similar to those in Exam le 171 ,aiong with 2 inL of -aeetonitrile. Eight equivalents ( 1 ,2 nimol) of the desired amine, aniline, hydrazihe-or alk yarnine' were added
ai 50 for one hour (overnight for aniline reagents]. Preparative reverse-phase HPLC was used to isolate die desired, product directly from th crude reaction mixture. A Waters Fractkmlynx preparative reverse-phase H LC - equipped with a Waters SunFire Prep C I 8, OCD S μΜ, 30 X 70 mm column and .running a 5-100 % gradient with a binary solvent system of 25 m.M ammonium acetate in xvater/acetoiutri!e - wa$ used to carry out the purification.
General .Library. Acviaf ion Pr cedure 1
[00282] Into a 3 -dram via! were added S-amitto-AH -CJjS-dimethox - .hen 1anrino)φlίn xaUn-2-yl)bet\^enes Ux.mamide (54 mg, 0.12 mmoi), prepared using procedures similar to those described in Example 15, DMA (2 niL) and the desired carboxy!ic acid (0, 17 mmoi), DtEA (70 !., 0.4 mrao!j followed by HATU (53 mg,0. M mmoi) were added to the vial and the reaction mixture stirred at 50 "C Overnight. Preparative reverse-phase HPLC was used .'to isolate the desired product directly from the 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.
General Animation Procedure la
[00283] 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.
l Animation Procedure ! b
(00284) A CE microwave reaction vessel was charged with N~ -{N"Q-
prepared usin procedure similar to those ia Example 374. the desired aniline (0.56? mmol, 4 e¾),-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.
General Acvl&tion Procedure 2
(002851 N-{3-(N-(3-(3 -dim'cUK>xy-pheny1am
•:sulfamoyi)phenyi)azetidine-3H;arboxamide (125 mg, .0.23 inraol), prepared usin procedures similar to those described in -Example 372» was dissolved into 5 mL DCE in a 10 ml. round- bottqm flask, DI.EA (1.17 mmol, 5.0 equ v.) was then added with stirring followed by aeid chloride (0,47 'mmol, 2.0 equiv, }. The reaction was then stirred at room temperature for i hour or until complete '.as indicated by LCMS, The solvent was subsequently removed tinder reduced pressure on a r ta y evaporator. The crude material was then re-dissolved in methanol. Purification of the final pro-duet was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NfLOAe/CAR A Waters Fraction! ynx preparative reverse-phase' HPLC; equipped with a Waters SuuFire .Pre CIS, OCD 5 Μ, 30 X 70 mm
icetate in water aeetonitri !e; was used to carry out the purification.
General Reductive Aininatkm Procedure 1
{00 86] To a solution ofN-(3-(AK3«(3,5*dti»ethoxy-phen^
yi)sidi¾moyl)phenyl)a¾eiidine~3-earboxamide (110 mg, 0.19 mmol), prepared using procedures similar to those described in Example 372, in 3 mL otDCE and 200 μΙ_. of DMF, aldehyde (0.7? mmol, 4.0 eq.)was added slowly followed by ietmmethylammonium triacetoxyborohydride (1.16 -mmol, 6,0 eq). The reaction was .stirred at room temperature overnight. LC/MS indicated the reaction was completed. The solvent was- subsequently removed under reduced pressure oft a rotary evaporator. The crude material was then re- dissolved in. methanol. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluettts 25 mM aqueous NiijOAc/CA . A Waters
Fractionlynx preparative reverse-phase HPLC; equipped with, a Waters SunFire Prep CI 8, OCD 5 μΜ, 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.
ocedure la
{00287] Into a■small 1 dram vial was added 3*(N-(3-(2^chloror5^methoxy-phe«y|atn.ino - qimioxalin-2~y!)sull¾moy{)ben2oic acid (61 nig, 0.13 mmol, 1 , 1 eqttiv), prepared usin'g procedures .described for Example 100. The acid was dissolved in DMA (I mL) and DIEA (42 μΐ., 0.24 mmol, 2 equtv) was added then added to the solution. The amine reagent (1 mL of 0.12 N4 solution in DMA) was added to .solution with stirring followed by HATU (64 mg, 0.17 raMol, 1.4 equiv). The reaction was stirred overnight at room temperature. Upon
Preparative reverse-phase HPLC was used to isolate the desired product. A Waters
fractioaiynx preparative reverse-phase HPLC - equipped with a Waters SunFire Prep CI S, OCD 5 μΜ, 30 X 70 mm..column nd running a 5-100· % gradient with a binary solvent system of 25 mM ammoahim acetate in water/aceionitrije - was used to, cany out th■ purification.
General Amide Formation Procedure lb
{09288} The procedure 'outlined in General Amide Formation Procedure la was used to incorporate' a number of amines chat contained a second amine group protected as the teri- butylcarbainate (he. where R\ wiUun NHR'R,"' contained a Boc-proteered amine group). The de-protection was carried o t after HPLC purification of the Sec-protected precursor. {00289} into
pheaylamino)qumoxaim>2-yl)suliamoyl)hen¾ok acid (61 nig, 0.13 nimot 1.1 equiv). The acid was dissolved in ! mL. of DMA and D!EA (42 uL, 0.24 mmol, 2 equiv) was added then added to the solution. The mono- Boe-proteeted diamine reagent ( 1 mL of 0.12 M solution in DMA, 1 equiv) was' -added to solution with stirring followed by HATH (64 rng. 0.17 mmol, 1,4 equiv). The reaction was stirred overnight at room temperature.: Upon completion as indicated by LCM5 analysis, 2 mL of methanol was added to the solution. Preparative reverse-phase HPLC was used to isolate die desired product directly from. this, crude reaction solution. A Waters Fractioiuynx preparative reverse-phase HPLC; equipped, with a Waters SuaFire Pre C 18, OCD 5 μΜ , 30 'X 70 mm col uraii and running: a 5- 100 % gradient with a binary solvent system of 25 mM ammonium, acetate in water/aeetonitri!e; was used to carry out the purification The product fractions were combined and concentrated to dryness' under reduced pressure by rotary evaporation, A solution of 4 N HCl in dioxane (2 mL) was added. The solution was then stirred at room temperature until no -patti material was detected. The deproteeted product precipitated out of solution as an HCl salt and; was collected by iBtratk , washed with ether and dried under vacuum.
Synthesis of Compound A
| i 29 | Crude Compound A can be prepared as described below and depicted below in Scheme 7.
}00291| One kg of 2,3 dicSilor quinoxa fine and one kg of 3-mtroben.zcnesulfbnsmide were .mixed 5 volumes of acetonitrile'. The reaction mixture was heated to reflux, 23 kg of DBU and 1 volume 'of acetonitrile were added. After completion of the.reactkm, the mixture was cooled down at 5 °€. Twelv volumes of methanol and 1 ,53 kg ofMCI were added, and the reaction■ mixture was filtered, The fitter cake as■ washed, with 6 volumes of methanol and dry under vacuum.
Synthesis of .(NH -({2-chloro-S~metho
uitrtibenzeiiesulfeiiamide):
1002921 A solution was prepared with 0.5.85 k -of■2-ch'lorOr5-methoxyaniline^HC!, 3.5 volumes of acetonitrile and 0.46 kg of DBU (solution A). Separately, .1 kg of N-( - chloraqutiioxaljft-2-yl)-3-n.itrobert2enesuii¾«atHide and 5,5 volumes o sieetonitrile were combined and heated to. reflux. Solution A and 1 volum of acetonitrile was then added to the reaction mixture, and the resulting mixture was heated at reflux. After completion of the reaction, the mixture was cooled down at 20 *C, diluted with 10 volumes of methanol and filtered. The resulting filter cake was washed 3 times with 5 volumes of methanol and then dried under vacuum.
Synthesis of 3-amino-N-i3- {2~chloro^5-tnethoxyphenyl)aininolquinoxalin-2i- yl}beuzenestilfoiisimide hydrochloride:
|00293] To 1 kg of N-■{3-[(2-ehion>-5-meihaxypheny1)aiiunojquinOxalin-2-y!} «3- mtiobenzenesulibnamide was added a catalytic -amount of platinum- sulfide on . carbon (Pt(S)C), 6 volumes of THF, 0.16 volume of water, and 2 volumes of ethano!. The resulting reaction. mixture was stirred and heated to reliux. An. aqueous potassium f rmate solution (1.4 volume of water ÷ 0.69 kg of potassium formate) was added. The reaction mixture was stirred at reflux: until completion of the reaction and then cooled down at 50°-C. After tlte addition Of 10 volumes f methanol und one. -hour of stirring, the catalyst was filtered off and washed with 3.4 volumes of methanol. The filtered solution was cooled down at.20 °C and 0.62 kg of HQ were added. The reaction mixture ' was stirred at 20 °G, cooled down to 5 °C and filtered. The filter cake was washed with methanol (6 volumes) and dried under vacuum.
Synthesis of N«|34{3-{(2^hloro^5-metbox> heayl)ami»o.lqttinoxalia*2r>
yi]s«liijmoyl)phenylj-2-mcdiyialaiiinatiiide (crude):
J002941 Synt esis of 2-m¾ hv¾¾ian l chloride ..hydrochloride. To 0,42 kg of 2-ammo-2- methylpropanoie acid, was added 3,7 volumes of acetomtrile, 0.04 volume .of
dimethyll rmamide, and 0.62 kg of oxalyl chloride. The reaction .mixture was stirred at 20 °C until completion of the reaction. Tl te mixture was the filtered, and the filter cake- was- washed twice with i volume of -acetoniirile and dried under vacuum.
00295 j To I kg of 3-amino-N~ 3-((2^hloro-S-meUn>x>^henyi)amino]qoinoxalm-2- yl}benzenesulrbna ide hy'droehtaride was added S volumes of dinteifaylfentiamkle arid 0.385' kg of 2~meihy½lanyt chloride hydrochloride at 5*C. After completion of the reaction, die .mixture was heated to 50 °G and a solution of 2HF04 (1 A kg), water (1.6.5 volumes) and ethanol ( 7-1 volumes) was added. The mixture was cooled down to 10 °C, stirred 2 hours at 10 and then filtered. The cake was washed 3 times with 1.0 volumes of water ami dried under vacuum.
Synthesis of Compound, of "Formula H
[00296] Compounds of Formula ΙΪ 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. Wiley and Softs, ί 9 1 >, JRodd 's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental•(Elsevier Science Publishers, 19S9), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 19 1), March's Advanced Organic Chemistry, (John Wiley and Sons, 4lh Edition), and Larocfc's Comprehensive Organic Transformations (-VCH Publishers inc., 1 89), These schemes are merely illustrative of some methods" which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in. the art having referred to thi disclosure. The starting materials and the 'intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterised using- conventional means, .including physical constants and spectral, data.
[6029'?] Unless specified to the contrary, 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.
(00298) 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.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B, Roche, American Ph'iarmaceut-ical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
[0629-9! The compounds of the invention, or thei pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of formula ί 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. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the 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,
{60300( The present invention also includes -oxide derivatives and protected derivatives of compounds of formula 11, For example, 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 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 <¾
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.
1003011 Methods for the preparation and/or separation and isolation of single
stereoisomers from racemic mi xtures or non-racemie mixtures of stereoisomers are well known, in the art. For example, optically active (!¾■)- and (Sj- isomers raay be prepared using ehiral synthons or ehiral reagents, or resolved using conventional techniques. Enantioniers (R- and. ^-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
chromatography in a ehiral environment, lor example on a ehiral support, such as silica with a bound ehiral ligand or in the presence of a ehiral solvent, it will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired
enantiomeric form, Alternatively, specific enantiomer may be synthesized by asymmetric Synthesis' using 'optically active reagents, substrates, catalysts, or solvents, or by con verting one enantiomer to the other by asymmetric transformation. For a mixture of ertatitiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield} by reerystaUization.
(00302} In addition, 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,
00303J The chemistry for the preparation of the compounds of this invention is -known to those skilled in the ait, In fact, there may be more than one process to prepare the compounds of the invention. For specific examples,, see . Barvian et 'al., J. Med. Chera. 2000, 43, 4606- 4616; S, N. VanderWei- et ah, J. Med. Chera. 2005, 48, 2371-2387; 1>, L. Toogpod et ai, J. Med. Chem. 2005, 4 , 2388-2406; J. Kasparec et ah, tetrahedron Letters 2003, 44, 4567- 4570; and reference's cited therein. See also U.S. Pre-grant publication US 2004/0009993 A l ( . Angioii i et al.), which is incorporated herein by reference, and references cited therein.
The following exaiiiples illustrate hut do not limit the- invention. All references cited herein are incorporated by reference in their entirety.
100304;} A compound of the invention, 'wherein Rf is optionally substituted alkyl, R" is hydrogen or optionally substituted -alky!-,. K* is methyl or ethyl, Rc> is phenyl or heteroaryi each of which is optionally substituted with 1, 2, 3, 4. or 5 groups (as defined in the
Summary .of the invention}, and R" is. hydrogen, can be prepared according to Scheme 8,
Scheme 8
solvent such as water is added a base such as sodium, carbonate and an. intermediate of formula 10 at room temperature. The reaction mixture is stirred' for overnight or less. After neutralizing, 11 is collected through filtration 'and followed by drying under vacuum. H is then treated with PGCJ? and the. reaction is heated to reflux for approximately 2 boors and then concentrated under vacuum to -dryness;. 1 can be used directly in the next reaction without 'further purification,
{00306} 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. The reaction i s 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
approximately 15 hours. After evaporation of solvent; the residue is triturated with acetone and collected: by filtration to yield 5.
10030$ 6 is prepared by reacting 5 with a .brom mating agent such as Br¾ 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.
00309) A Suzuki, coupling is then '.performed usin 6 and a boronie acid (or ester) of formula R(1B(C)H); in a solvent(s) such as a DMB-¾0 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 r½S<¼ to yield 7.
jOIBlOJ The .me ylthio group of 7 is then oxidized with w-CPBA in a solvent such as DCM at room temperature with stirring for approximately.4 hour. After removal of the solvent under reduced pressure. She product is treated with an amine of formula " i¾ in a solvent such as dioxane and stirred at room temperature for approximately overnight to yield a compound of formula i.
003111 Alternatively, a compound of formula 1 where ! is opti nally substituted aikyl, R is methyl or ethyl " is phenyl or heteroaryi each, of 'which, is" optionally substituted with 1 , 2, 5. , or 5 ' groups (as defined in the Summary of the Invention), and 2 is hydrogen, can be prepared according to Scheme: 9..
Scheme 9
(00312)· 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 UC 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. Treatment of .1 1 with, manganese (11) dioxide in a solvent sueh as methylene chloride or chloroform at room temperature provided aldehyde 12 upon filtration and solvent removal A Wittig reaction with aldehyde 2 can he'. employed.
refiuxmg THF to provides the common intermediate- 4. 4 can then be used to prepar a compound of formula I using the procedures described in Scheme ί .
(00313] A com o nd of the invention where lll is optionally substituted alk L is methyl or ethyl, R* is phenyl or he ternary! eac of which is optionally substituted with 1 , 2, 3, 4. or 5 R groups (as def ined in the Summary of the Invention),, and R" is. hydrogen am be prepared according to Scheme H).
Scheme .10
(00314] 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. The reaction is heated to approximately 100 *C and allowed to react for approximately overnight or less as needed for the reaction to go to completion to .form 16. 1.6 is then Optionally purified by colum chromatography. A Compound of formula I can then be prepared from. 16 by 'using the same reaction conditions as described in Scheme I (starting- at the point of the preparation of 5 from 4}.
(00315} A compound of the in entio where R5 optionally substituted alkyi, R* is methyl or ethyl, R"' is phenyl or hetereary! each of which is optionally substituted with 1 , 2, 3, 4, r 5 R'" groups (as defined in the Summary of the invention), and R* is hydrogen, can
.alternatively be prepared according to Scheme 11.
Scheme 11
23 24 25 t
(00316] An intermediate of formula 20 is prepared by reacting an intermediate of formula 19 with neat PQt¾ and heating. 20 is then treated with a primary -amine' R'Nj¾ 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. 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. Subsequently, 25 can be oxidized to the' 'corres ondin suIJ'one with »i-CPBA at room temperature and displaced with ammonium to provide 1.
[00317] The synthesis of specific compounds is describe in WO2007 0444813 which is hereby incorporated by reference in its entirety,.
Examples
Example 1
Treatment of Endometrial Carcinoma with Compound A or Compound B
{00318j A two-stage Phase 2 study is conducted to evaluate the safety and efficacy of Compound A in subjects: with endometrial carcinoma. The .formulation used in stage hvas a capsule formulation. For 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.
Study Objectives
{00 191 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. The secondary objectives of this study a e to assess 'the duration of response and PFS6 and to further characterize the
pharmacokinetic (P ) and plunnacodynainie- profiles of Compound A. The exploratory objectives of this study are to evaluate the correlation f the pre-existing status of
PB /PTEN patiiway cosnponents/modolators (eg, P1K3CA inutation ampSifieation, PTEN deficiency) with clinical outcome in subjects treated with Compound A; as well as to (i) evaluate assessment of circulating tumor DNA for KRAS, PI JCA, BRAF mutations at the iime of trea tment and impact of imitations detected in the circulation with clinical outcome: (ii) identity surrogate biomarkers associated with clinical activity of Compound A; and (iii) estimate the ORR and PFS in subjects whose tumors have a biomarker "signature" associated with the clinical activity of Compound A, if a signature is defined in this stud
Study Design
[00320] 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. In the original study design (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.
{00321 j 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.
[003221 During the course of the study, subjects' tumor sample (archival and/or from new biopsies) will be analysed for 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$ui¾" will be enrolled.
1003231 Each subject course consists of the foiiow iig three periods:
Pre-Treatment Period; Subjects ace consented and qualified for the study.
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
response per Response Evaluation Criteria in Solid Tumors ( ECIST)
Version 1.1 (Eisetihauer et; ai. 2009), Subjects will. rovide samples for PK.
and pharmacodynamic analyses, Compound Λ will he administered once
daily, hi the absence of radio.graphie PD pe ilEClST Version 1.-1 and
unacceptable toxicity, 'subjects may continue to receive study treatment for up to 1 year at the discretion of the investigator and beyond I year with the
agreement of the investigator and sponsor.
10032 1 Clinic visits for each subject will be every 2 weeks in the .first S weeks and every 4 weeks thereafter,
100325 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
37 days after the last dose of study drug- for a Post-Treatment Visit. Subjects who discontinue study treatment before documentation- of radiographic PD will continue to undergo .periodic tumor assessments until the earlier of
radiographic PD, death, or the initiation of subsequent anticance therapy.
It is anticipated that approximately '80 subjeets-vdil.be enrolled t
obtain the approximately 75 e valuable subjects per protocol, i f the
molecular profiling data obtained daring the course of the study
suggests a predictive -markerts) for objective response or Stable
disease, an additional 15 subjects whose tumors exhibit this- biomarker signature may be enrolled.
Target Population
1 03261 Subjects' will be eligible for enrollment a defined by the inclusion and exclusion criteria as follows on the- following pages.
1 iiclttsimi Criteria
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.
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
Version 1. i ,
it) A lesion within a previously radiated field is only considered measurable if there has been demonstrated progression in the lesion and documented by:
o At least two sequential CT or MR! scans performed after the completion of radiation, or
9 Histopathologic- evidence of persistent disease, > fX) days after t e completion of radiation therapy
Tissue sample of the subject's tumor of at least 125 micron thickness [175- micron preferable] of a cross-sectional area of at least 20 mm x 20 mm with a tumor cell .nuclei content of at least 25%, sections without cover slips from archival or fresh tissue, or a tissue block from archival or fresh tissue, or a tissue block of the subject's tumor should be- identified, in the possession of the participating site/institution, and designated tor shipment to the sponsor, or a laboratory designated by the sponsor,
The subject has organ and marrow function as follows:
a) Absolute neutrophil count > 1500/mnY
b)
c) Hemoglobin > 9 g/dL
d) Bilirubin < i .5 ¾ the upper limit of normal (ULN)
e) Serum creatinine < 1 ,5 x ULN, calculated creatinine clearance > 60 aiL niin, or glomerular .filtration rate > 40 ml./min
0 Alanine atnwptn sfetase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN 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. For subjects of chiidbeanng potential, 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
1 2 months, with the except on of those h had prior hysterectomy, oophorectomy, or surgical sterilization). However, subjects who have been anienorrheie for 12 or more months are still considered to be o -chiidbeanng potential if the amenorrhea is possibly due to prio chemotherapy, anti-estrogens, ovarian suppression, or any reason other than menopause.
Exclusion€ rtterht
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.
The. following restrictions on prior anticancer treatment apply;
a) Cytotoxic chemotherapy (including investigational cytotoxic agents) or biologic agents (antibodies, immune modulators, cytokines) within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks, before the iirst dose of Compound;
b) 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:
c) Any other investigational therapy within 4 weeks before the first dose of Compound A;
d) Prior hormonal therapy -within.2 weeks before the first dose of Compound A e) Prior whole pelvic radiation therap 'or palliative -radiation within 2 weeks before the first dose of Compound A; and
f) Prior major surgery within 4 weeks before the first dose of Compound A or if the subject has not recovered or stabilized from the surgery.
4. The subject has not recovered from toxicity dm to prior therapy to Grade 1 (excluding alopecia and peripheral neuropathy) or to pretherapy baseline. Grade 2 peripheral neuropathy or Grade 2 alopecia related to prior therapies will not affect the eligibility of the subject.
5. The subject has a known primary brain tumor or brain metastasis.
6. 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.
7. The subject has a diagnosis of uncontrolled diabetes mellitus (glycosylated hemoglobin AIC > 8%) or has a fasting plasma glucose > 160 nig dL,
8. The- subject is currently receiving anticoagulation with therapeutics doses of warfarin (low-dose warfarin < 1 nig/day is permitted).
9. 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 χ the laboratory ULN.
10. The subject has uncontrolled, significant intercurrent illness including, but not limited to:
a) Ongoing or active infection requiring systemic treatment
b) Symptomatic congestive heart failure
e) Uncontrolled hypertension (sustained blood pressure readings of > 140 mm.Hg
systolic, or > 90 mmHg diastolic)
d) Unstable angina pectoris, a myocardial infarction, or a stroke within 3 months before entering the study
ej Clinically significant cardiac arrhythmias
I S . The subject has a baseline corrected QT interval 470 ms
12. The subject is known to be positive for the human iromwiodefrcieney virus (HIV).
(Note: Baseline HIV screening is not required.)
13. The subject is pregnant or breastfeeding:.
1 . The subject has a previously identified allergy or hypersensitivity to components of the study treatment f rmulatioE.
Estimated Study Dates
[00327) 24 months for study accrual and treatment.
Compound A Dose/Route Regimen
[00328] 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).
Efficacy
100329] 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.
|00330] 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.
[00331] Tumor assessments will be evaluated by the investigator for subject management. An Independent Review Committee (IRC) may be used for the primary analysis of study endpoints. The procedures to be followed by the IRC will be defined in an IRC charter.
Safety
100332] Safety will be assessed by evaluation 'of adverse events ( AEs), vital signs, electrocardiogram, laboratory1 tests, and concomitant medications. Adverse event seriousness, severity grade, and relationship to study treatment will be assessed by the investigator.
Severity grade will be defined by the National Cancer institute Common Terminology
Criteria for Adverse Events v3,0 (CTCAE).
Pharmaeolvinteks
[00333] Blood samples will be obtained at predetermined time points for Compound A plasma conce trati n assessments.
[00334] in addition, 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
Pharraaeodynanfcs
[00336] 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.
[00337}' When possible, pharmacodynamic sample collection will coincide with scheduled PK time points.
[00.338] Detailed instructions for pharmacodynamic sample preparation and shipping will be provided, to the study si es in a separate Pharmacod namic Laboratory Manual.
(0033*)} 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„ PTEK RAS, c- ET, HER2, and L B-'l) on efficacy
Statistical Methods
(00340} 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 ,
[003411 Prior to amendment 3 (Part 1), the study was designed to test the following hypotheses:
H<;: O R h < 5% and proportion with PFS6 is < 15%
H.\: ORR is 20% or proportion with FS6 is > 30%
{00342} The sample size estimate of 71 subjects evaluable per protocol is based -on a single-arm, two-stage design by Sill and Yothers (2008) with a nominal alpha of 0.07 and power of 90%,
100343]' Based on the stopping rule defined in the original protocol (2-stage design), the study met the futility criteria for the overall study population. As of amendment 3 (Part 2),
the primary analysis population is changed to the subset of patients with only I prior line of treatmen for advancedtecurt'eHt endometrial cancer, and BGOG of 0 to 1 and the primary analysis of interest will be the estimate of co-primary endpotnts (G'RR and PFS6) with corresponding 90% confidence intervals.
[00344) if molecular profiling data obtained among the above subjects suggest a predictive mas-kerfs) for objective response or stable disease, n additional 15 subjects whose tumors express this bioraarker signature may be enrolled. A sample size of 15 ensures that if the true response rate is 20% or more then the probability of observing no response is less than 4 percent.
{00345} Secondary efficacy endpotnts of duration of response and median FFS will be estimated. Time -to-e vest analyses inc udin landmark es timates such as PFS6) will use Kaplan-Meier methods. Confidence intervals for proportions -will e - constructed using exaet methods.
}0034i>) For assessing safety, 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
Example 2
Treatment of Breast Cance with Letrozole in Combination with Compound A o
Compound 8
{00347} This is a Phase 1/2 dose-escalation study of Compound A or Compound B in combination with letrozole in Subjects with hormone receptor-positive, and HER2-Negative breast cancer refractory to a nonsteroidal arotnatasc inhibitor; The study consists of two amis., in Ann I , Compound A is tested in combination with letrozole. In Arm 2, Compound 8 i tested with letrozole. Each am will be evaluated independently; no formal comparisons between the arros are planned. Each ami of the tudy will consist of a Phase I component and a Phase 2 component. The Phase 2 component has two stages.
Study Objectives
{00348} The primary and secondary objectives as described below will be evaluated in subjects with recurrent, locally advanced, or metastatic hormone receptor-positive ER-;- and/or PGR ) breast cancer, who had disease progression o recurrence during treatment with nonsteroidal aroniatase inhibitor and who are enrolled in Ann. 1 (Compound A with letrozole) and Arm 2 (Compound B with letrozole).
{003491 The primary .objectives are:
« To determine the .maximum tolerated doses ( TDs) of the combination of Compound A with ieirbzoie and the combination. of'Compound B with !etrozole (Phase I).
* To evaluate the co-primary efficacy endpoints 1 ) objective tumor response rate
(OR ) (confirmed complete response [CR.1 or confirmed partial response [PR]) and 2) rate of 6-month (24 weeks) progression-ftee survival. (PFS6). in each arm (Phase 2).
« To evaluate the safet and tolerability of the combination, of Compound A with
letrozole and of t he combination of Compound B with ktrozole (Phase 1 and Phase 2).
|00350] The sec ndary' objectives are:
« To estimate PFS and the duration of responses (Phase' 2),
* To estimate the clinical benefit rate (CB ), defined as the proportion of subjects with a confirmed CR or confirmed PR at an time while the/subject is on. study treatment; or stabie: disease (SO) at 6 months (24 weeks) (Phase.2),
* To assess the pharmacodynamics and plasma phamiacokinetics (PK) of Compound A, Compound '% and ietroz ie (Phase I and Phase 2),
(00351 The exploratory objectives are;
» To define predictive markers of response and/or resistance to a PB! (Arm 1) or
PBR/ mTOR inhibitor (Ami .2) in combination, with, ietrozoie based on. molecular pro tiling of tumor tissue (Phase" 1 a d Phase 2).
* To evaluate the correlation of the pre-existing PIK3CA mutations and other
alterations of the PBK/ PTE pathway eomponen s modulators with clinical outcome in subjects treated with Compound B in combination with, letroxole or with
Compound B in combination with Ietrozoie (Phase 1 and Phase 2),
* 'To identify surrogate bsomarkers associated with clinical activity of Compound A in combination with Ietrozoie and of Compound B in . combination with ietrozoie (Phase 1 and Phase 2).
Study Design
i 0.0352) This is a ffiuitieenter* Phase i/:2, open-label, study of Compound A in combination with Ietrozoie (Ami I) . and Compound B in combination with Ietrozoie (Arm 2), in subjects with hormone receptor-positive (Eft-f and/or PGR*'}, HER2-negattve (HER2-) breast cancer whose disease i refractory So a nonsteroidal aromatase inhibitor. Subjects who had disease progression while receiving a nonsteroidal aromatase inhibitor for locally advanced or
metastatic breast cancer or disease. recurrence while receiving adjuvant treatment with a nonsteroidal -aronmtase, inhibitor will be treated with either Compound A r Compound B in combination with Ietrozole as follows.
{00(353} Treatment. Arm 1 subjects will receive:
* Compound A tablets, orally administered once daily (qd); and
• Letrozole tablets, orally administered qd, 30 minutes after Compound A.
{00354} Treatment Arm 2 subjects will receive:
• Compound B capsules, orall administered twice daily (bid), with the first dose
administered in the morning and the second dose 10-12 hours. after the first (morning)- dose.
♦ .Letrozole tablets, orally administered qd, 30 minutes after the first (morning): dose of Compound 8.
Phase I
1003551 Subjects, will be alternately assigned to Ami I and Arm.2. A *3*3' dose-escalation design will be employed to determine: the MTD of the Cornpound A tablet formulation in combination with Ietrozole and of the Compound 8 capsule formulation in combination with Ietrozole.. Subjects- ill receive the standard dose of 2.5 mg ietrozole qd (i.e., there -will be no dose escalation of Ietrozole); Cohorts of subjects will be accrued in each arm t .increasing doses of Compound A in combination with ietrozole (Arm 1) or of Compound B in combination with Ietrozole (Arm 2) until more Hum 1 of 3 subjects or . 33% of 3 to 6 (or more) subjects at a . dose level experience a dose-limiting toxicity (DLT) in the first 28 days of study treatment. Dose escalation in Arm 2 will not proceed beyond -an Compound. B dose of 50 mg bid (the MTD from single-agent Phase 1 Study Compound B-001), The single-agent MTD for die Compound A tablet fonnuiaiioti has not been determined.
[003361 ff more than 1 of: .3 subjects or > 33% of 3 to 6 (or more) subjects at a dose level, experience a DLT in the first 28 days of study treatment, this dose will be considered the maximum administered dose (MAD) for the treatment combination where the DLT occurs. Dose levels below the MAD will then be- explored lor safety and tolerability. The MTD in each arm will be defined based on six subjects. The decision to dose escalate within each treatment ana will be made by the Study Committee when ail subjects in the current cohort have had the opportunity to complete at least 28 days of study treatment. All available safety and PR data will be considered in the decision t dose escalate, de-escalate, or expand the current -cohort.
Phase 2
(00357} Once the MTD is determined in. 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.
(00358} li Ann 1, initial dose of Compound A was 200 mg in combination with leir zo!e 2.5 mg, 6 subjects were treated with no DLTs reported. The dose was escalated to Compound A 400 mg qd in combination with ietro¾oie :,5 mg, four patients were treated and no DLTs were reported in at least 66.6% of subjects treated at this dose level; dosing data will be 'completed b August 201 Ϊ . Preliminary PK data has not shown any interactions between Compound A and letrozole, MTD will be determined as Compound A 400 mg in
combination with letroz le 2.5 mg. Phase 2 pari of Ann .1 will open once safety data of the 6 treated subjects in this dose level is complete,
[0O359| In Arrn 2, initial dose of Compound B was 30 rag bid in "combination with letroxole 2,5 mg. 3 subjects were treated with no DLTs reported. The dose was escalated to 50 mg bid. One of si subjects at this dose level (k combination with letrezole 2.5mg) experienced a DLT (grade 3 skin rash). I eiiminary PK data has not shown- any interactions between Compound B and Sctrozo!e. MTD s' determined as 50 nig bid of Compound. B in combination with letrozoie 2,5 mg. Phase 2 part of Ann 2 of die study is open for enrollment.
(00360} For each arm of Phase 2, a two-stage design will be used to evaluate the co- primary endpoints of ORR and PFS6. in each ami, approximate ty 50 subjects will be enrolled to obtain 48 evaiuahie subjects per protocol. Stage 1 will enroll 24 evaiuahie subjects in each, arm. If at least two subjects achieve an objective response (a confirmed PR or a confirmed €11} or at least four subjects are alive and progression free for at least ij months, then that ami will continue to Stage 2 until 48 evaiuahie subjects (including both stages') have been enrolled.
(00361} .Each- arm will be evaluated independently; no formal comparisons between arms are planned,.
|tl0362| hi each a m, tip to 10 subjects AVfaose tumors have a documented PI K3CA imitati n or molecular signature may be accrued to estimate th -ORR in subjects whose tumors have this molecular alteration.
[00363} Each subject's course on study will consist of the following periods.
Pre-Treatment Period
{60364} Subjects am consented and qualified for the study. Qualifying screening
assessments mast occur within 28 days before- the. nitial treatment on Study Day i .
Treatment Period
j 00365) Subjects arc assigne to Ann I or Ana 2 and will stay in their treatment arm throughout the study. Subjects are treated and raonitored for safety (including laboratory assessments), signs of toxicity, and evaluated for PD and response (per Response Evaluation Criteria in Solid Tumors Rbreast cancerlSTj Version 1 .1). Subjects will provide samples for P and pharmacodynamic analyses. The cut-off date for study analysis is the date when every subject has completed a■.minimum of 28 weeks of study treatment or has permanently discontinued study treatment before 28 weeks. Subjects without radiographic PD per Rbreast cancertST Version i . I and unacceptable toxicity may receive stud treatment for up to 1 year at the discretion of the investigator and beyond i year with the agreement :o;f the investig tor and sponsor. A subject may continue to receive treatment with Compound A or Compound B if the subject is required to discontinue letrozole. The subject will enter the Post-Treatment period when she has discontinued Compound A or Compound .8 treatment.
Post-Treatment Period
[00366 j Subjects return to the .study site 30-37 days after the. last dose of study treatment (i.e., their last dose of Compound A or Compound B) lor an End-oi-Treatment Visit.. Subjects who discontinue: study treatment before documentation of radiographic PD wi ll conti ue to undergo tumor assessments: until disease progression (per Rbreast caneeriST Version 1...1 ), the ini tiation of subsequent anticancer therapy, or death.
Number of Subjects
j¾G36?j This study will enrol) approximately 124 subjects. Approximately 24 subjects { 1 subjects each to Arm I and 2) may be .enrolled in Phase 1. Approximately 100 evaiuahle {Per Protocol population) subjects will be enrolled in Phase 2.
Target Population
[00368] Subjects will be eligible for enrollment as defined, by the inclusion and exclusion criteri as follows on the following pages.
Inclusion Criteria
) The subject has histologically confirmed breast cancer that is ER and r PGR-h Note: Eligibility is .based on the most .recent■ assessment of ER and PGR status from the- rimary breast '.cancer or from recurrent or metastatic disease. Subjects whose most recent tumor samp!e(s) (primary breast cancer or metastasis) is ER- and PGR- are not eligible even if tissue from an older tumor sample was-ER-f and/or PGR+.
} The .subject's- breast cancer is: negati ve for HER2 o verexpression by IHC (defined as IHC score < l-f) or for RER2 gene amplification by fluorescent in. site hybridization (FISH) or equivalent method, (defined as HER2:CEP!7 of < 2.0 and HER2 copy number of < 4 copies per cell). If test results from both methods are available and discordant, the gene amplification test result will be u sed for assessment of subject inclusion. Note: Eligibility is based on the- most recent, assessment. f HER2 ovferexjpress'ion/ gene amplifieation from the primary breast cancer or from recurrent or metastatic disease,
} The subject ha recurrent or metastatic breast carreer that is refractory to a nonsteroidal aromaiase inhibitor defined as occurrence of either of the following while the subject is on treatment with nonsteroidal aromatase inhibitor:
* Disease progression f locally advanced or metastatic breast cancer; or
• Disease recurrence of early-stage breast cancer (i.e., recurrence while receiving
adjuvant 'treatment with a nonsteroidal aromatase inhibitor). Note; There is no washout; period for nonsteroidal aromatase inhibitors before starting study therapy,) Subjects previously treated with lerrozoie must be able to tolerate the approved dose and schedule of letrozole.
} For subjects enrolled in Phase 2 (both treatment arms}:
♦ At least .fifteen (15) 4-10 micron tumor tissue sections (> 1 5 unstained slides, 20 preferably, without cover slips), or a tissue block of the subject's tumor must be identified, be in the possesston-of the participatiBg-.site/'iastituttoo, and be designated for shipment to the sponsor. Subjects for whom archival tissue is not available or for whom fewer than fifteen (15) 4-10 micron tumorlissue sections (> I S unstained slides) are available must undergo a new core tumor biopsy procedure, and fresh tissue must be designated for shipment to the- sponsor or a laboratory designated by the sponsor. Note: With the approval of the cohort review committee, up to 10 additional subjects whose tumors have a documented Pn CA mutation or molecular signature, may accrue at the end of enrollment- in each Phase 2 ami.
Ail subjects in Phase 2 must have measurable disease defined as having at least one measurable lesion thai can be accuratel measured on computerized tomography (CT) -or magnetic resonance imagin (MRI) scan determined by the investigator using Rbreast canceriST Version i . 1. Subjects in Phase I may have non-measurable disease if at least one of the non-measurable lesions is in bone, skin, or the chest wail. Note: Lytic or mixed lYtic-blastic hone lesions with identifiable soil tissue components that can be evaluated by cross-. sectional, imaging techniques such as CT or MRi can be considered as measurable if the soft tissue cojnponetit meets the definition of measurability according to Rbreast canceriST Version L I■
7) The subject is a postme opausa female, defined a a sexually niature woman who:
* Has been araenorrheie iby.12 or more months and the amenorrhea cannot be attributed to Other causes, such as chemotherapy or hormonal therapy. Note: Subjects who have been on ovarian suppression 12 or more consecutive months prior to the proposed Day I of study treatment . may be eligible if they continue ovarian suppression through their time on study treatment, if there is uncertainty about the menopausal stains of the subject, It must be -sh wn that she has castrate levels of follicle-stimulation hormone (FS.H) and estradiol according to local laboratory ranges to be eligible; or
* Has undergone a bilateral oophorectomy.
S) The subject is> 1 8 years old.
9) If a subject is currently receivin bisphosphonates, the subject -must have received die Msphosphonates for at least I month before starting . study treatment.
10) The subject has an astem Cooperative Oncology Group (breast cancerOG) performance status of 1.
1 1 ) The subject has organ and marrow, inaction as follows:
* Absolute neutrophil count (ANC) 150'0/mnr
* Platelets > 1 (HKOOO/mrh5
* Hemoglobin > 9 g dL
* Bilirubin < 1 .5 χ the upper limit of normal
* Serum creatinine < 1.5 x the upper limit of normal or calculated creatinine clearance >
60 mL'min
» Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upper limit of nonnal (i.e., Grade < i by Common Terminology Criteria for Adverse Events (CTCAE) v3.0)
12) The subject has no other diagnosis of malignancy or evidence of other malignanc for 2 years before screening for this study (except nonmeianoma skin cancer or in situ
carcinoma of ihe cervix).
13) The subject is capable of undemandi and complying with the protocol recjuireraents and has signed the informed consent document
Exclusion Criteria
i.) The subject has received prior treatment with ats inhibitor of FOK, AKT. and/or mTOR (investigational or approved agents).
) The following restrictions on prior anticancer therapy apply;
* Small, molecule targeted (non-cytotoxic) inhibitors (mcluding investigational kinase inhibitors) within 2 -weeks or 5 half-lives of th^ compound or -active metabolites, whichever is longer, before the first dose of study treatment.
* Radiation therapy within 2 weeks before the .first dose of study treatment
* Hormonal therapy {oilier than non-steroidal aromatase inhibitors) within 2 weeks before the first close of study treatment.
* Cytotoxic chemotherapy {including investigational cytotoxic chemotherapy) within.
3 weeks, or nitrosoureas or mitomycin C within 6 weeks before the first .dose, of study treatment.
* Biologic therapy (including. antibodies, immune modulators, cytokines) within
4 weeks before the first dose of study treatment.
* Arty other type of investigational agent within 4 weeks before the first dose of study treatment.
* Major surgery, or not recovered from major surgery, within 4 weeks before the first dose of study treatment,
3) Subjects in Phase 1 must have received no more than five prior cytotoxic
ehe otherapeutic regimens for metastatic breast cancer. Subjects in Phase 2 must have received so more than two prior cytotoxic ehe-mo therapeutic regimens for metastatic breast cancer. Note: Consecutive retreatment with the same regimen counts as one regimen.
4) The subject has not recovered f om toxicity due to prior therapy to Grade < I or to pre- therapy baseline. Subjects with Grade 2 peripheral neuropathy or Grade 2 alopecia related to prior therapies are eligible.
1.0 Ϊ
) The subject has untreated, symptomatic, or progressive brain metastases. Subjects with brain, metastases must have no radiographic or oilier signs of progression in the brain for > 1 month alter completion of local therapy. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for > 4 weeks before the first study treatment in order io be eligible,
) The subject has io start cytotoxic djem dre apy due to rapid PD involving major organs,) The subject has prothrombin time international Normalized Ratio (W I l) or partial thromboplastin time (PTT) test results at screening that are above 1.3 x the laboratory upper 'limit of normal,.
} The subject is currently receiving anticoagulation with therapeutic doses of warfarin
(low-dose warfarin < I mg day is permitted),
) The subject has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant cardiac arrhythmias, hypertension, or any of the following within. 3 months:
* Symptomatic congestive heart failure
* Unstable angina pectoris
* Stroke
* Myocardial infarction
» The subject has a baseline corrected QT interval (QTc) > 470 ms (usin Bazett or Fridericia formula),
* The subject has a diagnosi of uncontrolled diabetes mcllitus {glycosylated
hcm.Ogbh.ra Ate [HbAl c] > 8% that is not attributed to another temporary preexisting condition such as prior treatment with, corticosteroids for brain metastases) or fasting plasma glucose (.PPG) > 160 rng/dL.
» The subject has recei ved hormone replacement therapy within 1 days of the start of study treatment or ma need to initiate hormone replacement therapy during the study.
* The subject is known to be positive for the human imnnmode eiency virus (HIV).
« The -subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.
* The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
Estimated Study Pates
[00369] The total duration of the study is approximately 24 months. Investigational Regimen: Do$e Routc/Duratio.n
100370} Compound A will be supplied as 100-, 150-, and 200-mg tablets and will be administered orally qd. The starting dose of Compound A will be 200 nig,
I0037XJ Compound B will be supplied as 10-, 3.0-, 40-, and 50-mg capsules and Will be administered orally bid. The first dose will be administered in the morning, and the second dose will be administered 10-12 hours .after the morning dose. The starting dose of
Compound B will be 30 mg. Compound A will be supplied as 100 tug capsules or 100, 150, and 200 mg tablets. Compound will be administered at a dose of 600 mg once daily
(capsule)' or 400 mg once daily (tablet).
Combination Brug(s)
(00372] Leirozole is commercially available as ,2.5-mg tablets. One 2.5-mg tablet of letrozoie will be administered orally qd, 30 minutes alter the Compound A dose or the morning dose of Compound B.
Safety
(0i)373j Safety will e assessed by evaluation of adverse events (AEs), vital signs, electrocardiogram (breast cancerG), laboratory tests, and eqncpmit it; medications. Adverse event seriousness-, severity grade, and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute CTCAE v3.0.
Tumor Assessments
(00374] Tumor response will be assessed in Phase i and Phase 2 using Rbreast canccriST Version I J (Eisenhauer et al. 2009). Subjects will be assessed using an MR! or CT .scan at screening, 8 weeks after the first dose of study treatment (Week 9 Day 1), and every 8 weeks thereafter until 'documented radiographic progression, the initiation of other auu ancer therapy, or death. Responses will, be confirmed by repeat assessments at least 4 weeks after the response .'criteria are met.
()037SJ Evaluation of tumor markers is not required in this study, if a subject has a tumor marker that is being followed and that has been shown to be indicative of disease progression
or response, it should: e documented at each, tumor assessment (at screening and during the study). However, changes of tumor markers will not be used for tumor response analysis.
Pharaiacokiiit ies
|0037<S| Blood samples for assessment of Compound A, Compound 8, aad !etrozole plasma concentrations, when given in combination, will be obtained at the time points during the study,
(00377] In addition, PK samples will be collected* if possible, whenever a subject has a study treatment-related serious adverse event (SAE) and when, a increase in QTc intervals leads to changes in subject management.
FUarmacpdyuanics
{iji>378| Blood and tumor tissue samples (and -nontureor tissue · obtained at the same time as a prior tumor biopsy, if available) will be obtained from consented subjects for analysis of a variety of established and exploratory pharmacodynamic markers on a defined schedule throughout the study.
(00379·) Before Week 1 Day 1, a blood sample will be collected for hio arker analysis. On Week I Da I, before the first Compound A dose or the Convpoimd B morning dose, two blood samples will be collected: one 'for plasma DNA genotyping and one for SNP analysis. In addition, blood samples for pharmacodynamic analysis will be collected at time points during the study.
(00380) Optional tumor- biopsies may be taken at time points during the study (total .sampling limit of up to three tumor biopsy time points). Procedures for tumor and nontumor tissue biopsies are readily available to the skilled practitioner.
Statistical Methods
fOOSSlJ Each arm will be■■evaluated independently; no formal comparisons between anus are planned,
(00382) in Phase 1, no formal statistical tests are planned. Confidence intervals may be calculated tor selected safety -and exploratory variables.
)00383| For Phase 2, the co-primary efficacy endpomts for- each, arm are: 1) ORR, defined as the proportion of subjects for whom the best' response is a confirmed CR or confirmed PR, and 2} PFS6, defined as the proportion of subjects who. survi ve and are progression free at
least 24 weeks after the date of the firs* dose of study drug. Determination of response and progression will be based on evaluation per libreasC caneerlST Version 1 ,1,
[00384} The study is designed to test the following hypotheses for each arm:
* HO: ORR is < 5% and proportion with PFS6 is < 1 ø%
* HA: ORR is > 20% or proportion with PFS6 is 30%
[00385.1 The sample size estimate of 48 subjects evaluable per protocol in. each arm s based on a two-stage design' by Sill and Yothers- (2008) with a nominal alpha of 0.07 and power of .90%.
[00386) For each, arm of 24 evaluable subjects in Stage 1. if at least two achieve an objective response or at least four are alive and progression .tree at 6 months (24 weeks) then the study will continue to Stage 2. Of the 48 total evaluable■ subjects, if at least six■"subjects achieve an objective response or at least nine subjects are alive and progression free at
6 raoaths, the null hypothesis will be rejected, and it will be inferred thai the true ORR is '> 5% or PFS6 is > 10%. Assuming that approximately 95% of enrolled subjects will be evaluable, approximately 50 subjects will be enrolled to ensure 4S evaluable subjects.
{003.871 Iff each arm. up. to 10 subjects' whose tumors have a documented PDGCA mutation or molecular signature may be accrued to estimate, the ORR in subjects whose tumors have this, molecular alteration. A sample sixe of 10 assures that if the true response rate is 20% or snore, then the probability of observing no response is less than 12%.
[06388! Secondary efficacy endpoints of duration of response, median PFS, and CBR will be estimated.
[00389} Duration of response is defined as the time from first documented c onfirmed ■objective response to disease progression or death and will be analyzed using Kaplan-Meier methods for subjects with objective response. Median FFS {including landmark estimates such as PFS6) will use Kaplan-Meier methods. CBR is. defined as confirmed CR or confirmed PR at any time while the subject is on study treatment; or SI) for 24 weeks. CBR will be summarized' -using frequency counts and percentages. Two-sided exact (Case!la 1986) 90% confidence intervals may be computed for CBR.
[.0 3 6| Exploratory analysis will he "performed t identify subject population(s) tor which activity of the compound is maximized,
[003911 Adverse event terms will be standardised using the Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by system organ class and preferred terra. Laboratory parameters will be presented with respect to changes from baseline.
fi.es Jilts
[00392 j Art anal sis of preUmmary data from, die hase 1 pari of the study is presented below based upon information from 20 of 21 patients that enrolled iu phase 1. The baseline characteristics -of die enroliees are summarized in the following labies.
Baseline Characteristics Table 1
Baseline Characteristics Table 2
J00393 The Arm 1 (Compound A ) and Ann 2 (Compound B) dose -escalation- data is summarized in the .following tables. The recommended dose, for phase 2 was determined to be Compound A 400 mg- QD in combination with letr zole 2.5: nig QD. The .recommended dose for phase 2 was determined to be Compound B 400 rag QD m combination- with letrozoie 2.S mg QD.
Arm t (Compound A) Dose Escalation Summary
(0039 j Safety data is stuRmarized in the following tables. Five subjects experienced at least one SAE. There were a total of 6 SAEs; 2 were assessed as related to IP. In Ann 1 (Compound A), three subjects presented with SAEs (Gr3 febrile neutropenia, 2 cases of Cr2 pneumotliorax k the sarae patient and Gt$ pneumonitis). In Aon 2 {Compound B) two patients presented with SAEs (Gr 4 increase in transaminases and Gr4 back pain).
Summary of Treatment Emergent: Adverse Events in > 10% of Patients in Ar m I
Summa y of Treatment Emergent Adverse E vents in > 10% of Patients in Arm 2
f0€395| Patient Disposition and Status for Arms 1 and 2 is summarized in the foUo mg iabie; No objective responses were observed in either arm. Five subjects were on treatment for more than 24 weeks (Arm .1 three patients and two in Ann 2],
Patient Disposition -and Stains
(003961 PK data tor each arm is summarimi it? the following Tables, in Ann 1. plasma concentrations of 'Compound A when given in combination, with letrozole were similar to when given alone. Mb major interaction of Compound A on ietroxole PK when conipared to literature data for ietroz&k monotherapy. Similarly, m Arm 2, plasma concentrations of Compound 2 when given in combination with letroxoie were similar to when given alone; Also, no major interaction of Compound B administration on lctrozole PK when compared to literature data ibr leti xtfe monotherapy.
PK Interactions Between Compound A and Letrozoie in Arm 1
* >letii; i (Raws**)
Ϊ 09
00397} in.summary, Phase I has been completed. Preliminary results are depicted in Figures 3-6, In the figures. "PIT means progressive disease and "AIT means adverse event The recommended doses for phase 2 are:
* Arm 1 ; Compound A 400 mg QD >■ letromie 2,5 mg QD
» Arm 2: Compound B SO rag BID + letrozole 2.5mg QD
There were no major PK interaction between either Compound A or Compound B with letrozole, and N Objective Responses have been observed so far. Phase 2 for both arms is currently ongoing.
[003981 The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarit and understanding. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and .modifications .may be made while remaining within the spirit and scope of the invention. It vviil.be obvious to one of skill in. the :art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is Intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead, be determined with reference to the following appended claims, along with the ull scope of equivalents to which such claims are entitled. All patents,, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same ex tent as i f each individual patent, patent application or publication were s individually denoted.
Claims
1. A method of treating endometrial carcinoma in a patient, comprising administering to the patient an effective amount of (a) a Compound of Formula la:
la
or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, wherein:
R50 is hydrogen;
R51 is methyl;
R is hydrogen;
R53 is hydrogen or alkoxy; and
R54 is hydrogen, alkyl, alkoxy, or halo; or R53 and R54 together with the carbons to which they are attached form a 6-membered heteroaryl; and
R3 is halo or methyl; and
R3a is -N(R7)C(0)-Ci-C6-alkylene-N(R7a)(R7b) where R7 is hydrogen and R7a and R7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.
2. The method of claim 1, wherein R51 is methyl; and R50, R52, and R53 are hydrogen and R54 is halo or alkoxy in the compound of Formula la, or R50, R52, and R54 are hydrogen and R53 is alkoxy; or a single stereoisomer or mixture of stereoisomers thereof.
3. The method of claim 1, wherein R3a in the compound of Formula la is - NHC(0)CH2NH(CH3), -NHC(0)CH(CH3)NH2, -NHC(0)C(CH3)2NH2, -NHC(O)- CH1N(CH3)2, -NHC(0)CH2N(CH3)CH2CH2N(CH3)2, -NHC(0)CH(NH2)CH2CH3, - NHC(0)CH2N(CH3)CH2CH2N(CH3)2, or -NHC(0)CH(CH3)NH(CH3).
4. The method of claim 1, wherein the compound of Formula la is:
larmaceutically acceptable salt, tautomer, hydrate, or solvate thereof.
The method of claim 1, wherein the compound of Formula la is:
6. The method of claims 1-5 wherein the cancer is Type I or Type II endometrial carcinoma.
7. The method of claims 1-5 wherein the compound of Formula la is administered as a capsule or pharmaceutical dosage form.
8. A method of treating endometrial carcinoma in a human patient, comprising administering to the patient an effective amount of N-(3-{[(3-{[2-chloro-5- (memoxy)phenyl]ammo}quinoxalm-2-yl)ammo]sulfonyl}phenyl)-2-memylalanmami pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof.
9. The method of claim 8, wherein the N-(3-{[(3-{[2-chloro-5- (memoxy)phenyl]ammo}quinoxalm-2-yl)ammo]sulfonyl}phenyl)-2-methylalaninamide, pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof is administered as a capsule or tablet pharmaceutical composition.
10. The method of claim 9, wherein about 100 mg to about 800 mg N-(3-{[(3-{[2-chloro- 5-(memoxy)phenyl]ammo}quinoxalm-2-yl)amino]sulfonyl}phenyl)-2-methylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered as a capsule composition once daily.
1 1. The method of claim 9, wherein about 200 mg to about 700 mg N-(3- {[(3- {[2-chloro- 5-(memoxy)phenyl]ammo}qumoxalm-2-yl)ammo]sulfonyl}phenyl)-2-memylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered as a capsule composition once daily.
12. The method of claim 9, wherein about 500 mg to about 700 mg N-(3-{[(3-{[2-chloro- 5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl} phenyl)-2-methylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered as a capsule composition once daily.
13. The method of claim 9, wherein about 100 mg to about 800 mg N-(3- {[(3- {[2-chloro- 5-(memoxy)phenyl]ammo}quinoxalin-2-yl)ammo]sulfonyl}phenyl)-2-methylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered as a tablet composition once daily.
14. The method of claim 9, wherein about 200 mg to about 700 mg N-(3-{[(3-{[2-chloro- 5-(methoxy)phenyl] amino } quinoxalin-2-yl)amino] sulfonyl } phenyl)-2-methylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered as a tablet composition once daily.
15. The method of claim 9, wherein about 300 mg to about 500 mg N-(3-{[(3-{[2-chloro- 5-(methoxy)phenyl]ammo}qumoxalm-2-yl)ammo]sulfonyl}phenyl)-2-memylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof is administered as a tablet composition once daily.
16. The method of claim 9, wherein about 400 mg N-(3-{[(3-{[2-chloro-5- (memoxy)phenyl]ammo}quinoxalm-2-yl)ammo]sulfonyl}phenyl)-2-memylalanmamide, or a
pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered as a tablet composition once daily.
17. The method of claim 9, wherein the endometrial cancer is advanced or recurrent.
18. The method of claims 1-17, wherein the effective amount of a compound of Formula la 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.
1 . The method of any of claims 1-17, wherein the effective amount produces an improved clinical benefit rate (CBR) according to the equation CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 months) as compared to other treatments.
20. The method of claim 19, wherein the improvement of clinical benefit rate is about 20 percent or higher.
21. The method of claim 20, wherein the therapeutic effect is an increase in overall response rate.
22. The method of claim 20, wherein the increase in overall response rate is about 10 percent or more.
23. The method of claim 19, wherein a comparable clinical benefit rate(CBR) according to the equation CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 dosing cycles) is obtained with treatment of N-(3-{[(3-{[2-chloro-5- (memoxy)phenyl]amino}quinoxalm-2-yl)ammo]sulfonyl}phenyl)-2-methylalaninamide.
24. The method of claim 23, wherein the improvement of clinical benefit rate is at least about 20 percent.
25. The method of claim 23, wherein a comparable clinical benefit rate (CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 months) is obtained
with treatment of N-(3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-2-methylalaninamide.
26. The method of claim 23, wherein the improvement of clinical benefit rate is at least about 20 percent.
27. A method for treating breast cancer in a patient in need of such treatment, comprising administering to the patient an effective amount of letrozole in combination with either of
or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof thereof; or
or a pharmaceutically acceptable salt thereof, wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, wherein for each cycle the letrozole is administered at a daily dose of about 2.5 mg and the N-(3-{[(3-{[2-chloro-5- (memoxy)phenyl]amino}quinoxalin-2-yl)ammo]sulfonyl}phenyl)-2-memylalaninamide, or pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is administered at a daily dose in tablet form of 400 mg and the 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-^pyrimidin-7(8H)-one is administered at dose in tablet form of 50 mg twice daily.
28. The method of claim 27, wherein the breast cancer is hormone receptor-positive (ER+ and/or PGR+), HER2-negative (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor.
29. The method of claim 27 or 28, wherein the effective amount comprises a combination of letrozole and N-(3- {[(3- {[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-2-methylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof.
30. The method of claim 27 or 28, wherein the effective amount comprises a combination of letrozole and 2-ammo-8-ethyl-4-memyl-6-(lH-pyrazol-5-yl)pyrido[2,3-<^pyrimidin- 7(8H)-one.
31. The method as in one of claims 27-30, wherein 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, and a pathologic complete response.
32. The method as in one of claims 27-30, wherein the effective amount produces an improved clinical benefit rate (CBR) according to the equation CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 months) as compared to other treatments.
33. The method of claim 32, wherein the improvement of clinical benefit rate is about 20 percent or higher.
34. The method of claim 33, wherein the therapeutic effect is an increase in overall response rate.
35. The method of claim 34, wherein the increase in overall response rate is about 10 percent or more.
36. The method of claims 27-30, wherein the effective amount achieves a synergistic effect in reducing a tumor volume in said patient.
37. The method of claims 27-30, wherein the effective amount achieves tumor stasis in said patient.
38. A composition for use in treating breast cancer in a human patient, the composition comprising a clinically proven safe and effective amount of letrozole and either of N-(3-{[(3-
{[2-cWoro-5-(methoxy)phenyl]aniino}qumoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylalaninamide, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate toereof, or 2-ammo-8-ethyl-4-methyl-6^
or a pharmaceutically acceptable salt thereof.
The composition of claim 38, wherein the letrozole is formulated for a daily dose of
40. The composition of claim 38, wherein the N-(3-{[(3-{[2-chloro-5- (memoxy)phenyl]ammo}quinoxalm-2-yl)ammo]sulfonyl}phenyl)-2-memylalaninamide, or pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, is formulated as a tablet for a daily dose of 400 mg.
41. The composition of claim 38, wherein 2-amino-8-ethyl-4-methyl-6-( lH-pyrazol-5- yl)pyrido[2,3-iflpyrimidin-7(8H)-one is formulated as a tablet for a dose of 50 mg twice daily.
42. A kit comprising a dose of letrozole and a dose of either of N-(3- {[(3- {[2-chloro-5- (memoxy)phenyl]amino}quinoxalm-2-yl)ammo]sulfonyl}phenyl)-2-memylalanmamide, oi pharmaceutically acceptable, tautomer, hydrate, or solvate thereof, or 2-amino-8-ethyl-4- memyl-6-(lH-pyrazol-5-yl)pyrido[2,3- ]pyrimidin-7(8H)-one, or a pharmaceutically acceptable salt thereof.
43. The kit of claim 42, wherein the kit comprises instructions for using the letrozole, t N-(3-{[(3-{[2-chloro-5-(memoxy)phenyl]amino}qumoxalin-2-yl)amino]sulfonyl}phenyl)- methylalaninamide or the 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- cf|pyrimidin-7(8H)-one in the method of claim 1.
Applications Claiming Priority (4)
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US201161534836P | 2011-09-14 | 2011-09-14 | |
US201161543529P | 2011-10-05 | 2011-10-05 | |
US201161562670P | 2011-11-22 | 2011-11-22 | |
PCT/US2012/055387 WO2013040337A1 (en) | 2011-09-14 | 2012-09-14 | Phosphatidylinositol 3-kinase inhibitors for the treatment of cancer |
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EP2755654A1 true EP2755654A1 (en) | 2014-07-23 |
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EP12766542.0A Withdrawn EP2755654A1 (en) | 2011-09-14 | 2012-09-14 | Phosphatidylinositol 3-kinase inhibitors for the treatment of cancer |
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EP (1) | EP2755654A1 (en) |
KR (1) | KR20140077911A (en) |
AU (1) | AU2012308414A1 (en) |
BR (1) | BR112014005858A2 (en) |
CA (1) | CA2848724A1 (en) |
IL (1) | IL231448A0 (en) |
IN (1) | IN2014CN02671A (en) |
TW (1) | TW201325592A (en) |
UY (1) | UY34339A (en) |
WO (1) | WO2013040337A1 (en) |
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CN113754565B (en) * | 2021-11-09 | 2022-02-22 | 南京威凯尔生物医药科技有限公司 | Method for preparing Shakubaqu intermediate in continuous flow microreactor |
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US4107288A (en) | 1974-09-18 | 1978-08-15 | Pharmaceutical Society Of Victoria | Injectable compositions, nanoparticles useful therein, and process of manufacturing same |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US7019002B2 (en) | 2001-12-11 | 2006-03-28 | Pharmacia & Upjohn, S.P.A. | Pyridopyrimidinones derivatives as telomerase inhibitors |
RS52953B (en) | 2005-10-07 | 2014-02-28 | Exelixis Inc. | Pyridopyrimidinone inhibitors of pi3 kalpha |
NZ594630A (en) * | 2005-10-07 | 2013-04-26 | Exelixis Inc | N-(3-amino-quinoxalin-2-yl)-sulfonamide derivatives and their use as phosphatidylinositol 3-kinase inhibitors |
WO2007044481A1 (en) | 2005-10-07 | 2007-04-19 | Basf Corporation | Clearcoat coating composition |
ES2438998T3 (en) * | 2007-04-11 | 2014-01-21 | Exelixis, Inc. | Combined therapies comprising a quinaxoline inhibitor of PI3K alpha for use in cancer treatment |
WO2010146391A1 (en) * | 2009-06-15 | 2010-12-23 | Generics [Uk] Limited | Regioselective synthesis of letrozole |
WO2012065057A2 (en) * | 2010-11-12 | 2012-05-18 | Exelixis, Inc. | Phosphatidylinositol 3-kinase inhibitors and methods of their use |
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2012
- 2012-09-14 KR KR1020147009539A patent/KR20140077911A/en not_active Application Discontinuation
- 2012-09-14 BR BR112014005858A patent/BR112014005858A2/en not_active Application Discontinuation
- 2012-09-14 TW TW101133789A patent/TW201325592A/en unknown
- 2012-09-14 WO PCT/US2012/055387 patent/WO2013040337A1/en active Application Filing
- 2012-09-14 UY UY0001034339A patent/UY34339A/en not_active Application Discontinuation
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- 2012-09-14 AU AU2012308414A patent/AU2012308414A1/en not_active Abandoned
- 2012-09-14 IN IN2671CHN2014 patent/IN2014CN02671A/en unknown
- 2012-09-14 EP EP12766542.0A patent/EP2755654A1/en not_active Withdrawn
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TW201325592A (en) | 2013-07-01 |
BR112014005858A2 (en) | 2017-06-13 |
AU2012308414A1 (en) | 2014-05-01 |
WO2013040337A9 (en) | 2014-04-03 |
WO2013040337A1 (en) | 2013-03-21 |
KR20140077911A (en) | 2014-06-24 |
UY34339A (en) | 2013-04-30 |
CA2848724A1 (en) | 2013-03-21 |
IN2014CN02671A (en) | 2015-07-03 |
IL231448A0 (en) | 2014-04-30 |
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