WO2013040337A9 - Phosphatidylinositol 3-kinase inhibitors for the treatment of cancer - Google Patents

Description

PHOSPHATIDYLI OSiTOL 3-KJNASE INHIBITORS FOR THE TREATMENT OF

CANCER

CROSS-REFERENCE TO RELATED APPLI ATIO S

{Θ0Ο!} This application claims the benefi t of priority of U.S. Provisional Application No. 61/334,83$, filed September 14. 20_:11, U.S. Provisional Application No. 61/543, 520, filed October 5, 201 1 , and US. 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 among women. The American Cancer Society estimates that there will he 42,160 new cases of 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 States 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 elmscopathologtcai and molecular characteristics. Type f is estrogen dependent and represents approximately 80% of sporadic cases. This subtype is well differentiated (Grade 1 or 2 endometrioid histology) and has a favorable prognosis. Phosphatase and fensiu homolog ^•on chromosome 10 (PTEN) loss (32-83%) an RAS mutations (10-30%) have been predominantl identified in Type I EC (CMa et at 2005; Doll et al, 2008: Gadducci et al, 2008), Type ϊ I 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, p33 i frequently mutated in Type- II EC (Doll et al, 2008). There is evidence that the P1K.3CA pathway may be activated in both type I and type II EC and by differing mechanisms (Salvesen 2009).

|Oi)04j Standard therapy for newly diagnosed patients includes surgery, radiation, hormone therapy, and chemotherapy. There has not been any treatment approved in the

United States or in Europe .for adjuvant treatment of advanced or recurrent EC. Cispiatin,

I earboplatin, paclitaxel, and doxorubicin have been investigated -as single agents- or in combination for the treatment of primary advanced and recurrent disease. Overall response rates were higher in combination studies than with single agent studies, Paelitasel in combination with carbopktm is increasingly being used as the. referred regimen in advanced and refractory EC based on a favorable toxicity profile and on relative treatment convenience (Akrara ei al. 2005; Scudder et al. 2005). However, toxicity associated with chemotherapy remains problematic and challenging in the therapeutic- field of EC,

{0005} Clinical studies have 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 doxonibicin and cisplatin has demonstrated an improved survival benefit (median survival of .15.3 versus 12,3 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; Humber et a!. 2007; McMeekin et al. 2007),

{00 6} Approximately two-thirds of breast cancers exhibit hprraone-dependeiH 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 activation, has been standard therapy after primary' treatment Aromatase inhibitors prevent estrogen-mediated breast cancer stimulation through suppression of estrogen biosynthesis rather titan b blocking activation of the ER and effectively reduce total estrogen synthesis after menopause (Geisler etal, 2002). Two highl selective nonsteroidal aromatase inhibitors anastrozole (Arimidex$) and ietrpzole (Fe ara®) and the steroidal aromatase inhibitor exetnestan (Aromasia#) are approved for use in both early- and advanced-stage breast ^'cancers in postmenopausal women.

10007} Letrosioie .specifically blocks production of estrogens by competitive, reversible binding to the heme of the cytochrome P450 subtmit of the- enzyme aromatase. Letrozoie has been s n to be more effective in die treatment of metastatic breast cancer and in neoadjuvant and adjuvant ^'settings than tamoxifen (Ellis et al. 200.1; Mouridsen et al.. 2003; The Breast International Group [BIG] Collaborative Group 2005). ^'Leirozole is indicated for the adjuvant treatment of postmenopausal women with .hormone receptor-positive (HR+) early breast cancer, for the extended adjuvant treatment of earl breast, cancer in

postmenopausal omen who have received 5 years of adjuvant^■■ tamoxifen therapy, for first- line treatment of postmenopausal women with 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 letrozole are effective in treatment of hormone receptor-positive breas cancer; however, many tumors become resistant t aromatase inhibitors. As a result,, a need remains for new therapeutic options for the treatment of breast cancer, particularly hormone receptor-positi ve (ER+ and/or progesterone 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 hormone receptor-positive (ER- and/or progesterone receptor positive (PGR- )} or RER2-negative (HER2-) breast cancer which is refectory to a nonsteroidal aromatase inhibitor.

SUMMARY

10009] Accordingly, methods are provided for treating- endometrial carcinoma .comprising administering to a patient in need thereof therapeutically effective amount of a Compound of Formula. I or of Formula- li or a single isomer thereof or optionally as a pharmaceutically acceptable salt, tautamer, hydrate, or solvate thereof:

where- the Compound of Formula 1 is

wherein: W^f ,

of W'.. W^?, W^", and W^'J are independently ~N= aiii .tlie remaining are -C(R^f }^:;:;; and where each R^! is independently hydrogen, alkyl. haloa!kyl, tiitro, alkoxy, haloalkoxy, halo, hydroxy, cyancr. amino, alkyl amino, or djaikyiamino;

R*^s is hydrogen or alkyl;

R^" is hydrogen or halo;

i^i!,

are independently hydrogen, alkyl, alkenyl halo, haioa!kyS, ha!oaikenyl hydroxy, alkoxy, alkenyloxy, haloalkoxy, niiro, a jmo, alkyianamo, dialkylamino, -N(R⁵⁵}C(0)-CrC₆-alky]eac- (R )R^5¾ _} aikylcaAcmyh alkenyicarhonyt earboxy, alkoxycarbonyl, cyano, a!kyifhio, -SiO); R"R^''"a _t or aik k rbonylamino and where R^5> and R^>>B are independemit 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 heterocyc.loalkyl;

B is phenyl substituted with._:R^ja and optionally further substituted with one, two, or thre -R:*;

or

B is heteroaryl optionally ^' substituted with one, two, or three R³;

R'³ is cyano; hydroxyamino; carboxy; alkoxyearbonyi; alkylaramo; dialkylamino;

aikylearbonyl; haloalkoxy:. alkylsulfonyl; arninoalkyloxy; alkylaminoa!kyioxy;

dtalkyiamirioalkyiOxy; or

a) - (R⁷}C(0)-CrG aikyiene-N(R^¾)(R^?¾ where R⁷ hydrogen, alkyl, or alkenyl and R'^a and R'* are independently hydrogen, alkyl, alkenyl, hydroxyalkyl hakmiky!, alkoxy, alkoxyalkyl,. nininoalkyf, alkytami.noai.kyl, diaikyiaminoalkyl, eycloalkyl, cyeloalkylalkyl, heterocycloalkyL he!erocycioalkylalkyl, heteroaryl, heteroarylalkyl aryl, arylalkyi, or arySalkyioxy and where the.ar l, eycloalkyl, heterocycloalkvl and heteroaryl rings in '^a and R:^,H (either alone or as part of arylalkyi, cyeloalkylalkyl, heterocycloalfcy kyi and heieroaryiaikyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from alkyl, amino, aiky!aniino, dialkylamino, hydroxy, halo, alkoxy, aikyitino, and. oxo):

b> ~C(0)NR^sR^S;! where R⁵ is hydrogen, hydroxy, alkoxy. alkyl, alkenyl, haloalkyl,. or haloalkoxy and ^ is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl,

alkoxyalkyl, aikylthioalkyl, heteroeycloatky heteroeycloaikyla.ikyl, eyeioa!kyl, eycloalkylalky!, heteroaryl, heteroarylalkyl, .aryl,- or arylalkyi. and where the aryl, eycloalkyl, heteroaryl, and heterocycloalkvl rings in R^¾* (either al ne: or as part of arylalkyi. cyeloalkylalkyl. heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1 , 2, or 3 groups independently selected from aikyl a!k ny!, alkoxy, halo, haloalfcyl haioalkoSy,. ydroxy, - hydroxyalkyl. oxo, amino, alkylaraino, dialkyiami.no, aikylcarbonyl, ammaa!kyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycar ony}, and -C(0)H;

e) -NR'C(OJR^ys where R' h hydrogen, hydroxy, alkoxy, alkyl aikenyl, haloalkyl, «r haloalkoxy and ^¾ is hydrogen, Cj-C aikvl aikenyl hydroxyaikyl alkoxyalkyl, eyeioalkyi eycloaikylaikyl, heteracycloa!kyl, heteroeycloaikylalkyl;, heteroaryl, heteroaryhUkyk aryl or arylalkyl: where the aryl, cycSoaSkyl eteroaryl, and heterocycloalkyl rings in ^¾ (either akrae or as part of arylalkyl, ^"cycloalkylalkyk heteroeycloaikylalkyl -and heteroaiyialkyl) are independently optionally substituted with I , 2, or 3 rou independently selected from aikyl aikenyl, alkoxy, hydroxy, hydroxyalkyl, S¾alo, haloalkyl, haloalkoxy, oxo, amino, alkyiamino, dlalky!araino, aikylcarbonyl alkoxvearbonyl ~C{0)H, aryl {optionally subsiiteied with one or two halo), arylalkyl, heteroaryl heteroaiyialkyl, heterocycloalkyl heterocyc oalkylalky cyloalkyl cytoalkyl^'aikyl, and cycloalkyicarbonyl;

d)

where K is hydrogen, hydroxy, alkoxy, alkyl aikewyl, faaioaikyl, aminoalkyl alkylammoalkyl, dialkyfaminoalkyl or

hydroxyalkyl and R^K> and R¹'* are independently hydrogen, alkyl aikenyl, haloalkyl aminoalkyl, alkylaminoalkyl, diaikylaminoalky! . or hydroxyalkyl;

e) - R^{; i}C{0)NR^{! is}R^{! s}* where ¹ is hydrogen, alkyl, aikenyl, hydroxy, or alkoxy and R^{l !} and R' ^{: l>} a e independently hydrogen, alkyl, aikenyl, aminoaikyl, a!ky!aininoaikyi, or dia Iky i a inos iky I

f) -C(0) ¹² where R^{! *} is heterocycloalkyl- optionally substituted with 1 ,-2, or 3 groups selected from alkyl, oxo, amino, alkyhun^'tno, and heteroeycloaikylalkyl;

g) -NR^"¾(0)OR^l¾ where R is hydrogen, alkyl, or aikenyl and R^{i 5a} is aminoalkyl .alkylammoalkyl, diaikylaminoalkyl, aryl, or arylalkyl;

h) -CiO) (R^S }N{R^{i ;i})(R^s*) where R , ^{s ¾} _s and R^{i h} are independently hydrogen, alkyl or aikenyl;

i) -SiO¾N(R'^s}-C₃ - Valkylene-NCR^{i 5a})R^,$fe where R^{, s}. R'^5ft, -and R^!ib are independently hydrogen, aikyl, or aikenyl;

j) -C{O)N{R" Ct-Cf_>-alkylene-C(O)0R-^!'i'^!' where R¹" is hydrogen, alkyl, or aikenyl and i ^ta is alkyl or aikenyl

k) heteroaryl. optionally substituted with one or two aminoalkyl, alkylarainoalkyl, or dialkyjaminoalkyl 1) -N(R^,7 C.(=N(.R^s7¾R^{, ¾})K R ^cR^) where R*⁷, R^{] ¾}, R^{i ¾} R^{S 7}\ and R^p,t are independently hydrogen, alkyl, of aikenyl;

m) -N{R^{i S})C(Q)-C| id.kylene-N(R^{i; l,})C(0)R^i&a where R^{t Sn} is hydrogen, a!kyt, aikenyl, or aikoxy and R⁵ and R^{1 b} are iadepeiideijtly -hydrogen, -aikyl, or aikenyl;

«} -C(0}N(Rⁱⁱⁱ)~CrC₍ralkyle«e-C(D)R^i¾ where R^,f> is hydrogen, aikyl or aikenyl and

R '³ is amino, a yiamino, dialkylamino, or heterocycioalkyi;

) - C -^CCOj^Ci-a-alkylene-CCdj ^ where R-²⁶ is hydrogen, -aikyl, or aiken l and

R^¾la is eyd aSfcyl or h teroeycfoaikyl;

p) - R²¹S(0)rCrCV^Ikykne-N{R^2,fe}R² where R^2S is hydrogen, alkyl, or aikenyl and

R^2fa and R^2i¾ are independently hydrogen, alkyi, or aikenyl;

q) -N{R~)C(Q>C,^-s k 1ene. (R³²VW^22cK ^22a where R²², R^22a and R ^2t> are independently hydrogen, aikyl, or aikenyl;

r) - ^-alkyiene-N(R^i}}-CrO-alkyi:ene- (R^22i,)R^Jia: where R²\ ^2ia and ^23b are independently .hydro-gen, alkyi,_. oralkenyl; or

a)

a!kyi, or aikenyl and R^2¾ is aikoxyaikyl or aryl oprionaliy substituted with one or two halo; or alkyl; ^'and

where each of the -aikylene in R^¾ is - independently Optionally further substituted with 1, 2, 3,

4, or 5 groups selected from halo, hydroxy, amino, alkylamina, and dialkylamino; and each R^"' (when R³ is present) is independently alkyi; aikenyl; alkynyl; halo; hydroxy; oxo; aikoxy; eyano hydro syaniino; ea hoxy; afkoxycarbonyl; amino; aikylamino;_..

dialkylamino; aikylearbonyl; batoalkoxy; alkyisullbnyl; aminoa!kyloxy;

alkyla inoatkyloxy: dia!kyiamiooalkyloxy; or

a) -Nf R^CiO^^rC al ylen - lR^ii ⁷^ where R⁷ is hydrogen, alkyl, or aikenyl. and R^:a and R^;b are Independently hydrogen, alkyi, aikenyl, hydroxyaikyL haloalkyl, aikoxy, aikoxyaikyl, atninoaikyL alkylami oalkyl, dialky!anvmoalky!. cyeloalkyi, eyeieaikylaikyl heteroeycloalkyl, heterocyeioalkyla!kyi, heteroaryl, heteroarylalkyl aryl, arylalkyl, or aryla.lkyioxy and where the aryi, cyeloalkyi, heteroeyeloalkyl and lieteroaryl rings in R'^a and R^' (either alone or as part of arylalkyl, eyeieaikylaikyl, 'beteroc-yeloalkyla!kyl and heteroarylalky!) are^■independently optionally substituted with I, 2, or 3 groups independently selected from alkyi, amino., aikylamino, dialkyi.anii.no, hydroxy, halo, aikoxy, a!ky!ihio, and oxo);

b) -C(G}NR¾* where * is hydrogen, hydroxy, aikoxy, alkyi, aikenyl, haloa!kyl, or haloaifcoxy and R^sa is hydrogen, alkyl, aikenyl, hyd^'roxyalkyl, eyanoalkyi,

aikoxyaikyl, alkyithioalkyl, heteroeycioaikyl heterocycioalkylalkyi, cyeloalkyi, cycioaikylaikyl, Iieteroaryl helcroarylalky.,- aryl, or arylalkyi and where the ar l, cycioaikyk heteroafyl, and heterocyeloalkyi rings in R*³ (either alone or as part of arylaiky!, cycioaikylaikyl, heterocycioalkylalkyi and heieroaryiaikyl) are

independently optionally substituted with I, 2, or 3 groups independently selected from alkyk alkenyl, alkoxy. halo, hakalkyl, haloalkoxy,- hydroxy, hydroxyalkyl, oxo, amino, alkySarnino, dtalkylamino, aikyicarbonyl, aminoalkyi, alkylarninoalkyl, dialky!amiiioalkyl, alkoxycarbony!, and -C(0)H;

c) ~NR*C(Q)R^¾ where is hydrogen, hydroxy, alkoxy, alkyk alkenyl, lialoalkyl, or haloaikoxy and ^s'a is hydrogen, C;-Ci.-a!kyi, alkenyl, hydroxyaifcyi, alkoxyalkyk eycioaikyl, cycioaikylaikyl, heterocyeloalkyi, heteroeyeloalky!alkyL heteroaryl hetevoarylaikyl, aryl, or arylatkyl: where the aryl, cycioalky!, Iieteroaryl, and heterocyeloalkyi rings in R ^a (either alone or as part of arylalkyi, cyeioaikylalkyl, heterocwcloaiky kyl and heteraaryklkyl} are independently optionally substituted with 1 , 2, or 3 groups independently selected froni aikyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyk haloalkoxy, oxo, amino, alkySamino, dialky!amino, aikyicarbonyl, alkoxycarbonyl, ~C(0)H, aryl (optionally substituted with one or two halo), arylalkyi, heteroaryl heteroarylalkyl, heterocyeloalkyi, heteroeycloalkylalkyk eyloalky!, cyloalkylalkyl, and eycloalkylearbonyl;

d) -C(0> (R^i¾)'Oi^-alkylene- (R^K¾ R^uib where K^m is hydrogen, hydroxy, alkoxy, alky I, alkenyl, haloalkyl, or hydroxyalkyl and R^{f 0} and R^m are independently hydrogen, aikyl, alkenyl, haloalkyk or hydroxyalkyl;

e)

alkenyl, hydroxy, or alkoxy and R^{! i} and R^ui> are independently hydrogen, aikyl. alkenyl, aininoalkyl,

alkylanunooalkyi, dialkylaminoalkyl;

f) -C(Q)R^!2 where R^;2 is heterocyeloalkyi optionally substituted with 1 , 2, or 3 groups selected ftora aikyl, oxo, amino, alkylanuno, and heterocycioalkylalkyi;

g) -NR^uC(0)OR^{! ¾} where is hydrogen, aikyh or alkenyl and R^{! !} is aminoalkyk aikylaminoalkyi, .dialkylaminoalkyl, aryl or rylalkyl);

h) -C{0)H{R^M) {R^{i i>})(R^{5 l}j where R^H, R^m, and R^{5 b} are independently hydrogen, aikyl, or alkenyl;

i) ~S(D}2N(R^{s i})-CrG6-alkylene-N(R^{:i s}*)R where R¹³, R^iS and R^{J 5h} are independently hydrogen, aikyl, or alkenyl;

j) -C{0)N(R^i:i Ci -C6-alkyleric-C(0)OR^s¾ where R^tS is hydrogen, alkyi or alkenyl and R^;<¾i is aikyl or alkenyl; k) heteroaryl optionally su.bsiitu.ied itli one or two aminoaifcyi, alkykminoalkyl, or dialkylaminoalkyl;

I) -N{Rⁱ⁷)-C(-N(R^{!7 ,})(R^{i 7}¾(NR^i¾R^17iJ) where Rⁱ⁷, R^m, R^{l ¾}, R^!¾, and R.^{i 7d} are

independently hydrogen, alkyl, or alkeny!:

m) - (Rⁱ⁸)C(0) rQ aikylcne-N(R^}8l C{Q)SL^iSa' here R^!*^a is hydrogen, alkyi, aikenyl, or aikoxy and - R^i!> and R^m< are independently hydrogen, alkyi, or alkenyl;

n)

Rⁱ⁹ is hydrogen, alkyl, or alkeay! and

1^{5 8} is amino, aikylaminD, diaikvlaramo, or heteroeycloalkyl

o) -N(R^?9)C{0).CrC^alkylene-C(0)R^2C3 where: ^¾) is hydrogen, alkyl, or alkenyl and

R^"¾> is eycioalkyl or heteracydoaikyi;

p) -NR^2!SfO)rerC a!kylene. (R^{3 ib})R ^la where R²¹ is hydrogen, alkyl or alkenyl and

R^{" i!i} and R^{2! l>} are independently hydrogen, alkyl, or alkenyl;

q) -N(R²²)C(0)-CrC_fraSkylene-^ where R²², R^22a and R"^¾ are independently hydrogen, alkyl, or alkenyl;

r) -¾r₆-aikyiene^ (R^2s)-C C aSkylene-M(r '¾R^{2 3} where R ³ R²⁵ and ^2¾ are independently hydrogen, alkyl, or alkenyl; or

s)

or alkenyl. and R^24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl;

wherein each of the alky I ene in R' is- independently optionally further 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, R^aj is hydrogen or methyl, R" is hydrogen or methoxy, and R^"" is hydrogen or methoxy, then B is not 2,3-dihydn -i ,4-beriz;odios.fnyL tS.iien-2-yi, or th.ien-2-yl substituted, with one E' where R is halo;

where the Compound of ^'Formula 0 is

Formula 11

wherein^*

R. is hydrogen, optionally substituted alkyl, optionally substituted eycioalkyl, optionally substituted cydoalkylalkyh optionally substituted, aryk optionally substituted aryialkyi, optionally substituted heteroeycloalkyi, optionally substituted heterocycloalkyiaikyf, optionally substituted heteroaryl,.or optionally substituted

hetemarylalkyl;

* 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, acyj, or heteroaryl wherein the phenyl and heteroaryl 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!aminoalkyl, or alkoxyalky!amino; and

each Rvw-'heti present, is independently halo, alkyl, haloalkyl, aikoxy, ha!oalkoxy, cyano, amino, alkyiamino, dia!kylamtno, altoxya!kyl, carhoxya!kyl, alkoxycarbonyl, aminoalkyL eycloalky!, aryi, arylalkyi., aty!oxy, heteroeycl aikyl, or heteroaryi and where the eyc-loalkyl, and, heteroeyeloalkyl, and heteroaryi, each either alone or as part ^:bf another group within R\ are independently optionally su stituted 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 ofFor ula I is a compound of .Formula ia

la,

or a single stereoisomer or mixture of stereoisomers thereof and optionally as a

pharmaceutically -acceptable salt, i atomer, hydrate, or solvate thereof, wherein;

R ' is. hydrogen:

is methyl;

R^''~ is hydrogen;

R^i"< Is hydrogen or aikoxy; and fC⁴ is hydrogen, aikyt aSkoxy, or halo; or R^ and R^> together w.iih the earbOris to which they are attached form a ό-membered heieroaryl; arid

R" is hal or meihy!.; and

R³* is -N(R^?)C{0)-CrC^ailcylene-N(R.^¾)(R⁷ ) where R^T is hydrogen and R^¾ and R ^'^are independently hydrogen, alky], aniinoalkyl. aikylammoalkyl, or

diaikylaininoalkyi

(00.1 Ij In one embodTment, the compound of Formul S. and of Formula, la is Compound

A:

Compound A

or a (autoraer, zwiiteriom or pharmaceutically salt thereof.

{0012} Corapound A: is known by its chemical name -(3~ {[(3-{ 2-ch1,oro~5~

(meytox J hen llaminQ ^

In one embodiment, the Compound of Formula 11 is a compound of formula II A.

1IA

or a pharmaceutically acceptable salt thereof wherein:

R^! is alkyi,. cyeloaikyl, eycloalkylalkyl, aryl, arylalkyl, heterocycloaikyl,

heteroeycloalk>¾lkyl, heteroaryl, or heteroaryialkyl;

R" is hydrogen or a!kyl;

R is alkyl;

R^' is hydrogen;

R" is phenyl, 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 iadependently halo, alkyl, !ia!oalkyi. alkox , haioaikoxy, cyano, -amino, ai ylaraitio, dialkylaraino, alkoxyalkyl, earboxyalkyl, alkoxycarborryi, aminoaikyk c cioalkyl .aryl, .arylalkyl,. arylpx-y, heteroeyo aikyl,: or heteroaryl and where the

1.0 cycloalkyl, aryl, heterocye!oalkyl, and heteroaryl each either alone or as part of another group w utt K^"', are independently optionally substituted with 1 , 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, lia!oalkoxy, amino, alkylamino, and diaik lamino,

(00141 In another embodim 0 is Compound B

(0015 j Compound B is known by its name 2-araino-8-ethyl-4-niediy!-6-{ ! /-pyra¾K>l-3- yl)pyrido|2 -ii pyriinidsn-?( /}-o)ie, Compound, 8 is disclosed in WO (Ϊ7 04 813, the entire contents of which are incorporated herein by reference.

(09 ! 6{ hi ooe embodiment, the cancer is Type I or Type II endometrial carcinom .. jOOi 7] In another csnbodiment, the cancer is advanced or recurrent endometrial carcinoma,

|001$j in another embodiment, the compound of Formula Ϊ or Formula 11 is administered as a tablet or capsule pharmaceutical composition.

(001 J In another embodiment, the compound of Formula I or Formula II is administered as a tablet pharmaceutical composition.

[0020] In another embodiment, die compound f Formula 1 or 11. is fidrninistered 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 rale, or a pathologic complete response.

I_.0021J In another aspect,;meth.ods are provided herein tor treating breast cancer comprising administering t a patient in need thereof a therapeutically effective amount of letrozoie in combination with a Compound of Fonnula I, la, or Compound A as described herein;: or letroxoie in combination with Compound it, HA, or Compoun B as described herein.

[0822} In one embodiment, the compound of Formula 1 or Formula 11 is administered orally as a tablet or capsule pharmaceutical composition,

{^'00231 hj another embodiment, the compound of Formula 1 or Fonnula 1.1 is admi iste ed as a tablet p armaceuUcal composition,

i i |ί >24| In another embodiment, the ompound of Fonftula I or II is administered in an eifective amount, wherein the eifective 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,

BRIEF DESCRIPTION OF THE FIGURES

j^'0.025f 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 1 33 & A D 1 1439) for Compound A.

| 26J Figure 2 shows a plot individual and mean/SD (Bold, horizontal lines with error bars) for Compound B AUC{0- 12), ss after doses of 30 and ^'50 rag capsules BIO in Ann 2 com ered, to historical data (TED 1 1440) for Compound B (above).

[0027] Figure 3 depicts preliminary results f rom a Phase I results from a breast cancer clinical trial,

|O 2Sj Figure 4 depicts preliminary results from a Phase I results from, a breast cancer clinical trial.

(0(⁾29| Figure 5 depicts preliminary results from a Phase I results from a breast cancer clinical trial.

|0030| Figure 6 depicts preliminary results-front 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

1 Ac I acetyl

i br 1 broad

\ -c decrees Celsius

i c- eyclo

! CBZ CarboBenZoxy^' enzyjoxvs arbonyj f d doublet

! dd doublet of double t

I dt doublet of triplet

i DCM diohlbromeihane

i DMA 1 Dtmethvlacetamide

ί DME 1 ,2-dimethoxyeihane

! DMF Λ',Λ'-dimethvlformamide Abbreviation Mean: jag

1 032 The symbol ^■ means it single bond, means a double bond, ^{> ν} means a triple bond, means a single or double bond. The symbol ^B«Aiw" 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. 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 be 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 the right-hand structure. Sometimes a particular atom in a structure is described in te tual formula as having_, a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -C¾C1¾-. It is understood by one of ordinary skill in the art thai the aforementioned descriptive techniques are common in the chemical art to provide brevity and simplicity to description of otherwise complex .structures.

group " " is depicted as "floating" on a ring system, as for example

then, unless otherwise defined, a substim-eni "R." may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, s long as a stable structure is. formed..

}0835j If a. roup "R." is depicted as floating on^', 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 ~NH- in the formula above), implied hydrogen (for example as in 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-) frp.m 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-membered or the 6-tnerabered 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,

|9036| When a group. "R" is depicted as existing on a ring system containing saturated carbons, as- i r example in the formula:^'

where, in this exam le, "y can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "RY" may reside on the same carbon. A simple example is when R is a methyl group; there can exist a gerninal dimethyl on a carbon of the depicted ring (an ''annular" carbon). In ^'another exam les two R's on the same carbon, including that carbon, may form- a ring, thus creating a spiroeydie ring (a "spirocyeSyr group) structure with the depicted ring as for example in the formula;

|0037| "Acyi" means a -C(0)R radical where R. is optionally substituted alkyl, optionally substituted alksnyl, eycioalky!, cyeloaikySaiky!, aryl, .aralkyl, heteroaryl, heteroandkyl, hererocycloslkylj or heieroeyeloaiky!alkyl, as defined herein., e.g., acetyl,

trifiuoromethyicarbonyk or 2-methoxyethylearbony/l, and ⁽he like.

[0038] "Aeylaroino" means a - RR radical where R is hydrogen_*. hydroxy, alkyk or alkoxy and IV is aeyl. as defined herein,

0O391 "Acyloxy" means an -OR radical where R is aeyl as defined herein, e.g.

cyanoinethyicarlx nyloxy, and the like,

[00411] "Administration" and variants thereof .(e.g., Administering'' a compound) in reference to a compound of the invention means introduc ing (he compound or a prodrug of the compound into the system of the.animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents, "administration^*" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and oilier agents.

[004 ! j "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-eny and 1 -pent-3-em-i and the like.

[00 21 "Alkoxy" means an -OR. group where R. is alkyl group a defined herein.

Examples include methoxy, ethoxy, propo y, isopropoxy, and the like.

[0043] "Alkoxyaikyf ' means an alkyl group, as defined herein, substituted with at least one, preferably one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymeihyl and the tike.

1_.0044.1 "Alkoxyalkylainino" means an ^»NRR' group where R is hydrogen, alkyl, or alkoxyalkyl and R' is alkoxyalkyh as defined herein. 10045] "Alk xyalkyiammoalkyr' means alky! group substituted with at least one, specifically one or two, alkoxyalkylamino groupis), as defined herein.

|0046] "Alkoxyq-arboayF means a -C(0) group where R is alfcoxy, as defined herein. 10047) "Alky!" means a linear saturated monovalent hydrocarbon^■ radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 6 carbon atoms, e.g., methyl ethyl propyl, 2-propyl, butyl (including all isomeric forms), or peniyl (including all isomeric forms), and the like.

10048] ⁱ Alkytamino" means an -RH group where 11 is aikyi, as defined herein.

| CI4*>| 'Alfcyiarmnnaikyn means an alky! group substituted with one or two aSkylamino groups, as defined herein.

)00S0{ 'V kyla inoaikylo y" means an O group where R is alkylaminoa!kyk as defined herein.

10051] ^SiAikyiearbonyr means a -CfO)R group where R is alkyl. as defined herein. 10052] "Alkynyl" 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., elhynyl, prepynyl, butynyl, pentyN-2-yl and the like.

[0053] "Amin " means

10054] "Ainmoalkyr means an alkyl group ..substituted^' with at least one, specificall one, two Or three,, amino groups,

10055) 'AminoaikyioxY" means an -OR grou where. R is aminoaikyl, as defined herein, 100663 "AryP means a monovalent six- to tburteen-membered,. mono- or bl-earfaoeyclie 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 riug within the radical, valency rules permitting. Representative examples includ phenyl, naphthy.l, and indanyS, and die like,

]0057) "Arylalkyl" means an alkyl radical, as defined herein, substituted with one or two aryl groups, a defined herein, e.g., ben¾yl and phenethyi, and the like.

(0058) "Arytoxy" means an -OR group where R is aryl, s defined herein.

|{ )5«>] ^'"Carboxyalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, ~C(0)OH group(s).

10060} "Cyeloaikyr means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), .monovalent hydrocarbon radical of three to ten carbon ring •atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency ^'rules permitting. One or two ring carbon atoms may be replaced by a -C(0)-, -C(S)-, or -C(=NH)- group. More specifically, the term eycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyi, cycloperttyl, cyclohexyl, cyclohexyl, or cyclohex~3~enyl, and die like.

[00611 "Gyclpaikylalkyl" means an aikyl grou substituted with at least one, specifically one or two, eycloalkyl group(s) as defined herein.

[00621 ".Dtalkyj raino" means a -NR ' radical where R and ' are aikyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino,

or iV-raemylelhylamino, and the like.

(0063| "Dialkylaminoalkyl" means an aikyl group substituted with one or two dialkylamino groups, as defined herein.

|0064| "Diaikylaminoalkydoxy" means an -OR group where R is diaikylaminoalkyi, as defined herein. Representative examples include 2-(A^r,iV-diethy1amino)-ethyloxy, and the like. j0065| ^wFu$ed-porycyclic^w or "fused ring system" means a polycycUc ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures, in this application, fused-polycyciies and fused ring systems are not necessarily ail aromatic ring systems. Typically, but not necessarily, fused-poiyeyclics share a vicinal set of atoms, for example naphthalene or 1 ,2,3,4-tetrahydiO-iiaphtha!ene. A spiro ring systefn is not a fused-polyeyciid b this definition, but fused poly cyclic ring systems of the invention may themselves have spin) rings attached thereto vi a single ring atom of the fused-polyeyciic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to fonn a -ring- structure. The fused ring_, structure may contain heieroaiotns and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fitsed groups (i.e. saturated ring/structures) can contain two substitution groups.

|0066| "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[Q06^*7| "Haloalkoxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifiuoromethoxy or 2,2,2~tTiiltK)roethoxy, and the like,

|0{)68] "Haloalkyl" mean an aikyl grou substituted with one or more halogens, specifically one to five halo atoms, e,g,, trifluoromethyL 2-chloroethyl, and 2,2-difluDroethyl, and the like,

[0069) "fleteroaryl" means a monocyclic. Fused bicyclie, or fused tricyclic, monovalent radical of 5 t 14 ring atoms containing one or more, specifically one, two, three, or four ring hsteroatoms independently sel cted from -0-, -S(.C . (¾ is 0, 1 , or 2), -NC ")-, and the 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 bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonarotna tic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(Q)-, -C(S , or-C(~NH)- group. R^x is hydrogen, alkyi. hydroxy, alkoxy, acyl, or alkyisuiibnyl. Fused bicyclic radical included bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of die heteroaryl -group, valency rules permitting. When the point of valency is located on the nitrogen, " is absent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazoly!. 1 ,5-triazol l. plnhalimidyl, pyridinyl, pyitolyl, iniklaxoiyL thienyl, ftiranyi,

(including,, for example, 2,3-dihydro- i/:/-inclo!>2-yl or 2.3-dihyd^'ro- l.H-indol-5-yl, and the like), isoindo!yl, indolinyl, isoindolmyl, bctEa Vidazolyl, beazodioxol-4-yl, benzofluranyl, cinnolinyl, indolizinyl, naphthyridin~3-yl, phthala/.tn-3-y!. phUmtazm-4-yl, pterid yl, purinyl, quinazo!inyi, quinoxalmy!, etrazoyi, pyrazo!yl, pynvzinyi, pyrimidinyi, pyridazinyL oxazoiyl, isooxazolyl, oxadiazolyL benzoxazoly qumolinyl, tso iiinotinyl, tetraliydroisoquinolinyl (including, for example,.

ietrahydroisoqoino0.ii-4-yl or tetmhydroisoqumoim-6-yl, and the like), pyrralo[3,2- cjpyridinyl . including, for example, pym->kip_s2~c|pyridi.rs~2~yl or pytToio[3,2-c pyTidin»7-yS. and the like), benzopyranyl, thiazolyl, isothiazolyj, thiadiazolyl, benzothiazoiyl,

betvsothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof.

0070] "HeteroarylalkyF* means an al.kyl group, as defined herein, substituted with at. least one, specifically one or two heteroatyl group(s), as defined herein.

{0071 j "Heieroatom" refers to Q, S, , or P.

{Q072j "Hetergcycloalkyr' 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 a oma ic) mon valent fused bicyclic rou - of 5 to 12 ring atoms in v hieh one or more, specifically one, two, three, or four ring heteroatoras independently selected .from 0, 8(0),, (n is 0, 1 , or 2), N, N(R^y) (where R^y is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsultonyi), me remaining ring atoms being carbon. One or two ring carbon -atoms maybe replaced by a -G(Q^'H -€(SK dr ~C(~NH)- group. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group ma be located on any atom of any ring within the radical, valency .rules permitting. When "the point; of valenc is located on a nitrogen atom, R^y is absent More specifically the term heteroeyctoalkyl. includes, but is- not limited to, azetidinyl, pynolidinyL 2-osopyrrolidinyi, 2.5-dihydro- 1 H-pyrr lyl, pipertditryi, -pip.eridon l, raorpholinyl, piperaziny!, 2-oxopiperazinyl, tetrahydropyraoyi.

2-oxopipendinyi, tluomorpholinyi, thiamorp oiinyl, perhydroazepmyi, pyrazolklinyi, imidazolmyl, imidazolidinyi, . dilrydropyridiuyl, tetrahydropyridmyi, oxazoHnyh oxazoiidm h Isaxazolidinyl, thiazolinyi, thiazolidi yi, quinuclidinyl, isothiazolidinyl, .octahydroiadolyl, OGtahydreisoindGlyl, decaliydroLsoquinoiyi, letrahydrofur l, and teltahydropymn l, and the derivatives thereof and N-oxide or a protected derivative thereof.

|ββ?3}

means an alky! radical, as deimed herein, substituted with one or two heterocycloalkyi groups, -as defined herein, e,g., morpholmylroethyl, iY-pyrroiidmyiethyl, and 3-{A-azetidmy!)propyl, and the like.

{0074} "He eroeyclo¾Ikylaikyloxy means an -OR group where & is heterocyclo .ikylaikyi, as defined herein.

[0075] "Saturated bridged ring system" refers to a bicycHc or polyeyolie ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturatios but not aromatic or heteroaromatie rings in its core structure {but may have aromatic substitution thereon). For

?-aza-bieyeio[2.2.1 ]hepiane, and l ,2_!3,4,4a,5,8.¾<Ktahydro--napht.halene are ail included in the class "saturated bridged ring system.

[0076} "Spirocyelyr or "spiroeyelie ring" refers to a ring originatin from a particular annular carbon of another ring. For example, as_: depicted beiow, ring atom of a saturated bridged ring system {rings B and B^'). but not a bridgehead atom, can be a shared, atom, between the saturated bridged ring system and a spirocyciyi (ring A) attached thereto. A xpiroeyclyl can be carbocycUc or heteroalkyelk.

[0077] 'Optional" or '"optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not, One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterieaHy practtcal and or syntheiicaliy feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term. So, for example, in the term "optionally substituted arylC'₃ aikyl," optional substitution may occur on both th&^' "Cf-» alkyi" portion and the aryl" portion of the molecule may or may not be substituted,- A list of exemplary optional substitutions is presented below in the definition of "substituted."

10078} 'Optionall substituted ai.ke_.xy" means an -O group where RJ_.S optionally substituted alky), as defined herein.

}^'0079J 'Optionally substituted alkyi" 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, alkylcadioiiyi, alkenyiearbonyl, eycloalkyleart>on l, aik lcarbonyioxy, alkcnykarbony xy, amino, alkylamiao, diaikylamino, -aminocarbonyl, alkylammocarhonyl, dialkylaminocarhonyl, eyaoo, eyanoalkySanimoearbonyi, alkoxy.

alkenyloxy, hydroxy, hydroxyalkoxy, .halo, ear oxy,^■■alkyiearbonyiamrao, alkylcarbonyjoxy, alkyi-S(0)(i.:-, a]kenyl-S(D it).;-, aoiiuosulfouyl, alkylaminosulfonyl, dtalkylaminasuifonyl. aikylsult¼ l~ R^i:~ (where R^c is hydrogen, alkyi, optionally substituted alkenyl hydroxy, .alkoxy, alkenyloxy, or cyaaoalkyi), aikyiaminoearbo!iy!oxy, dialkyia inecatboByloxy, alkykraiiioalkyioxy, dia!ky!aininDalkyloxy, alkoxyearbonyl, keny!oxyearbonyl, iilkoxycarbonyfamino, alkytaminocarbonylamino, dia!kyla moearbonyiamino,

alkoxyalk lo y, and -€(0)Ν¾¾^!'' (where R^a and R^b are independently hydrogen, alkyi,. optionally substituted: alkenyl, hydroxy, alkoxy, alkenyloxy, or eyanoalkyi),

J0080) "Optionally substituted lken l means an alkyi -.radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or -.five groups, independent ly selected from alky (earbonyl , s-1 kenylearbonyi, eye ion Ikylcarbonyk ii!kylearhonykTxy, ^:aikenylearbonyloxy, amin * alkylamino, dialkyianiino, aminocarbon i, alkylatuinocarbonyi, dia!kylatninocarbonyi, eyano, eyanoalkylaminoearbonyl, alkoxy, alkenyloxy, hydroxy,, hydroxyalkoxy, halo, earboxy,- alkylearbonylaramo, alkylearbonyioxy, aikyl-SfO);),!-, alfcenyl-S(0)<>:r, araraosulfonyl, aik laminPsu tbny , dialkylaminosulfbnyl, alkyisulfonyl- ^'R*- (where R^t: is hydrogen, alkyi, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or eyanoalkyi}, alkylaminoc-arbony xy, dialfcylammoearijony!oxy, alkyl&ffimoalkytoxy, dialkyiaminoaikyioxy,, alkoxyearbonyl, alkenyloxyearbonyk alkoxyctsrbonyknnino, alkylani noearbony-lamino, diaikylaminocarbonylamino,

aifcoxyalkyioxy, and ~C(0)NR^aR^!> (where Rⁱ and R^fe are independently hydrogen, alkyi, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or eyanoa!kyl).

{0081] "Optionally substituted amino" refers to the group -N(H)R or-N(R)R where each R is independently selected Irom the group: optionally substituted, alkyi, .optionally

substituted alkoxy, optionally substituted arv optionally substituted heteroeycloalkyl. optionally substituted heteroaryi, acyl, carboxy, alkoxycarbonyl, -S(0)3-(opUonaHy substituted a!kyi), -S(0).2-optionally substituted an !}, ~S(Q)r(op.tionaliy substituted heteroeycloalkyl), -S(0) (optionally substituted heteroaryi), and -S(0)2-(0ptionally substituted heteroaryi). For example, "optionally substituted amino" includes^■diet ylaraino, metiiyisulfonylaini.no, and furaayl-oxy-suUbnamino..

[ 0821 "Optionally substituted aminoalkyr means an alkyi group, as defined herein, substituted with at least one, specifically one or two, optionally substituted amino gronp s), as defined herein.

[0083] "Optionally substituted aryP means an aryl group, as defined herein, optionally substituted with one, two, or three substituenti* independently selected from aeyi, aeylamino, acyloxy, optionally substituted alkyi_* optionall substituted aikenyl, alkoxy, aikenyioxy, halo, hydroxy, alkoxycarbonyl, alkenyloxyearbotvyl, amino, alky i ami no, dialkylaimno, nitro, aminoearborryk alkylamuiocarbony!. dialkyian nocarbonyl, carboxy, cyano, alkyJ.th.io, alkylsultuiyl, alkylsultbnyl, ammosuifbtiyi, lkylaminosuli nyL di alkylaraijiosul fonyl, al&yixulfonylaraino, aminoalkoxy, or aryi is pentafiuorophesi l Within the optional substittients on "aryl", the alkyi and alkenyl, either alone or as part of another group

(including, for example, the alky! in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.

[110841 "Optionally substituted .arylalky/ means an alkyi group, as defined herein, substituted with optionally substituted aryl, as defined herein.

(0085) 'Optionally substituted cyeloaSkyH means a eycioalkyl. group, as defined herein, substituted with one, two, of three groups independently selected from acyl, acyloxy, aeylamino, optionally-substituted alkyi, optionally substituted alfceayl, alkoxy, aikenyioxy, alkoxycarbonyl, aJkenyloxycarbonyl, alkyltoio, alkylsoitlnyl, a.lkylsul.t¾nyl, antinosulfonyl, alkylarainosulibnyi, dialkylaniinosuiibnyl, alkylsulfbnylamino, halo, hydroxy, amino, aikylammo, dialkylamino. aminocarbouyS a!kyiiiminocarbonyl, diaikylaminoearhonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alkylaroinoalkoxy, dialkySaminoalkoxy, carboxy, and cyano. Within the above optional s bsti litems on ^cyeloalky ', the alkyi and alkenyl, either alone or as part of another suBs iuent on the eycioalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haioalkyi, haloatkoxy, haloalkenyloxy, or haloaikylsultbnyL

[0086] "Optionall substituted eyeioaSkyialky]^" means an alkyi group substituted with at least one, specifically one or two, optionally substituted eycioalkyl groups, as defined herein. [00871 "Optionally substituted heteroaryF^* means a heteroaryi group optionally

substituted with one, two, or three substituents independently .selected from acyl, acylamino, acy!oxy, optionally substituted alkyi, optionally substituted alkenyl aikoxy, alkenylojty, halo, hydroxy, alkoxycarfapnyl, alk.eny^xyearbonyl, amino, alkylarfti.no, dialkyiaraino, nltro, aniinoearhonyl. alkylammocarbonyl, dialkytamiaoearbonyi, carboxy, eyano, aikylthio, alkyisu!fiiiyi, aIkylsulib:¾d_y aminosuifonyl, a!ky!aminosulfonyl, djaikyiaminosuifenyl, aifcylsulfonyia ino, ami oa!koxy, alkylaminoalkoxy, and dtalkyiaminoalkoxy. Within the optional substituents on "heferoaryr, the alkyi and alkenyl, either alone or as part of another grou (including, for example, the alkyi in alkoxycarbony!}, are independently .optionally substituted with one, two, three, four, or five halo.

}0088] 'Optionally substituted hetcroarylalkyl" means an alkyi group, as defined herein, substituted with at least one, specifically one or two, optionall substituted heteroaryi group(s), as defined herein.

[00891 '^Optionall -substituted heteroeyeloalkyr means a heierocyelealkyl group, as defined herein, optionall ^'substituted with one, two, or three^■substituents independently selected from acyl, acylamioo, aey!oxy, optionally substituted alkyi, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyi amino, aikytemioo, di lkylamino, tiiiro, aniinocarbonyl, alk iaminoearbonyl, dialkyiaminoearhonyi carboxy, cyano, aikylthio, alkylsuifmyl, alkyisulfonyk aminosulfoiiyl, aikyiaminosulfonyl, dialkylaminosulf nyl, alkylsulfonylanuno. ammoalkoxy, or r l is pentafiuorophenyL Wiihi the optional substituents on "heteroeyeloalkyr ^*, the alkyi and alkenyl, either alone or as part of another group (including, for example, the aikyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.

[00901 'Optionally substituted heteroeyeloalkyialkyi" means an alkyi group, as defined herein, substituted with at least one, specifically one or two, optionally substituted

heterocyc!oaikyi groupfs) as defined herein.

[00911 "Phannaeeoticai composition^" comprises 1 ) a Compound of Formula 1 or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof; and 2) a pharmaceuticall acceptable carrier, exeipie.nl, or diluent. As used herein, "Compound A,^" which is a com oun of Formula I. and of

Formula la, has the

Compound A is known by its chemical name N-(3-{[(3- {[2-chloro-5-(nietlioxy)phenyl]amino ^

yi)aminc^uii nyl) pheijy.l)-2-raethy!{ilaftt«amk¼. As discussed in more detail below, the com ound may exist in several tauto eric forms. Accordingly, as used herein the terms "Compound A" and "N 3-{[(3- [2 hlor0-5-(metho y)phenyl]amino}qm^'noxaUn-2- y.i)ammo]sulfonyi }phenyl)-2-methyialamnamide^" encompass all possible tautomeric and i'Aviiterionie forms of the compound.

|<K)93 j As used a Compound of Formula II and of

Formula Ha, has die

mpound B is known by its name 2- atmno-8vethyl-4-methyl-0^«(l^ Compound B is disclosed in WO 07/044813, the entire contents of which are incorporated herein by reference,

1 09 } "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.

{0O95J "Patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other r nisms. Thus the methods are applicable to both human therapy and veterinary applications, in a preferred embodiment the patient is a mammal, and in. a most preferred embodiment the patient is human.

(0096} The terms "effective amount" or "pharmaceutically effective amount" or ^therapeutically effective amount" ref er 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 of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system, i n 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 administered in one or more administrations. The effective amount of Ihe drug or

composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (hi) inhibit, retards skrtV t some extent, and preferably stop cance cell intUtfiition 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 iitmor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. For example, an

!¾i¾ctive amount" for therapeutic uses is the amount of Compound Λ or a metabolite thereof; a pharmaceutically- acceptable salt r 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,

J0O97J 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 an .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 "'pha maceuticali 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, li>83„ which is incorporated herein by reference or S. M. Berge, et ah, "Pharmaceutical

Sails, ^'' J. Phami. Sci,, 1977 66: 1 - 19 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, irifiuoroace ic acid, propionie acid, hesanoic acid, cyclopentanepropjonic acid, glycolip acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, raalonic acid, succinic acid, fiiraarie acid, tartaric acid, citric acid, ^'benzoic, acid, cianamic acid, 3r(4-h.ydroxybenzoyl)ben2o.fc acid, niande!ic acid, inetlianesuliomc acid, ethanesu!lbnic- aeicl |.,2-ethaaedisui.fo:nic acid,

2-hydroxyethanesulf .nic acid, henzenesullOnic acid, 4-eh-loro^'ben¾enesull¾me acid, 2-naphthalenesulfomc acid, 4-toiuenesulfonic acid. camphorsuUbnie acid, glucohep mic acid, 4,4'-methylene is*(3-bydroxy-2-ene-^'l -carboxylic acid), 3-phenyipropkraic acid, tmnethylacetic acid, tertiary butylaeetie acki_vkuryi sulfuric acid, gluconic acid, glutamic acid, hydroxynaphmoie acid, salicylic acid, stearic acid, mueonie acid, p-to!uenesu!fonic acid, arid-salicylic acid and the like.

{00100] -Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from .pharmaceutically acceptable organic non-toxic bases include, but are sot .limited to, salts of primary, secondary, and ternary amines, substituted amines including naturally occurring substituted amines,, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamiae, trimethylamine, diethy!amine, trklhylamine, tripropylarame, ethanolamine,

2-dimethylantinoethanol, 2-diethylammaethanoJ, dieyciohexyiamine, lysine, arginitse, histidinc, caffeine, procaine, ..hydrabamine, choline, betaine, cthyienediamine, glucosamine, methylgiuearaiue, theobromine, purines, piperazine, piperidine, N-ethy!piperidinc,

tromethamme, ,Y-me iylglucamine, poiyaniine resins, and the like- Exemplary organic bases are isopropylaraine, dieihylamme, ethanoiamine, trimethyiamin.e, dicyclohsxylamine, choline, and caffeine,

[00101[ "Prodrug^"1 refers to compounds that are transformed (typically rapidly) is vivo to yield 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- r branched chain. Acceptable esters als include eycloalkyi esters and. ary!alkyi esters such as, but not (united to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, bat are not limited to, primary amides, arid secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods, Λ thorough- discussion of prodrugs is provided in ^"f . Higuehi 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 B. Roche, American - Pharmaceutical Association and Perganioii Press, 1987, both of which are

mcd po rated herein by reference for all pur oses.

(00102} "Metabolite" refers to the break-down or end product of a compound or its salt produced by mctabolisnj^or.biotransiorniationin the animal or human body; for exam le;, bioiransf nnatiori to a m re- olar molecule such as b oxidation, redaction, or- hydrolysis,- or to a conjugate (see Goodman and Giimao, "The Pharmacological Basis of Therapeutics" -8.sup.lh Ed., Pergamon Press, Oilman et a-1. (eds), 1990 for a discussion of

biotransformation).. As used herein, the metabolite, of a compoimd of the invention or its salt may be the biologically active form of the compound in the body; In 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 is discovered .serend.ipitously, -thai is. no prodrug design per was.tuKfcrtaken. An assay for activity of a metabolite of a compound, of the present invention is known to one of skill in the art i 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; and relievin the disease, disorder, or syndrome, that is, causing regression of the -disease, di sorder, or syndrome. As is known in the art, in the context of treatment, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may he 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 front occurring i 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 die disease, disorder, or syndrome but does not yet experience or display symptoms of die disease, disorder, or syndrome.

.Embodiments

[00105] The following paragraphs preseni a number of embodiments- that can be used to practice the invention. In each instance, the embodiment includes both the reci ted compounds as well as individual isomers and mixtures of isomers, in addition, in each instance, the embodiment includes the pharmaceutically acceptable salts, hydra tes, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereo f [ΜΙ^βδ in one embodiment, methods: arc .provided for treating cancer which method comprises administering to a patient an effective amount of a Compound of Formula f or fa or a pharmaceutical, composition comprising a Compound of Formula 1 or la,

ίόθί 07| 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 a pharmaceutical coinpostiion comprising a Compound of Formula 1 where the cancer is EC in some embodiments, the cancer is Type 1 EC, In other embodiments, the cancer is Type ii EC, .

fOOliiSj Any of the .following embodiments, including the representative compounds described belo w, may be used to practice an of the methods d isclosed herein.

Compounds of Formula J

[001 9 j The Compound of Formula,! is selected from any of the following enibodiments, including from the Representative Compounds in Table 1.

f t!Ol 1 J One embodiment ( A) of the compound of Formula ί is where W % W\ and W" are ~C(R⁵)~; or one or two of vv', w\ W^'\ a dW are independently -N= and the _. remaining are -C(R^,)^B£5 where each R¹ is independently hydrogen, al.kyl,_:ha oalkyl, nitro, aikoxy, baloaikoxy, halo, hydroxy, eyan.o, amino, alkyiamiiio. or dklkylamino; and all other groups are as defined in the Summary of the Invention, in another embodiment, W^!, W^:, W\ and VV^* are -C{R')~ and each R^! is independently- hydrogen or alkyl; or one of W and W" is ~N~ and the other is -C(H)=> In another embodiment, W , W*, \Ψ and W are -C(R^! )^™ where each R¹ is independently hydrogen or alkyl In another embodiment, R^! i hydrogen,

[00111| Another embodiment (B) of a Compound of Formula Ϊ is w here R^¾t> is hydrogen, alkyl, alkenyi halo, haioa^'ikyl, haloaikenyl, hydroxy, alkoxy, alkenvloxy, baioaikoxy, nitro, amino, alkylamino, d alkylaromo, -HC ^CCOJ-Cs-C^-alk lene-HiR^'^ ³³^ alky!carbonyl alkenyicarbonyl, carboxy, alko ycarbonyl. cyano, alkyiihio, *S(Q)5NR*'R,^W*_» or

aikyicarbonyliinrino; where R⁵" and- R"^a? are indepenilentit hydrogen, alkyl or alkenyi and R⁵⁵"* is hydrogen, alkyl alkenyi, hydroxy, or alkoxy; and all other groups .are as-defined in the Summary of the invention, in another^' embodiment, R^Jii is hydrogen.

[00112] Another embodiment (Q of a Compound of Formula Ϊ is where R^{J f} is hydrogen or alkyl; and at! other groups are a defined in the Summary of the invention. In another embodiment, R^{¾ i} is alkyl In another embodiment, R^5! is methyl. 1(10113.1 Another embodiment (D) of a Compound of Formula I is where R⁵" is hydrogen or halo; and ail other groups are as defined in the Summary of the invention, in another etn!xxliment ³² is hydrogen or fiuoro. in -another embodiment, &⁵~ is hydrogen.

(00114 j .Another embodiment (E) of a Compound of Formula 1 is where ³³ is hydrogen, alkyl, alkenyl, halo, haloalk l, ludoalkenyl, hydroxy, aikoxy, alkenyloxy, haloalkoxy, nitro, ammo, alkykmino, dialkylamin , ^ (ft^'s^)C(0)^»Ct-C_&-alkylefie^>N(K^33a)R** ^ ^ca,^ⁿy^ alkenyicctrbonyl, cafboxy, alkoxycarbcmyl, cyano, alkylthio, -S(Q_.} NR^a5R^S5* or

alkylcarbonylaffimo; 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 ar as defined in the .Summary of the Invention, In another embodiment, is. hydrogen, aikoxy, nitro, amino, or - {R^>s)C{0)-C -C^iky!e.ne^« { ^>3)R^¾iis>. In .mother embodiment, ^si is hydrogen, methox , nitro, amino, or -NHC(0)CH2 (CH,i)2,. in another embodiment, is hydrogen or snethoxy, (0U115j Another embodiment (F) of a Compound -of Formula I is where- R ^! is hydrogen, alkyl, alkenyl, halo, .hiiloaikyk haloalkeayi, hydroxy, aikoxy, alkenyloxy, haloalkoxy, nitro, amino, aikyiamino, dialkylamino, -H R^C-CQ^Ci-C alk lene-NiR^^ ⁵^, aikylcarbonyl, a!kenylcarhonyl, carbo y, aikoxycarboijy), cyano, alkylthio, -SfOja ^ ⁵¹'², or

ulkyiearbonyla md; where ^{" '} and ^{> 1}' are independentlt hydrogen, alkyl, or alkenyl and R^¾5a is hydrogen, alkyl, alkenyl, hydroxy, or aikoxy; and ail. other groups are as defined in. the Summary of the Invention. In another -emfeodime-nt, R*^* is hydrogen, alkyl, aikoxy, or halo. In another embodiment, R⁵⁴ is hydrogen, methyl, meihoxy, bromo, or chioro. In another embodiment, ^"'* is hydrogen,, meihoxy, or chloro,

jOOI Ify Another embodiment (G) is directed to a com und of Formula I wher R? R'~, and are hydrogen and s halo or aikoxy; R ', ^, and R*⁴ are; hydrogen and is aikoxy; or R^'v,) and. ^5* are hydrogen and R^5<* and R" ^? together with the carbons to which- they are attached form a 6-membered hetero ryi; and all other groups are as defined in the

Summary of^" the invention, in another embodiment, R^Mi, ^"2, and R^'3 are hydrogen and R ^t i cbJo^'ro o meihoxy; R"¹, " and R^3'' are hydrogen and ^s'' is .ethoxy; or R^3t' and R^J ' are hydrogen and R^{" 3} and R~⁴ together with the carbons to which they are attached form

pyridlrryi. Even more specifically, R' " R^'", and R^5J' are hydrogen and is-.ehloro or snethoxy; or R''', R**, and R' are hydrogen and R^?i is meihoxy.

0t>l 17} in another embodime t (Gl) of embodiment G is -a compound of Formula 1 where R^' ' is methyl.

|0 il8). Another embodiment (J), B is heieroaryi optionally substituted with one, two, or three R³. fit another embodiment, B is thien-J-yl, pyrki.inyi, pyttm.idi.nyl, pyridazinyk pyrazinyi, oxazolyl, ispxazoiyl, pyrrolyl, unidazolyl, pyrazolyl, or ihiazolyi, each of which is optionally substituted with one or t o R".. In another embodment B is thien-3-yl, pyrklin-2- l, pyridin-3-yi, pyritUn-4-yl, oxazol-2-yl, oxazo!-4-yL oxazol-S-yl, isoxazoi-3-yl, isoxazol-4~ yi, isoxazol-S-yk imida¾oi-2-yl, pyrrol-2--yi, pyrrO.l-3-yl, imida oH-yL itmdazohS-yl, pyraz l-3-yl, pyrazoM-yi, or pyraeoi-S-yl, each of which is optionally substituted with one or twoR\ In another embodiment, S is thien-3-yi, pyridin-3-yl, pyridin-4-yl, isoxaz0l -yl, or pyfirzoM-yl each of which is optionally substituted with one or two R^"\ in another embodanetu,_. B is pvTid -3-vL 2-hydroxy-pyridin-5-yi, ¾oxazoI-4-yl, or yrazol-4-yl, each of which is optionally substituted with one or two R\

f 00.11.9} Another embodiment (K)_: R^¼ is eyano: hydroxyamino; earboxy; alkyisui onyL aminoaikytey alkyto

(R^7a)R¾ -C(0)NR¾^¾3; - R¾fO)R^9il; :(0)N(R^l!))-C₁.C_i>-alkyie«e. (R^ua)R^,i¾;

- R^uCf0)NR^u¾^!, v¾ere R^!!:f; -C(0)R^{"; - ^CiOlOR^'; ^(Q)i <R^, )N Rⁱ⁴ⁱ)0i^{, !}'); -S{0); (R^!i}-CrC_ira!iq eiie- (R^!ii:)R^iih: -C(0)N{R^ _{-.Q-alkylene-C(0)OR^i6a;

heteroatyl -optionally substituted with one or two aminoaiky.l,-.alk¾tiamoal¾yl, or diaikyiammoa!kyk -N(R'^?)-C(^«N(R^i?fc)(R^,¾))( R^!7cR¹⁷⁸}; -N(R^l8)C(0.)-C,-Q-<itkyleBe-

C C_ft- lkylesie-OR²*; where each of the aikylene m R ^?a is independently optionally further substituted with 1, 2, 3, .4, or 5 groups selected from halo, hydroxy, amino, alkylaroinO, and dialkylamino; and ail other groups are as defined in the Summary of the Invention.

JOOI 21)| in another embodiment; R^¾ is:

- HC(©}CH₂NH(CH₅], - HC(0)CHjNH(CHCHj), - HC(0)CH(CH₃) H₂,

- Hqi )CiCH5}_;Ni¾i₅ -NHC{0}C¾NiCH,_;)_2l . HC{ )CH₂N(CH₃)CH:Cl-i₂ ( ¾)2« -NHC(0}CHCNH.)CH₂CH₃ -NHC(0}CH₂NiC¾}CI¾CS¾ (CH_s¾,

- HC(0)CH{CHj) H{CHj , -NHC(0)C¾N% -M4C(0)H, .NHC{0)CH₂(azeiidra^« 1 -yl), 'NHC(())(pyrrolidin-2-yl), - !-lC(0)Cfi( H₂)CH₂OH,.-NHC(0)(a¾etidin-4-yI),

-NHC(D)C(CHj)₂NH(C¾), -NH₂, -NHC(G}CH₂NH(Ci¾CH₂CH¾), -NHC{0)C11₂CH₂ H;. - HOH, - HC{0){piperidin-3-yi}₁ - i-lC(0)C:H₂(4-fnethy]-!_?4-d.ia2:epafi-l-yl},

-NHC(0)CH(NH₂)(CH₂CHj), ^«NHC{0)CH₂NH{CH2.CH{OH}(CH3)),

-NHC{0)Ci. NHCH₂CH₂F, -NHC(O_:)CH₂ H(OCH₂CH(CH.₂), - HC(0)( 1 - asniB cyclopi-op-l-yl), - FtC{0}CK₂NHteH₂cyelopropyi), . -NHC{0)CH₂3- (dimeihylamino}-azetidin-l-yi), -NHC(OKpiperidin-2-yl), -NHC(0)(mqrpholm-4-yl), -NHC{0C;H.₂(pyrroUdin-l-yi), - liC{0)CI i(Ni:i₂)CH₂CH₂CH₂CH₂N(CH₅)_:, -NHC(0)CB₂ (C¾XCH₂C^

1 -y!). - HC(0)CH3 H(CH₂CH(CH}₂X ~ HC(Q)CH2 (CHj.)(CH:CH₃},

-NHC(0)(A-(in3{daxoH-ylniet!wi)-azeudH^

- HCH₂N(atCH₂^^^

-N HC(0)CH2N(GHi)^'(CH2CH₂N(C¾)2}, - HC(0)CH2{3-hydroxy-pynOlidjn- -yt ), -NMC{0)( i-amino-cyc buH -yi), - HC(0)CH₂NH(CH2)JCHJ₅ -NHC(0)C¾(3-piperidin-l yiazetidin-lyl), - HC(0)NH₂, -NHC{0)(l-hydroxyeyd propyl), - Hi¾O)CH₂NH {CH. 2, - HC{0)NH(CH₂)₂N(CH₅. , -NH€(0}C«₂ H, -NHCiO)(pyridazis-4-yi -NHC(0){ - methyi-piperidtti-4-yl), -NHCiC¾a¼NHCH(CH₃)_?i -NflC(0}CH₂{3-dimeihySamitio- pyrroHdin- 1 i), - HC(0)CH₂NH(CH₂)2N(CHs)_2i -NHC0)( I -cyclopropylmet yl-aze⁽idi!i-3 yi), - HC(0)CH₂NH(CH3)_3> -NHC(0)(imidazol-2-yi), -N C(O)(imidazoS-4-y ,

-NHC(0)(1 ,2-oxa¾pH-yl), -NBG{0)CH₂NHCH₂CF_¾ - HC(0)Ci¾C¾fpiperids»-l -yi), -NHC(0)f 3-oxo-cyeiopent- Ϊ -yi), - HC(0)(2-liydroxy-p rid!ii-6-yl)_? - HC(0)CH_:NH(3- fi oro-4-hydroKyphettyi), -NSiCfO)fCIi₂)jN(CHj)_2i -NHG(0)( I -(iitran-l-ylmet ylj-az ttdiii 3-yi), -NHC(0}(p>Timtdm-5-yl), - HC(0){pyrroi-2-yi}_; - HC(0)CH3N(CHj)CI S(CIij}_2> - MH (0)Ci¾M(C¾Ci4₃)₂^^ amino- teirahydropyran.-2-yi), -Ni-iC{ )CH₂(4-met¾>%m!no-piperid{n-l-yl),

- HC{0)(piperidin-l -yi), - HG{O)(<V-ra thyi-pyrroiidm-2yl), -NHC(0X<iuen-3yi),

- HCCOifA^Ce clopo lcai-bO y azetiditi-S-yi). -MHCf 0)CH2( -methyi ipera2m- i -yl)* -NHC(0)(A-b<;iizyia¾;iidiB~3-yl), ~N.HC(0)(2-cliloiB-pyridin-.3:-yi)_! -NHC0JCH₂(pyTidm-4- NHC(0)CH₂NH(b.enzyi), ~NHC(Q)CH₂OCH_3>

-NHC(0)(pyridm-3-yl), - HC(0)CH2NHCH₂CH₂0CH3,> HC(0)(i-CC(O)CH^iperidm-4-yi), - HG(0)CM₂(2- raetiiyl-pyrmlidin- ! -yi), -NRC(0}{i an-3~yl)_; -NHC(0)CHjN(Cli;)_2; -NHG0)(2-chioro- pyridi 5«yl)₅.-NHC{O 2-chioK>phenyl), -NHCfO)CH₂(pyridm-2-yl}_; ^«NHC{0)GH₂{3- dimet ylnmiiTO-ifeetidiQ- i -yi), - HC(0)Gii₂(pyridia-3-yl), «Nf iC(0)C ijfS-chiorophenyl), -NHC(0)CR₂N(CHj)CH₂CH₂CB₂N(CH}), -NHC{0)GH₂H(CH₂GHj)CH₂CH₂OH,

- HG(0)Ci½(2-benzy!--pyiToiid!H_;-!~yi)₍ -NHC(O)(.ft«un-2-yl, -NHG(0)(2-chloro-pyridm-4 yi), -HHC(0)CH₂MHCCO)GH₃, -NHGfO)CH₂CH₂CH₃₍ -NHC(0)(^"4-chtojO henyl),

-NHC(0)(4-m f yI-phenyi). ~ HC(0}CB₂ HC(0}OiC¾k -Ni-iCCO)(beo2ofdl[ i Jjdioxol 5-yl), - HG{0>CH₂NHOCi¾(2-ineiiioxypheiiyi), -NHC(0)(pyridia-4-yi), . -MHCfO)CH₃[4- (3,4~dicbloropb«.nyi.)-piperas.in- i -yl], -NtiC{0)CH₂CH₂(pyi kijii-3-yS),

-^^•^(^'^(reirah dKjfaran-S- i)^ -NHC(0)CH2NHCH^:i(2^melhylphenyi), -Nl'iC(0}CH(CHi}C¾CHi₍~ HC(0}CH₂(3-i]iioropiienyi.), -HHC(0}C¾C(CH_3:}₂ph ayl. - HC(0)(2-niethyl-cyclf(pr p-l--Yl), - HC(0)(2-methyi-4-metIi xyp eiiyl)_J -NHC(0}(2~ met ylpyridm^3-yi)_; >NHC(0)(4-merb xyphetjy¾ - HCCG)CH₂i4-ethylpiperazin- 1 -yl), -NHC(0)iihien-2-yl), -NH (0){3-fluoro-2-mcthyiphenyI>, -NHC(0){2-bromo-thien-3-yl), -NHC(0)(4-fluoroph<myi)_t - HC(0)C¾(3-t«ethylpipcridm-I~yI), - HC(0)CH(CH₃)₂, - NHCCOXCH CH - HC(0)C¾OCHiCH,,-NiSC(0)CB₂NH(2-fluorophenyi)_!

- HC(0}t3-d»neihylainijiophcnyi)v- llCfO)C.H

-^^'HC(0)C¾NH(2-fl-ptopyiphenyi)^N:HC(0)phenyL- H -NHC(0)(3- tluoro-4-methoxyphenyl), -NHC(0)C(CHjhCH₂CMj. - HC(0)eH>0(4-fluorop enyi), «NHC(OX!-me¾yicarb(.>iiyl-a2eti m-3-yl>₅- -NHC(OjC¾NH(4~methy!.s>!¾enyf),

^N-HCCO^CH^NHCphenyl), - HG(0)CH₂{4-aIlyl-piperazm- 1 -yl ), - HC(0)(2-metliylpheiiyl}₍ -NHC(0)CH;GH₂OCH.j₅4«(G}(3-raeihyl«airan-2«yl). -NHC(0)C(CH₃)₃, - HCiOiGHiNHO enz i, -NHC(0)CifcNl!(3- h! rophetiyl}. ~NHC(0)CyclobutyL

- HC(0)C¾(3-raethoxypheiiyl}_! -NMC{0)( l-raethyicycioprop- 1 -yl), - NHCCOX3-¾rophe«yl), * HC(0)(4^minhylammopheijyl), -NBC(0)(3,4-iichloit!p enyl>, - HC( )CH₂NHa^

NIK(0)CI:I₂N(CH₂CH5)CH(CH₃)₂,-NHC{X))(thiazo.l-4-yl), -NHC(O)CH₂N(C¾ ben¾yI, -

MHC(D)CH₂NHC¾(thien~2~yi), ~NFiC(0)CH₃NHCH₂{pyriditi-2-yl}, -NH€(Q)(3~ methoxypficiiyl), -NHC(0)CH₂NHCH:(3 hloro-4-methyiphe«yl)_; ~

metbylphenyl), ~NHC(0)CH₃0{2- ethyIpheny¾ -NHC(0)CH₂(€Yclohcxyl), - HC(0){2- phenyl-cycloprop-l -yl), - HC(0)(3-chlorophenyl)., -NHC(0)CH₂(2-me⁽hGxyp enyl), ^BC(0)GH₂CH₂(3-meUK>x^

-NHC(0)CH2NHCH₂(3-nuofO-pheoyl)_i- HC(0)CH:{4-meiJioxy-pbeRy , -NHC(0)bcnzyl, - iIC(0)(2_!4-dicb!orophenyi)_! -NHC{0){3-oxo-Gyclohex-l-yl)_; -KHC(0)CH₂ H(3- iiuemphenyi), -NHC(0)CH₂(3-cWo.ropheny^:l),

NHC(0)C¾NHCH₂(2,4-dimeihylphenyi) -NHC(0)CH₃(2-mchyl-pipericiin-l-yl)_;

-M HC(0)CH₂NH(2-nieihoxyph ?iy!}, - H0O}CH( 1₅2 ,4>.etrabydroisoqiimolin-2-yl),

-NHC(0)CH₂NBf2-met yipberiy1)₍ -N! iC(0)C¾(4-oxo- pipersciiB-1 -yl), -HHC<0)(2-t¾oropheayl), n HC(0)CH.₂NHCl.(CH;r)pheiiyl, -NHC{0}(2- fluo!O-6-methoxyphenyl), -NHC(G)CH₂N! (2-isopTOpyiphenyl)₎ -NHC(0)CH₂CH₂(2- melhoxyphenyt), ~ ]-iC(0)CH₂CH₂CHfai_{3 3} -NHC(0)CH₂(2-phenyi-moipholi ^-yl), -NiiC(0)CH₂CI¾H-^iS:¾oxyp eny!}, -NHC(0)C¾ <allyi)byctopeatyl_s - NHG(0)CH2N^!(CH₃CH₂GH₂OC¾₅ -NHC(0}CH₂CH₂C(O)cyciopjopyL NHC(0)CH₂NH{3- feri-buiyipheayi), .- HCiO -l-hN j-propylXcyclopropyimelhyl), -NHC(0)CH>(2- xo- cyclopetrtyi), -NHC(0)CH₂ H{4-e tarophenyl)^

yi)_?. - HCiO}C¾{4-cyclopentyipiperazm-l-yl}_! -NHC{0}CH₂(2-raethy.phenyl)_>

-NHC(0)CH3NeCH₂(3-fluoro-6-!nethyiphmyl), - B.C(0}CI¾C(GHj}₃, -MHCiO)C¾NH{2- chiorophenyi), -NH.C(0).(3-ilui)n>6~raet ylphenyl), -Nf:iC(0)(4~iluoro-3-niethylphenyl}_!

dimethylphcnyl), -NHC(0)(2-fluoro-5-methylp enyl)_> -NHC(0)C¾NHOC¾(4 - Hiet yljphenyl), - ilC(0)CIlj(4-isopropylpiperazl»- i -yt), - H€(0}CH₂i4~iluorophenyl), -

propylptperid.tn-l-yl}_} - ilC(0)Cff^(3-ffiethylpireny), -N^THC(0)(etrahydrofuran~2r-yi), -NHjC{0)CH₂(3-hydroxymethylpiperidin~l-yi), -NHC(0)( 1 -j¾r-butpxyearfaonyipiperiljn-2-- yi), - HC(0)CH₂N(CH₅)Ci-b(pyridin^«3-y1), iHC(0)CH₂N{CHjCi¾)phenyl,

-NM )C¾OCH₂CHiOCHj_t -NHCO)CB₂C¾(eyctopemyt)_t -&HC(0)i 5- dicMorop enyi), ^«HHC(0)C¾{4>raetljy!car o»ylpipera2in-'l->yl>, ~NHC(OX^'5- uoro-2- meth xyphenyl), -NHC(0}CHiNfCH₂C .i)cycloS½xyL -NHCiO)(5-methyl- 1 ,2-oxazol-3-yl),

dichlorophenyl), .NHC^O)CH₂{tWazolidin3-y¾ -NHC(O)C >(4-[C{0)H]-pipeia/in- 1 -yl), ♦NHC(0}CH₂{2-pyridijR-4-ylpiperidin- 1 -yi), -NHC(0)(2-m thoxyp eiiyi), - NtlC(0)GH₂N(CH CH₂C^

~ ΗΟ( )(Ι- ¾βν1ΰνο1ορΓί>ρ-Ι-·ν1), -NiiCiO}CH:2,6-dimeil:iyl:raorpboIln-4-y!}

NHC(0)CH_i(2-phenylpymjlidm.1 -yi), -NHC{0)CHj(m«ipho.I«i-4-yl)_s - C(0) HCH(CH₃)C¾NiCH₃) -C(0)NHCH₂CH₂N(CH_¾):, ~C(0)NH(pynOlidin-3-yl)« - C( )NHCl¾CH2(pyn-oiid.in ^«y , -C(0) HCH₃CH₂NH₂, -CfO}N{C¾}CH₂CH₂ (CH,)₂, - C(0) HC¾(piperidin-2-y!}_! -C(0)NH(l-}« -hy.!azctidm-3>yi), -C{G)NHGH₂C¾{piperkiin- i- l), -G(G)NHCH₂CH₂N(CH2CH₅)2₅ -C(0) H(1 -methylpiperidin-3- l),

-G(0) H(piperidiiv3-yl), -C(0)N^H€.¾(l-iijethylpiperidin-3-.yi), - C(0) HC^ίCH2N(CH2CH_^OM)₂, (0) H( etl^yl i[βridίn^«3'yί), -C(0)NH₂, -C(0)(3- :amwopyiT lidin-l-yl); -^OXS-mcth laramo rjrolidm-l- l), -C(0)OH, - 0(Ο) Η€>¾αϊ_2.(ηϊ0φΗοΐ -·|}, -C(0)NHC¾(l-ethyipy:!TOijdm-2÷yl), «C(0)(4-ai»i:no- 3-oxo-pyra^oiidin-l-yS), -C(0)NHCHj₅ -CiO -amiaocvclah i- 1 ~yj). -C(0)N CI¾(pyri.din~ 3-yl, -C{0)ivHCH₂C¾OH, -C(0)NH(3-oxo-pyraz )idin.4-yi), ^MCH₂CH₂(imida¾ol-4-yi)_t -C{0)(3-diraethylaminopyrroIidiu- ! -yl), -C(0)NHC¾(pyridin-4-yl)_? -C{0)N(CH₃)( 1- iBethyl-pyrrolidin-3-yl), - (0}(3-di.ediyJaffiinop>mii.idi!i-l-yi)_^ - G{0)^«CH₂CH₂CM₂ipyrra1idin-i-yt)₅ -C(0)N{CH₅)C¾C¾C ,.-G{0)NHCH₂GH₂OCH_3i- C(0)N{C¾C«i)CH2CH_zCN, -C{0)(3-affiiiiopiperidm- 1 -yl), <{0) HC¾CH₂C¾ (CH3)2₅ -CCO HCmorphoKn^-yt), -C(0} H iCHj)-, -C(0} HCH₂CK₂CH₂(imidazol-! -y!)₍ - C{0} HC¾CH₂CH₂N(CH_;eH₃¾,

•C(O}NlKlI₂C¾CN -CfO) H;CH:CH:C(0}OC¾, -C(Q)NHCH₂C¾SeH₂,

-(0)NtiCH₂CH₂SeH₂CH₃, -C{0}H(C¾CHj}CM„CH2NCCH3¾_t -C(0)NHC¾CH_:.CH₃(2- oxo-pyrroHdnv 1-yJ), -C{O) HCH2C«j(pyridin-4-yl), -C(0)^' HCH₂CI-i_;CH20CH₃C¾, -e(0)NBeB₂€H₂CH n^

-C(0]NHCH2C¾C(0)OCe_;CH,₅ -C(0)NHC¾C¾C¾OCH(CH₅);,

-CiO}NHC(CH-);C{ia( ip ridm-l-:yl. -G{0}N<CH₂)CH₂CH₂CH₃, -C(0)NHipiperkiin- 1 -yl), 'C(0)HHCH(CH₃)CH₂OCH_¾ -C(O) Hr{ H.₂CH2(inorpholin-4-ylX -C{0){2- diniet ylaniinomethylpiperidin-l-yi), -C(O)NH( H2)j0(CM2¾CJ¾_>

-C(0)NHCH(CH3)(C¾)_iN(CH_;CH_?)₂, -C(0)NHC(CHv)₂Cfa)(pipendiri-l-yl), -C(0)(4- inei yipiperazin-l -yl), -C(0){2-piperidin~ l-ylmcthy!-pipencSiB-l -yl), cyano. -NHCHh, -CB(CH.?)KMCHiCH fCB:_;) ₍ -C(G)CH_3> -S{0):NHCH.Ci¾N(Ci¾)₂,

-S<0)₂NH(CH₂)₃ (CH₃}.,

. HCH₂CH₂N(CH3>2, -N(C¾)₂,. -OCH₂GH₂ (CH:y}₂, - HC (CHj)₂][-N(CH₃)₂]_t -OGHF_2> ^«S(0)₂CH₃, -OCF₃, or ~NHC(0)e¾(4-dimethylanimopiperidm-i-yi).

[Oill! j In- another embo iment (L), R-^¥ is hydrsxyamino, -M(R^v)C(D)-CrC^alkylene- N(R*XR*). -C(0)NR¾^¾, - R¾0)R^:a, *C(0) CR^!¾)~Ci--G^a!kyieae-N(R^K,il)R^R

-NR- ' oJNR¹-'^ ^,b, - CR^C^^ C alk lene^C- ^NC -^C ²²⁸), -Nft^l3C(0)O ^s'¾ ₍ - i ^ - O^C-C_fi-alkylene-NR^VfO '^ , -NR²C(0)-C₁.C₍riitky]enc-OR^{2 a}. or- N(R²⁽ⁱ)C(0)-C_rC_{ a!kykne-CfO)R^:¾; where each of the a!kylene in ^¾ is independently optionally further substituted with 1, 2, 3, , or 5 groups selee-teU from halo, hydixyxy, and amino; and all other groups are as defined in th Summar of the: Invention. In another embodiment, ,R^3a is - HC(0)CH₂NH{CH_3:), -NHC(0)CH(CR₃)NH₂, -NHC(0)G(CH;s)₂NH_2> -NHC(0)CH₂ (CH , -NBC<Q)CH₂N< H) ¾^^^

.NHC{O)CH₂ (CH. CH₂CH₂N(GH₃}_2; -NHC(0)CH(GH₃)NHCCHj)_} -NBC(0)H,

> HCCO)C¾(a¾etiditt- 1 -yl), - HC(0)(pyrrolidm-2-yi), - «C{0)CH(NH₂)CH₂OH, -NH€(0)(azetidm-4-y.l), - HC(0)C(CH₃)₂NII{CH₃)₅ -N«C(0)C¾ H(C¾GH₂C¾),

-NFfC(0)C¾CH₂NB₂, -NHOH, or -NHC(0)(piperidin-3-yI).

1001221 hi another embodinient fM), R^3;l . (R⁷)C{0)-Ci-G alkyieiie-N(R^¾)(R⁷ⁱ'); and R⁷ is hydrogen or !kyl and IV⁴ and R^"i! are independently hydrogen, aikyl, arain alkyl, alk iaraiswaSky or diaikyisniinoalk l; and all other groups are as defined in the -Summary of the Invention. In another embodiment* R^3a k .NHC(0).GH₂NH(C¾),

-KHC(0)CH(CH_s} H₂, -NHC(0)C{C¾)₂NH_¾ -NHC.(0)CHjN.{CH3)₂, - NHC(0)CHjN(CHj)CH2CH₂N(CHj)2, - HC(0}CH(NH₂)G¾CH₃, - HC(0)^'CH2 (CHJ)CH₂CH2N(CHJ)2_s or -NHC(0)CH(CH)NH(CHj).

[00123} Embodiment (N) provides a compound of Formula I where each R^J is

independently halo; cyan©; aikyl; alkenyl; aikoxy; hydroxyamino; carboxy; aikyisuiionyk ammoalkylox ; alkylaramoalkyloxyj/dklkykminoalkyloxy; -N(R')C{0)-CrQ-alkylene- N(R^7A¾R^¾); -G(0)NR¾^SIL; ~NR¾(G)R⁹³; -C(D)N(R^IFT}-C rC^alk le e- iR^j '^ -NR^HC{0}NR^mR^,ib where R ^a; -C(0} ^!J; -NR^uC{0) R^l3s: :(0) (Κ^)Ν(¾^{Ι ;>}Κ ^!*);

heteioaryl optionally substituted with one or two ammoalfcyl, aikyteimnoatkyi, or diaiky!arainoai^

N{ ^iSb}C(0)R ^J; -C(0) (R^w)-Gi-e6-alkyien^C(O)R^l¾; -N(R²²)C(0)-C , -C aSkyiene- N{ -^A)~ (R¾ -NR^3''G(0)- Ci alkyiene-QR *;. where each of the alkykate in R^? is independently optionally further substituted with I, 2, 3, 4, or 5 groups selected frora halo, hydroxy, amino, aikylamino, and diaikykmho; and alt other oops are as defined to the Summary of the Invention,

[§0124) in another embodiment, each R^* Is independently methyl, bromo, ehlo.ro, fluoro, ~ HC(0)CH₂ H^'fCH j), ~NHC(0)CH2NH(Cl¾CHj), -NHC(0)CH(CH_i) H₂,

-NMC(0)C(C.H₃)2 H2* -NHC(0}C¾N(C¾b, -NHCCOJCI-fc iCHjJCHiCHiNiClIj)^ -NMC{0)CB(NH2)CH₂C¾^

-NHC( )CH(CH3)NH{CH3), -NHC.(0)C¾M¾, ~NHC(0)H, -NHC(0)CH₂(a¾i;tidui-.l^i}, - H€iO)i n¾iidm-2^

- HC(0}C{CH₃)2 H{CHj),- H2, - HC<0)CHjNH(CHjCH₂C.H₃),

- HG(0)CH₂^¾ H_2s - HOH, -NHC(0)(piperidin-3-yl j, -NHC(0)C¾( -methyl- 1 ,4- diazepan-l-yS), - HC(0)Ci:i{N¾}(CB:CHi), - HC{0)CH2 H{CH₂CH{OM)(CHj)),_. -NHC(0)CH2 HCH₂C jF, - HG(0)C¾MH{OCH₂CH(CH₃)2)₅ - HC(0)( 1 - aminocycloprop- 1 «yl), - H:C(Q)CH₂ H(Cil₂eyelopropy!), ~NHC(0)CB_S(3- (dimethylantinoj-axetidin-l-yl), -NBC(0){piperid -2-yI), ~NliCCO)(morpi-!olin-4-yl}, - HC(0)C¾(pyrroUdk-l-yl), - HC{0)CH{NH2)CH₂Cl-{₂CH₂CH2 (CHj)2_s - HC(0)CB₂ (CH₅)(CH₂Cii₃), -NBCiOie iimn a oI-S-vi:), -NHG(0)(.^ammoeyclopent- 1 - l), -NBG(0)CB: H( CH₂CH{CM_S}₂}_!•. HC{0}CH2N{CB₅XC¾GHi}_f -NHC(0){iV» (iraidazoi-4-y!metiiyi)-3zetidin-3-yi)_; - HefC))(iV-ethyI-azetidin~3-yi}_?

-K¾CH₂N(C!¾eH₂CH₂^^^^

-NHC(0}CH₂(3i3iperidin-]- ylazetidm-lyl), -NHC{0)NH_:> -NHC(0)( 1-hydioxycyciopropyt), - HC(0)CH_n HN(C¾)₂, -NHC0)NH(CHj)N( -li)2»-NHC(0)CH₂0H, ^«NHC(0)(pyrida¾m^yl)_s ^ HC(0){H- pyirolidiri-lyl), >NHC(0)C¾NH(CH₂)₂N{CH0i, - HC(Q)( I -cycioprop ietliyl-azetidi.n~3~ yi), ~NMC(0)CH₃NH{CH<}₂, -NHCiOj{imidaxoi-2-yi>, -NHC(0}(imidazol-4-yi),

-NHC(0(l_;2-oxazoI-5-yl), -MHC(0)CH₂NHCH₂CFj, - HC(0)CH₂C¾{piperidin-i-y!X -NHC(0)(3-o)co-cyclopeHi- 1 -yl), - HC{0}(2-liydroxy-pyridj«-6-yl), - HC(0)CHiNH(3- fluom-4-hydroxypiienyl}, -NHG0)(CH₂)j (CH3)2, -NHC{0}Cl-(r¾ian-,2~yliftei yl)^»a¾etidiii-

-NHC(0)CHiN(CH₂CI¾}₂ -NHCiO)CH₂i3-methyM,2-oxa¾ol->5-yl).

- HC(0}CH₂NFC1¾(3-hydTOxyplienyi), - HCiO)(A¾neihyl-p>W)i-2-yl), -NBC(0}(2- amino-ietrahydropyran-2-yi), - H 0)CH¾4-methyJamiao-pipep,dm-i-y)^

-NHC(0)(piperidi - 1 -yl}, -NHC(0)iV-m.eihyl-pyrralidin-2yl), .MHC(0)tthieti-3yl),

- HC(0)(i¥ cycHpt¾^ylcarbot)yi)a¾etklin-3-y!X -NHqO)CH₂(4-met%Ipiperazm> 1 - l),

-NHC(0)CH₂(pyridin--4- yl), -NHC(0)CH₂N(CH?)(CH₂CH :H -NHCtOJCHiNHibenz l), - HG(0)CH₂OC¾, - MHC(0)[1 -iC{O)GH: H ~aze« m~3. I]:, -NHCCQXpyridm-B-yi),

-MHC(0CH_? HeH₂€H^

methyl-pyrrbliditi-l-yl), ~NHC(0)(tu«m-3-yl), - HC(0)eH₂N( H?)2,-NHC^'(G)(2-ch ro> p ridin-5- l), -NHC{0)(2-ch!orophenyt), - HC(0) Hj(pyridin-2-yl), - HC(0)CH>(3- djmeihyla.nmQ-azetidin.-1-yl), -MHC(0)CH₃i pyridm-3-yl), -NHC{0)CH₂(2-ehtoropheriy!), -NHC{O)CH2N(CH₃ -H₂CHiCl¾ {CH 5, - HCiOCI-fc CCftCHiJCHjCHiOH, - Ni'lC(0}CIi₂{2-beii¾yl-pyrroIidin- 1 - !), -NHC(0)(furan-2-y^ -N HC(0)(2-c¾ ro-pyridin-4- yl), - HC(0}CH₂NHC(0)CH_5i -NHC(0)CB₂CH₂CH_3; - HC(0)(4^hIorophcnyi), - HC(0)(4-meihyi_i>fa nyl), -NHC{0)CH₂ HC(0}G(CB_?)₅, - HC(0)(feenzo|d] L3]diDxo)- S-y!), ~NHC(0)CHjNHOCH>(2-methoxypheiiy|), -NHC{O){pyridm-4-y3), -mCtOjCH A- (3,4-diGh_.loropbenyl)-piperazia-l -yl), HC( )CH₂CH₂(pydditi-3-yl),.

-NHC(0)(tet_.rahydrof ran-3-yi), ^NHCfO}CH₂NHCH₃(2^methylphsnyl)_:

-NMC(D)CH(C¾)CH₂ ¾. - HC(0)GH₂{3-iuoroptoyi}, -NHC(0)CH₂C{O )_:phenyL - NHC(0){2,methyl-cycl prop- l-yS), -NHC{O)(2-methyl-4-m thoxypfeeiiyl), - HC(0)i2- raethylpyndm-3-yl), - HC(0)(4-m©thoxyphe0yi), -NHC(0)CH₂{4-«thylpipefii¾i«- 1 -yl), - MC(0)(« en-2-yl), -NHC( )(3-.fl«oro-2rmetliylphe yI), - HG{Oj(2-bromo-thien-3-y¾ -NHC(0)(4 1uorophe^ -NHC(0)CH(CH?}:, - BQOXCH^CH^ - HC(O}CH;0C¾C¾, -NHC(0)CH₃ H(2-fluorop eriyi),

-KiiC(0}i3-dimei yiamkophei)yl), - HC(0)Ci¾(4-jiiethylp5peridm-l-yn,

-NHC(0}CH₂ Hi2-?7-propyiphenyl), - HC(0)pbcnyl, -NHC(0)(pyrazin2-yl}- - HC(0){3-

. HC(OX 1 -meih lcafbQa zeii in-3- l)₅ -NaC(0)CHnNH(4-metli ^hettyl},

- HCiO}C!¾NH(ph tiy!}, -NHC(0)C¾(4-aISyl-pipera2in-i ~yi}_! -NHC(0)t2-methylpbenyJ)_; -N!IC(O)Cl GH₂0CHj, - HC(O_.K3-metUyl-ftlran-2>yl), ^«NHC(Q)C(C¾.h, - NHCiOJCHjNHpbcnzyl, -NHQO H₂NH<3-clilorophettyi), -NHC(0)cyciobiityl,

-NHC(0)C¾(3-methoxyph.enyl), -MHC(0)(1-metbylcyc]<>prop-i-yt),

-NHC(O)CK_; iiCH₂(2-m«{ yiibi0pSienyi), - fjEC(0)CH₂(2 iuorophe«yl),

.NHC{ )CH₂ ¾CH, CH(CH5),-NHC(O)(thi8XoM-yi)_t -NHG(O)C¾N(CH_. beBZyL -KHG{;0)CH₂NHC¾(tii3e«-2-y!), - Η0(Ο)€¾ Η€¾(ρνΓϊ(!ίιι-2»ν1), -NHC{€>)(3- methoxyphenyl), -NHC(0)CHjNHCH₂(3--chioro--4-methylphenyl)_!

-NHe( X3-i]iioro-4-methyIphra l ^

-NHCXOJCHsCcyc!ohexy!), -NBCiO)(2~phenyl-eydoprT⁾p- 1 -y! ), -NHC{O){3-c1ioix>phenyl), -NHC(0)C1:i₂(2-raeth.oxyphe«yl)₅ > HC(0)CHsCH₂(3_'mth(> e l),

fluoro- -m¾thyl-plienyl), -NH OJCHj HCHsiS-fiuom-phen i), -NHC(P)CH₂(4~ ethoxy- phenyl), -N HC(0)benzyi, -NHC(0}(2,4^iohlorophe»yI), -NBC(0)(3-oxo-eyclohex- 1 -yl), -MI-iC(0)CH_s H{3-f!uorophenyI), -NHC(0)CH₂(3-chlorophenyl), - ^C(0)C¾ HC¾CM^

- HC<0}CH₂{2-m<^

- fiCC JCHiti ^^-tetrahyds-o!soquinolia^- i}, ^ HC(0)CH₂CH₂CH-CH_2!

-NHCfO)CHiNH(2-roethylpheny)}, -NMClOJCH^-oxo- i eridin-l-yl}, -NHC(0){2- Duoropbeayl), -NHC(0)C¾NHCHfCHj)phenyL - tiC(0)f2-j-1u0ro-6-niet oxypheny{)_> •- HC{O}CH₂ H{2- oprop Ipitenyl), -NHC(G)C ₂€¾(2-mfetboxyphen>'i}₅

-NHC(P)CH₂GH₂CH{CH. ^^^{^}^ HC{.O^H;CM₂(4- ^■meihox.yphet.yl), -NHC P)CH (ailyi)cyclopentyi, -Nl:!C{0)CH₂N(CH;,)CH₂Cl^;;iiOCHj,~

propylKcydopropylmet yl^

c lof phenyl),- HC(P)CH₂(4-piperidm -y}piperidm- l-yt), - HC(0)CK₂(.4'

cy !t!peatyipiperazin-i-yi), -NliC0)CH₂(2-rneihyipheiy!), -NHC(0)CH HGH₂(3-?luoro- 6~me&ylpheiiyi), - HC(0)C3¾C(CHJ)J, - HC(0)CH_:NH(2-chloK)phenyi)_? -NHC(0){3-

^«NHC(0)CH₂OphenyI, ^<KHC{0)Ci¾ H{2 ^im6t¾1phen 1),- H {0)( ~fluoro>

S-methylphenyl), W

.isopropy!piperazin-l-yS). >NHC(0)CH₂(4-BuoRphenyl.), -NHC(0)CH₂CH(CH5)₂

-NHC O)(2-avetlHX\y-4-meihy.IpfieByi, - i-if'(0)CH2f4-ii~propylpiperkim-!~yl),

-NHC(0)CH₂0(3-methy!p eny!), -NHCCOXtetraliydroftinia-2-yl), -NHC(0)CH;(3- hydrosyniet yipiperidki-i''yl),: -NHC(0)(J^»?^b»oxy¾tl?p.oyi|?ipefidi«'-2-ⁱyl),

-NHC(D)CH₂ iO¾^

-NHC(0)CH₂OCB₂CH_;OC¾, -NHC{0)CH₂GB₂(cyel0peotyi), ~NHC{0}(2

di iterdphem-i), -NHG(0}G¾(4-melhyicafbo«yip!perazlH-l-yI)_i -NBC(O)(5-fiu0K>~2~ methoxyp enyl), -NHC(0}C¾ (CH₂eH₃)eyelohexy -NH.C(0)(5-methyH,2-oxa2ol-3-yl)_t - HC(0)(3-raetiwipyridin-3-yl)_! -NHC(0)(2-i«8ii\oxypyiIdjn-3-yI), - HC(Q)(3

dichtoropheoyl), - i-lCfOJCffciihiazolidu^-y!), ~ Ηαθ)€Η₂(4-€(0)ί1]-ρ5 βΓ»ζίπ-1-νΙ), -NHC(0)CH2(2-pyridin-4-y1piped(lfii~l ~yi), ~NHC(0}(2~methoxyphenyJ).

-mC(0}CH₂NH^'CH₃)CH₂CH(CH₃)_∑> - HC(0)CH₂.{4-C(d}H^om ipeR^i« ^ i

-NeC(0)(l-p enylcycopmp-l-yl), - HCfOlCilji^e-dimeth imoip olm^-yS),

NHC(C5)CB2 -p en l yrroUdin- 1 -yt), -^HC(0)CH₂(itt rphoIin-4-yl),

-C(0) HCH₂CH₂ (CH3.)2- -C(O)NH(pytto «-3-y , -C(e) HCH₃C¾(pyrroiidift-l-yl), -C(0)HHeii₃,€¾NH₂ -C(0 (CH₂)CH₂CH₂ {eH )₂, - C(0)NHeH{p!peridin-2-yl), -C(0)NH( 1 -methylazetidin-3-yl), -C(D}NHC¾CB_:(psperi.din- i-yl), -C(0) HCH₂C.¾N(Ct¾CH₃)_¾ -C(0)NH(l-rnetiiyip5peri<iin-3- l)_;,

~C(G H(piperidin-3-yl), -C:{Q) HCH>{ 1 -mcihylpiperidin-3-yi),

-C(0)NH H∑CM₂H(CH₂CH2OH)2, 'C(0)HH(l.e ipipemU»-3-yl)₅ -C(0)N¾₅. -C(0)(3- aramopytroUdirt-l.-yl)j -C( )(3-:meth larainoyirQli!di}1,- i), -C(G)G:H, -

3-yi), -eCOJNHCHiCHsOH, -C(G)NH(3-ox0-pyrazolidin- >yI), -NHCH₂CH₂(lrmdazol.4-y!), -C(0}(3~dimeihylaminopyiToiidtn-i-yl), .C(0)NHCH₂(pyndin-4-y!), -C(0)N(CI¾}(I~ ractyi-pyrroiidsa-3-yi), ~C{OK3-djeihylaminopyrrofidla-!-yt), -C{0)NH(pyrrol-l-yl), -C0) HC!:l₂CI^:I₂C¾pyiTOiidin-- 1 -yt)_:, -CiO) (CH_i)CI-I₂CH₂CN, -C{0)NHC¾CH₂QC¾ -C(0} (CH₂e¾)CH^

-C{0} HCH₂C!-l₂CH₂ CHj)₂ -C(0)NHimorphoUn-4-yl), -C(0) H fCH₃:)2, - C(0)NHC¾C¾CH^ -C(0}NHCH₂CH₂C -C(O) HCBjCH₂C(0}OCe3₉ -C{0)NHC¾CHjSCH_?,

-C{0) HC¾CH2SCH2.CH₃,-C{0) {CH₂CHj)CH₂CH₂ {CH3)₂, ~C(0)NHCH₃C¾CH₂(2- oxQ-pyrrolidm- 1 -y!), -C(0) H^'CH₂CHi(^:pyridm- -yl), -C{0)NHCH₂Cf¾a¾QC¾CH3, - C(0)NHC¾CHiC¾(morp]ioHn- ~y!), -eiO)NHCI¾CH₂CH₂OCl¾,

-C{0)N:MCH2CI:I;CH:OC.l-t₂CH2CI- ,.

-C0 HGH₂CH₂CO)OCH2CH_?? ~C(0jN C ₂CH₂C1¼OG (G¾)₂, - C(0)NHC{CH₃¾C¾(piperidiu-l-yl), -C(0)N(C1^)C¾C¾CH_?, -C(0}NH(piperidin-l-y1},

-0{0)(2- dimet yiamiuomethy Ipiperidm- i -yl), -C(0}KH{Ci¾)jO(CH₂}3C¾, - C(0)NHCH(Cfi₃)(CH₂)5N(C¾CH>)2, -C(0) HC(CH3i),C{0)(piperidin-l-y!), -C(0)(4- ^•methypiperazinrl-yl), ~C(0)(2>piperidia- 1 -ylraethyl-piperidin- -y!), cyano, -NHCBj,

-S(0)2 H(CH₂)₃N(GH₃)2₅ S-CAvA'-diinethylaminoinediyi}-^] _s3,4-oxadsa¾:ol-2~yL

-NBCHjCHjNCCHs , ~N(CH₃)_2> ~C⁾CH₂C¾N(CH₃h, -NHG( (C!¾)₂K-NiGB>fc}, -GCHF;, -CFj, -S(0)2CH₃₎ -OC .5, .-NHG(0)CH₂(4-dime(hylaminopipe¾k ->1)_> or etboxy.

012S_.1 in another embodiment (F), R^J is independently halo, a!kyi. hydroxyamino, - <R⁷)C(0)-Ci-G a{kyJene.N( ^¾)(R^¾), -C(0) R*R^ , -M ^'C(0}R^¾, -C(O)N(R⁵ }-C₃-C alkyIene-N(R^i0;i}R^:'*-NR^{l ?}C(0)NR^{f ,8}Rⁿ* -N(R³)C(0)-Ci-C aikylene- (R")- (R"¾R^22a), - R^l3C(0)0R^!3\ ^« (R^,8)G(0)-C_rC^alkyiene- {R^iSb)C( )R^K% , -NR²⁴C(0)-

each of the aikyieue in R^~ is independently optionally further substituted with 1.2, 3, 4, or 5 groups selected from .halo, hydroxy, and amino; and all other groups are as defined in the Summary of the invention, in another embodiment, each R^J is independently methyl, chior ,

-NBC(0}CH₂ H(CH_i)_! -NHC(0)CH(CH₃}NH_2! -NHC(0)C(CHj}₂Ni b,

-NHC(0)CH₂N{CH₃)_¾ - HC(0)Ci¾ fCHi}CH₂C¾N(CH₃)2, -NHG(0CH( H₂)CH₂CB₃, - BC{0)CB₂N(GH}CH₂CH₂N{CH₃)₂,. -KHC(0)H, - NHC(0)CH₂(azetidin -yl),-NHC(0)(i>yrrolidjnr2-yl), ~NHC0}CB(NH₂)CH₃OB,

- HC(0)(azetidta-4-yl), - HC(0)C(GH₃)₂NB(CHj), -NH_2} -NHC<0)CH₂NB(CH₂CH₂CB₃),_: . HC(0_.)CH2CH₂ H2, -ΝΗΌΗ, or - HC(0)(piperidin-3-yl).

[001261 in another embodiment (Q% R⁵ is alkyl or -N(R^?)C(0)-C_f -C₆-alkyleoe- N(R'*)(R'^b); and R^; is hydrogen or alkyl and R^'"a and^'R^iC>are independently hydrogen, alkyl, •aminoalkyl- alkykmunoaikyt, or dialfcylarainoalkyl; and ail other groups are as defined in th Summary of the Invention. In another embodiment, each ΙΙ^Λ is independently methyl - HC(OiCH₂NH(C¾}, - HC(0)CH(CH.vj H₂, - HG(0)GCCH₃)₂NB₂₅ -NHC(O)- C¾N(CH₃)_2t -NHC(0)CH₂ (CH₃)C¾CHjN{CH₃>2, -NHC(0)CH(Hfi₂)CH₂CH3,

{00127} In another embodiment f R), B is phenyl, R^'' is not present or R³ is halo, alkyf or aikoxy; «.^¼ is -C(0)M ¾^s -NR^siC(0)R^¾ ₍ -N(R⁷)C{0}-CrC_i(-aikyteae-NiR^'i3){R^¾). or -C OjNi ^-Ci-Q-alkylenevMC '"⁸)^'* where each of the aikyieae in. "^a is independently optionally further substituted with I , 2, 3._t 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Stmuuar of the Invention.

[001281 In another embodiment (R 1) of embodiment R, R^sl!, R^'2, and R ^! are hydrogen and R^i:! is halo or aikoxy; R^5l\.¾^>"', and R'*^'are hydrogen and^'R⁵ is aikoxy: or R⁵" and R^?i are- hydrogen and ^iJ and R^J" together with the carbons to whic they are. attached form a 6~membered heteroaryl; and all other groups are as defined ia the Summary of the .Invention. In another embodiment, .R^ Rⁱ², and ^> are hydrogen and R ⁴ is halo or aikoxy; or R^{? '}, ⁵ , and IV" are hydrogen and R ^<* is aikoxy.

[0 129 In another embodiment of (R2) of embodiment R, R^{> !} is methyl. Compounds of Formula ia

[08.130^'! In. another embodiment, the compound of Formula I is a compound of 'Formula la:

ia

or a- pharmaceutically acceptable salt, tautomer, hydraie, or solvate thereof wherein;

R⁵ⁱ is hydrogen;

R^" is methyl;

~^~ is hydrogen;

R" is hydroge or aikoxy; and

R^'"4 i hydrogen, alkyi, aikoxy, or halo; or ^> and * together ^'with the carbons which they are -attached form a { -meMimred heteroaryl; nd

R^'' is hal o methyl; and

¾ is -N(! ^' )C(0}~< :^ R' is hydrogen and R^7a and R^, isre independently hydrogen, alky I, a irioaikyl. aikylamiooa!kyl. or

di a Iky ί am moa Iky 1 ,

jOP13I{ In one -embodiment of the compound of Formula la, R^>! is methyl; and R^i_ _s and: R^' * are_. hydrogen. -and R" is halo or aikoxy or ~ , R^"\ and R^'" are hydrogen and R^"" is aikoxy; or a single stereoisomer or mixture of stereoisomers thereof.

[001321 la. another embodiment, R-^¼ is ~ MC(0)CH->NH(G¾), - HC(0)CH(CH}NH_2j - HC(G)C(CH₅)2 H;, -Ni-i O)-CHlN(CH3)₂,-NHC(0)CH-₂N<CH,)CH₂CH₂-NCH₃)₂, >

NHC(0)eHfNH₂)Cl¾a )₃₍ - MC(0)CM2 (CH3.)CH2CH₃H{CH5)2, or -

NHC{0)eH(C¾)NH(C¾).

[O0133| i another 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.

a pharmaceutically salt, taiitomer, hydrate, or solvate thereof.

Compound of Formula II

100135] In one embodiment, R^! in the compound of formula H is hydrogen, optionally substituted alkyl, optionally substituted eycloaiky!, optionally substituted cyetoalkyfaikyk optionally^" substituted aryl, optionally substituted aryla!kyl, optionally substituted

heteroeycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted

heteroaryl or optionally substituted heteroary kyl. Specifically, R^! is hydrogen,_. optionally substituted alkyl, optionally substituted eyeloalkyl, optionally substituted arylalkyl, or optionaliy substituted heterocycloalkylalkyl.- More specifically, R^l is hydrogen, alkyl, alkyl substituted with one or two hydroxy, alkyl substituted with alkoxy, cycloaikyl, arylalkyf, or !ieterocyeloalkylalkyl. Even more specifically, R¹ is hydrogen, methyl, ethyl propyl, isopropyL 2-hydrosypropyL 3-hydroxypropyL 2-ethoxyethyL 3-methoxypropyf,- 3-ethoxyp!Opyi, 3-isopropoxypfopyl, eyclopropy!, ey obutyl, cyelopentyL c-yeiohexyl, benzyl, or 2-ptperidin- 1 -ykthyl. Yet even more specifically, R^! is ethyl, ssopropyi, eyclopentyt, or eyciohexyi Yet even more specifically, R^! is ethyl.

100136] In another embodiment, R" is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, , 4, or 5 R* groups. Specifically,. R" is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three R^h groups. Mor 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, iro_.m amino, alkylainino, dialkylamino, and halo. Even more sp.eeUieal_.ly, R⁴ is hydrogen, methyl, ethyl, propyl, isopmpyl, ieri-butyi, 3 -amino ropyl, 3-(;A'^'~methy!amlno)-propyl, 3-(A^f. A iinrethyl£innno)-ptOpyl, 2-iTuoroethyl, or

2,2.2-triOuoroethyi. Yet even more specifically, R" is hydrogen or ethyl. Yet even more preferably, R" is ethyl .

i 00.137] In another embodiment, R^" is hydrogen.

1001.381 in -another embodiment, R is optionally substituted alkyl. Spec! fieally, R⁴ is methyl or ethyl. More specifically, R⁴ is methyl. 100139] ϊιι another .embodiment, R* is aeyl. More specifically, R^f' is alkyiearbonyl. Even more specifically, R^i; is acetyl

106140} in another embodiment, R^i! is phenyl optionally substituted with 1 , 2, 3, 4, or 5 R^v groups-. Specifically, Rⁿ is: phenyl optionally substituted with one or two R^' groups; and each R^!>, when present, is independently selected from aryL halo. aikoxy, aryloxy, and hakralkyl. More specifically,_. R^fi is phenyl optionally substituted with one or two R⁹ groups; and each R^!>, when present, is independently selected from phenyl, iluoro, chloro, methoxy, pheny!oxy, and mfiuOfomefhyl Even more specifically, R'^f h phenyl, phenyl substituted with phenyl,, .fluorophenyl, difluorophenyl, c orophenyS, djehlorophenyl, phenyl, substituted with chloro and fiuoro, medioxyphenyhdiniethoxyphenyL phenylosypheriyi, or trilluoron ethylphenyl- Yet even-more specifically, R° k phenyl, 2-phenybphenyL. 3-phe»yl-phenyl, 4-phenyt- pbenyL 2-iluorophenyi, 3-lluorophenyl, 4-fluorophenyl, 2,3-diilttorophenyl,- 2,4- difhiorophenyi, 2,5~diiiuor p.henyl, 2,6^difiu(>rophenyl, 3,4-dif!uorophenyi,

3,S-diil.«:oiOphcnvL 2-ehlorophenyl, 3-chlorop^:heayU_: 4-chl^'Qtophenyl_> 3,3-dich rophenyl,

2.4- dieblot'Ophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dieMorophenyl,

3.5- dichloroph.enyl, 3*ohloro-4-fluorh-phehyl, 2~methoxyphenyl, 3-raetho yphenyi,

4-methoxyphe.uyl, 2,3-diihethoxyphenyl, 2,4-diiuethoxyphenyl, 2,5-diraethoxyphe.iw ,

2.6- dimethoxyphenyl, 3,4-dime_.thoxypheny.l, 3,5-di.methoxypoenyl, 4-pheoyloxyphenyl, 2~irUluorqra.efiiylphenyi, 3-triOuommethylphenyl, or 4-irifluoronvethylphenyl,

{001411 In another embodiraeat, W is hcteroary! optionally substituted with I, 2, _.3, 4, or 5 v groups.

1001421 in another embodiment, R^;> is a ό-membered .heteroaryi optionally substituted with one or two R , More specifically, * is pyridlnyl, pyra;dnyL_: pyriniidinyL 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-yi, pyridin-4-.yl 3-Ou0ropyiidm-4-y!, pyraziii-2-yl, pyrazm-3-yl, pyri.raidin-2-yl, 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 pyrazm i pyrimidinyl, or pyridazirryl, each of which is optionally substituted with one wherein. R\ when present, is halo. Even more specifically, . R is pyrazin-2-yl, pyrazin-3-yh pyriniidin-2-yi, pyrimidra-4-yL pyrimidm-5-yl, pyrklazi.n-3 -yl, o p ridazi n-4-y 1.

{00.1. 4j In another embodiment,- R* is a 5~membered lie-teroaryl optionally substituted with one or two R^'?. Specifically R^f! is pynm>lyi_y imidazolyl, diienvi, unazolyl, oxazolyl, s soxazolyi, oxadiazoiy l, furanyl, pyrroly.1, iriazolyl, or tetrazoiyl . each of which is optionally substituted with one R wherein R⁹, when present, is a!kyt aryla!kyL eyanq, aiyi, alkoxy arbonyl, or halo. More specifkally, R^(> is pyraxojh 1 -yl,- pyrazol-3-y.j, pyrazol-4-yL pyrazol-S~yl, iraidazol- I-yL imidazol-2-yi, imitiazoi- -yi, imidazoi-S-yl, thieti»2~yl, thien-3- yl, rbiazo 2-yl, thiazoM-yl, thiazol~5- l, oxazo!-2-yI, oxazoM-yl, oxazol-5-yi, isoxazol-3- yi, IsoxazoM-yi, ispxazoi-S-yL UJ^ a iazoM- L J-oxadiazoi-S-yi f.₅3,4«oxadi&2Gj-2- yi, l ,2,4-oxadiazol-3-yS, 1 ,2,4-oxadia'.¾}}-5ryt_} uran-2-yl, furan-3-yi, pyrrol- 1-yl- pyrrol-2-yL pyrrol-3-yI, triazol-i-yl, triazol-4~yI, tria¾oi-5-yl, tetrazoi-l-yb or ietrazoI-3-y!;_: each of which is optionally substituted with one R- wherein. R^"', when present, i methyl, benzyl, cyano, phenyl, A^eri-butoxycarbonyl, or ehloro. Even more specifically, R* is pyrazoi-3-yl, pyraxol- 4-yl, pyrazol-S-yl, imidazol-2-yi, imidazol-4-yi, i idazol-5-yl, ihien-2-yl, thiett-3-yi, ihiazoi-

2- yl, thiazoM-yl, thiazol-5-yl, oxazol~2-yL oxazol-4-yl, oxazoi-S-yi, isoxazoi-J-yl, isoxazol-

4- yl isoxazoi-5-yb 1 ,2,3-oxadiazol-4-yi, i ,2,3-oxa :ia¾ai-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, triazoi-4-yl, triazol-S-yl, or tetrazol-5-yl; each of which is optionally substituted with one wherein R^'', when present, is methyl, benzyl, cyano, phenyl, Λ'-fert-butoxycarbonyl, or ehloro.

(001451 in another embodiment, R^(> is diienyl, pyrroiyl, luranyl, pyrazoiyl, thiazoiyl, isoxazoly!, imidazolyi, triazoiyS, or tetrazolyi, 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 t e.n-2-Υί, thien-3-yl, pyrrol-2~yL ¾nm-2-yl, furan-3~yl, pyrazol-3- vL pyrazol-4-yL pyrazol-5-yl, tliiazol-2-yL thiazol-S-yl isoxazoM- l, anidazol-S-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 ehloro. More

specifically, R" is th.ien.-2-yl thien-3-yl, . 5-cyano-4hien-2-yl_s 4-metbyl-thien-2-yi, 4-methyl- i!iien~3-yi, 5-chioro-thien-5-yb 5-phenyl-ihien-2-yl, pyrrol-2-yl- A-ie/ -butoxycarbonyl- pyrrol-S-yl, N-methyl-pyo¾l~2-y!, funm-2-yl, iiiran-3-yl, pyrazoi-3-yl, pyira ol-4-yi, <V- benzyl-pyrazol-4-yi, pyrazol-5-yl, tSiiazol-2-yI, thiazol-5-yl, isoxaxol-4-yt, imidaxol-5-y iriazol-5-yi, or tetrazOl~S-yk

[00146] In another embodiment, R* is thien-2-y.l, ihi ii-3-yi, pyrro!~2-yl,. furan-2-yl, furan-

3- yb pyraxol-3-yL. pyraaol-4-ylv pyrazo!-S-yl, ihi-azoi-2-yl, thiazol-5-yi, isoxazo -yl, imida oi-5-yl, triazol-5^«yl, or tetrassoi-S-yl, each of which is optionall substitute with one R^'* wherein R^'5, when present, is methyl, benzyl, cyano, phenyl, JV- m-butoxycarbo»yI, or ehloro. 1081 71 another embodiment, R° is indoiyi benzi.nrida¾M. benzofuraiiyi,

benzoxazolyi, or benzoisoxazolyi, each of which is optionally : substiUited with 1. 2, 3, 4, or 5 R⁹ groups. Specifically, is indol-2-y.l, mdol-3-yl, indol-4-yi, indoi-5-yl, indol~6-yl indoi- 7-yl, benzimida£ol-2-yl, benxi raidazo 1 -4-y 1, benzimidazol-5 -yl, b zi raidazol-6-yl, benzimida2ol-7-yl, beazosfta¾n-2-yl, benzol wan-3-yl, benzofuran-4-yl, benzomran-5-yl, heox»&nm-6-yL beazoftiraa-7-yl, benzoxazol-2-yl, bet zoxa bM-yl, benzoxa ol S-yl, heRzoxaxot-6-y1, benmxaz0l-7-yl, benzoisoxazol-3-y^'l, benzdisoxazoI-4-yl, benzoisox zol-S- yi henzoisoxazoK yi or benzo¾oxazoi-?-y!; each of which is optionally substituted with i, 2, 3, 4, or 5 ^¾ groups. Mare specifically, ⁶ is iiidoi-6-yi

1 61 8} In another einbodiraent. R^f is hydrogen, optionally substituted aikyl, optionally substituted cycloaikyL optionally substituted heteroeycioa!kylatkyl, or optionally substituted aryialky!; X is -KH-; R" is hydrogen or alky) where the alkyl is optionally substituted with one or two R* groups; R is aikyl; R⁵ is hydrogen: R* is phenyl or Ueteroaryl wherein the phenyl and heterQaryl are optionally substituted with one, two, or three ⁹ groups; each R^s, when present, is independentl amino, alkylamiho, iaikylammo, or halo; and each R \ when present, is independently alkyl, arylalkyl, cyano, and, aikoxyearbonyi, or halo.

{001491 In another embodiment, R^ft is pyrazol-3-yl, pyrazo)-4~yl, pyrazol-5«yl, imidazoi-2- yt knkliizoI-4-yi, imidazol-5-yl, thien-2-yl, ihien-.3~yi, thiazal-2-yl, thiszol-4~yi. t azoi-S-yi oxa¾ol~2-yL . oxazol-4-yi,^■oxazoi-5-yl, isoxazol-S-yL isoxa¾ol-4-yl, isoxa¾ol-5-yl, 1 ,2.3- oxadiazoM-yi, i _:2,3~oxadiazo!-5-yt Ϊ _!.5,4-oxadiazoI-2~y'i, L2₅4-oxadia2oi-3-yL 1 ,2,4- oxtsdtazol-S-y!, furan-2-yl, furan-3-yl, pyrrol-2-yl pyrrol-3*yi,_. triazoi-4-yL triazo!-5-yl, or letnizol-S-yl; each of which is optionally substituted with .1, 2, 3, 4, or 5 R⁹ groups,

{00150} In. m he embodiment, R^l is aikyl or eyeioatky! is methyl; and R" is heteroaryl optionally substituted with one or two R* groups. Specifically, each R^'*, when present, is independentl alkyl, arylalkyl, eyano, ary!, aikoxyearbonyi, orliaio. Specifically, R^f! is pyraz.ol-3-y!, pyrazol-4-yi, pyi¾zoi-5~yi, imkiazo.l-2-yl, invidazol-4-yl, hnidazol-S-yl, thien-2-yi, ihien-3-yf, thia¾ol-2-yl, thiazol-4*yl, thiazol-S-y!, oxazol-2-yi, oxazol- -yl, oxazoi- 5-yL isoxuzoi-3-yL isoxa.zoi-4-y!, ssoxazol-5-yl. L2,3-oxadiazol-4-yl, 1 ,2,3-ox8dutzol-5-yl, 1 , 3. ,4-oxadiazol-2-y 1 , 1 ,2,4-oxadiazol~3-yl, i.,2.4-oxadiazol-5-yl, furan-2-yl, fu^'ran-3-yi, pyrroi-2-yl, pyrrol-3-yl, tnazoi-4-yl, , triazol~5-yi, or^■ tetrazol-5-yl; each of which is optionally substituted with one R wherein R⁹,. when present, is inethyi benzyl, cyano, phenyl, or N-t&i- butoxyeafbcmyt

(00151 } in another embodiment, is hydrogen.

(00152} tn another embodiment, R~ is methyl or ethyl.

4i? |0pl53| In another embodiment R^l is alkyl or cycloalkyl; R⁴ is methyl; and. R* henyl optionally substituted with, one or two 1 ^' groups. Specifically each R\ when present,, is independently halo, alkoxy, or haloalkyl.

[001541 In another embodiment, R^! is alkyl or cycloalkyl; R* is methyl; nd R~ is hydrogen.

Ift another embodiment, R¹ is alkyl or cycloalkyl; R" is methyl; and R^* is optionally substituted alkyl.

Compounds of Formula ΙΙΛ

{0 155] la another embodiment, 1 is a compound of formula HA.

ilA

or a harmaceu icall acceptable ^'salt .there f wherein;

R³ is alkyl, cycloalkyl, eycloalkytalkyl, aryl. arylalkyl, heterocydoalkyl,

heterocyeioaikylalkyl, heteroaryl, orheteroaryialkyl;

Vi" is hydrogen or alkyl;

4 is alkyl;

R^'" is hydrogen;

& is phenyl, aeyi, or heteroaryl wherein the phenyl and heteroaryl are is optionally substituted with 1, 2, 3, 4, or 5 R^'* groups^';- and

each R\. when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, e anO_s amino, alkylamtno, cii lkylamiuo, alkoxyalkyi oarboxyalkyl, aSkoxycarbonyL aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heierocycloalkyl, or heteroaryl an where the cycloalkyl, aryl, -heierocycloalkyl, and heteroaryl, each either alone or as part of another group within R", are independently, optionally substituted with 1 , 2, 3, or 4 -groups selected from halo, alkyl. haloalkyl, hydroxy, alkoxy, haioaikoxy, amino, alky!amino, and

dialkylamtnoi

100156} In one embodiment. R^! is alkyl, cycloalkyl, heterocycloidkylalky!. or arylalkyl; R^* is hydrogen or alkyl; Ι is alkyl; iV is hydrogen; R° is phenyl r heteroaryl wherein the phenyl and heteroaryl are is optionally substituted with one, two, or three R groups;.

100157! in another embodiment, R is methyl. {001581 l another embodiment, R^! is alkyl, cycloalkyl, or heteroeycloalkyt,

[00159] In another embodiment, ^! is aikyl.

100160] In another Lwbo i eoL ^h is heteroaryl optionally su¼tn ited with 1 , 2, or 3 R' groups.

100161 f In another embodiment, each R⁹, when present, is independently alkyl arylalkyl, eyano, aryl, lkoxycarbonyl, or halo.

1001621 In another embodiment, ll" is pyrazolyL imidazolyt thierwi, thiaxoSyl, oxazolyl, tsoxazol l, oxadiazolyi, ftsrarryl, pyrrolyi, iriazo!yl, or tetraxoiyl; each of which is optionally substituted with 1 , 2, or 3 R groups,

[ 0J 63] i another embodiment, R⁶ is pyrazol-3-y1. pyrazoi-4~yl, pyrazoi~5-yi, imidazoi-2~ yl. i ida«o 4-yl, it«idazo!-5-yI, ihien-2-yl, duen~3~yL ihiazol-2-yL thiazoM-yl, r azol-S-yi, oxazo!-2*yl, oxazol-4-yl, oxazol-5-yl, isoxaxol-3-yl, isoxazol-4-yi, isoxazoS-S-yl, 1 ,2,3- oxadia o!~4~y l,2,3K)xa to¾>l-5-yl, L3,4-oxad! xol-2-yk ,2,4-0xadiazol-3-yl₅

i,2,4-oxadiazoI-5-yL ltett^yi iwraii-S-yl_^p iT^I-l- l, pyrrol-3-yl triaz i-4-yl,, triazoi-5-yi, or ietrazof-5-yl; each of which is optionally substituted with 1 , 2, or 3 R groups.

[00164] in. another erafoodi erii, R^fi is pyrazmyl, pyrimidinyi or pyridazmy! each of which is optionally substituted with 1, 2, or 3 R^y groups and IT is methyl.

100165] in another embodiment, R^* is hydrogen, 1 is methyl, R¹ is optionally substituted alkyl, cycloaikyl, or heteroeycloaikyl, and " is heteroaryl optionally substituted, with ί, 2, r

3 R groups.

[00166] hi another embodiment, the compound of formula Ila is selected form:

2^«aoim0-8 e3o entyM-methy^

|08167] in another embodiment, die compound of formula O A is Compound B. which is

2-amino÷8-ethyi-4- ei yI-6-(.I ^^

B) or a pharmaceutically acceptable salt thereof.

Additional E mbod ί men is

Treatment of Endometrial Carcinoma

{001681 in one embodiment, the invention provides a method of treating endometrial carcinoma in a patient, comprising administering, to th patient an. effective amount of Compound A or Compound 8.

[00169] in another embodiment, Compound A or B is administered as a capsule or tablet pharmaceutical, compos i^'tioii.

j.00170} In another embodiment, the amount Compound A or B in. the tablet or capsule formulation is sufficient to produce saturation of absorption when administered otice daily. |()0t7ll Tit another embodiment, about 100 rag to about. 800 mg Compound Λ is administered as a capsule composition once daily.

100172] in another embodiment, abou 200 .nig to about 700 mg Compound A r B is administered as a capsule composition once daily.

[00173] In another embodiment, about 500 rag to about 700 mg. Compound A or B is administered as a capsule composition once daily.

[001741 In another embodiment, about 100 mg to about 800 rag Compound Λ or B is administered as a- (ablet composition once daily. W7$1 in another embodiment, about 200 rag to about 700 mg Compound A or B is administered as a tablet composition once daily.

[0U176I in another embodiment about 00 mg to about 30 mg Compound A or B is administered as a tablet composition once daily,

j^'(HH77| n another embodiment, aboiu 400 rag Compound A or B is administered as a tablet composition once daily.

|00178{ In another embodiment, the endometrial cancer is advanced or recurrent

[001 91 In another embodiment. Compound A or B is administered as a capsule consisting of Size 0 capsules filled with drug substance only. There are no additional excipienis other than the capsule gelatin and coloring agents. The composition of the hard gelatin capsule shell and color demarc tion are presented in the tabic below.

Gelatin Capsule Composition

Swedish Orange Opaque Capsule

Component (for 10O«m« 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 i 0^l)

[00.1801 in another embodiment, Compound A or B is administered as a 100. 150, or 200 mg tablet. The tablet strength will be distinguishable by shape .and/or size. The tablet formulation eon tains^' Compound A, siUcified. micraciystailine cellulose, partially

prej latinized maize starch, sodium starch alveolate, hypromeiiose, colloidal silicon dioxide, stearic acid, and magnesium, stearate. All three tablet strengths are manufactured from a common blend with the composition listed in the following Table.

Composition of the Compound 100-, ISO-, and 2«J0-mg Tablets

Ingredient Batch Formula (% Av)

Compound or B 50.00

Silicified MieroerystaUirse Cellulose. 14.75

Partially Pregeiatmized Maize Starch 20.00

Sodium Starch Oiyeolaie 7.00

Mypromellose 2910 6,00

Colloidal Silicon Dioxide 1.00

Stearic Acid 1.00

agnesium Steara te U . i j

Purified Water a

* Essentially removed during manufacture. jOOi 8i Ϊ in another embodiment, the effective amount of Compound A or B that is administered in the method produces at least one therapeutic effect selected fro the group consisting of reduction in s . of a tumor, reduction in metastasis, complete rem ssion^ partial remission, stable disease, increase in overall response, rate, or a pathologic complete response. [(KHS2 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) > 6_: months) as compared to other treatments.

[001831 In -another embodiment, the improvement of clinical benefit rate is about 20 ercent or higher.

[00184] In another embodiment, the therapeutic effec is an increase in overall response rate.

[0 183 In another embodiment, the increase in overall response rate is about 10 percent or more or higher.

(00186) In another embodiment, 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 Compound A or a pharmaceutically acceptable salt thereof.

[00187 ] In ano ther embodiment, the improvement of clinical benefit rate is a t least about 20 percent or higher,

[O tSS] in another embodiment, a comparable- clinical benefit rate (CBR - CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 months) is obtained with treatment of Compound A or a pharmaceutically acceptable salt thereof .

[001891 In another embodiment, the improvement of clinical benefit rate is at least about 20 percent or higher.

Treatment of Breast Cancer

[00190] In another embodiment, the invention provides a method for treating breast cancer in a patienf in need of such treatment, comprising administering to the patient an effective amount of (A) letrossole in combination with

or a. pharmaceutically acceptable salt* {dutiom.ec,. hydrate, or solvate ^'thereof; or (B) !eirozofe in combination with

or a pharmaceutically acceptable salt thereof;

wherein th method comprises at least one cycle, wherein the 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 for of 50 mg twice daily.

1001911 In one embodiment, the breast cancer is hormone receptor-positive (ER- and/or FCtR.÷}. HER2-negaisve (HER2-) breast cancer which is refractory to a nonsteroidal aromatase inhibitor.

f t 01%! hi 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 !eirozole and

Compound A.

100193] In another embodiment, the breas cancer is hormone receptor-positive (ER+ and/or PGR+), HER2 - egativ (HER2-) -breast cancer which is refractory to n nonsteroidal aroniaiase inhibitor and the effective amount comprises a combination of letrozole and

Compound B. [00194] in these and other embodiments, the effective amount produces at least one therapeutic effect selected from die 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.

[00195] Alternatively, in these and other embodiments, the effective ' amou t 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; f ii) the: therapeutic ef feet is an increase in overall response rate;

(iii) the increase in overall response rate is about !O percent or more.

[00196] in another embodiment, the invention provides a composition for use in treating breast cancer in a human patient., the composition comprising a clinically proven, safe and effective amount of letrezole and either Compound A or a pharmaceutically acceptable salt thereof, or Compound B or a pharmaceutically acceptable salt thereof.

J00197] in another embodiment, the ieirozole is formulated for a daily dose of 2,5 nig.

[00198] in another embodiment, the letrozole is formulated for a daily dose of 2.5 mg and the Compound A is formulated as a tablet for a daily dose o 00 mg.

[001 In another embodiment, the letrozole is formulated for a daily dose of .2.5 mg and the Compound B as a tablet for a dose of 50 mg twice daily.

[00200] in another embodiment, the invention, provides a kit comprising a dose of (A) letroxoie and a dose of either Compound A, or a pharmaceutically acceptable salt thereof or Compound B or a pharrtiaceuticaUy acceptable salt thereof in this and other embodiments, the kit comprises instructions for using the leirozole, as well as the Compound A or

Compound B in the- method. as disclosed herein.

Letrozole with Compound A

100201 ] 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 leiroxole in combination with Compound A.

{002021 In another embodiment, the Compound A is administered as a capsule or tablet pharmaceutical composition.

[00203] In ano the r embodiment, tire amount of Compound A is sufficient to produce saturation of absorption when administered once daily . [002041 hi another embodiment, about 100 rag to about 800 rog Compound A is administered as a capsule composition once daily,

{00205] In another embodiment, about 200 mg to about 700 mg Compound A is administered as a capsule composition once daily.

100206] In another embodiment, about 500 mg !o about 700 mg Compound A is administered as a capsule composition once daily.

|002ϋ7] In another embodiment, about 100 mg to about 800 rag Compound A is administered as a tablet composition once daily.

[00208] In another embodiment, about 200 nig to about 700 m ^'Compound A is administered as a tablet composition once daily.

[00209] in 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 once daily,

[00211 ] In another embodiment. Compound Λ is administered as a capsule consisting of Size 0 capsules filled with drag substance only. There are no additional excipteius 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 1 0-rng strength)

FDA E171 titanium dioxide 0.4002%

FDA/E1.72 red iron dioxide 1 .4706%

Gelatin qsp 100%

FDA, Food and Drug Administration; > quantity sufficient for 100%.

[00212] i another embodiment, Compound A is administered as a 100, I SO, or 20 mg tablet. The tablet strength will be . distinguishable b shape and/or size. The tablet formulation contains Compound A, siiieified nucrocrystalline cellulose, partially pregeiatinized maize starch,- sodium starch glyeolate, hypromellose, colloidal silicon dioxid stearic acid, and magnesium stearate. All three tablet strengths are manufactured from a common blend with the composition listed in the following Table. Composition of^' the Compound 100-, 150-, and 2Q0-mg Tablets

ingredient Batch ormula :{% w/w)

Compound. A 50.00

Siiieified Macrocrystalline Cellulose 14.75

Partially PregeSatinixed Maize Starch 20.00

Sodium Starch Giycoiate 7.00

Hyprome! lose 2910 6.00

Colloidal Silicon Dioxide 1.00

Stearic Acid 1.00

Magues ί urn S teara te 0.25

Purified Water

^B Essentially rene ed- during manufacture.

Letrozo^'le with Compound B

{00213} in one embodimen the invention pro ides a method of treating breast cancer in a patient in seed -of such treatment comprising _..administering to the patient an effective amount of ietroxole in combination with Compound. B.

[00214] la another embodiment, the Compound B as a capsule or tablet pharmaceutical composition.

(00215] In another embodiment, the ^'amount of Compound Bin the tablet or capsule formulation is sufficient to produce saturation of absorption when administered once daily. f002 l<t j 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] In another embodiment, about 10 mg to about 100 mg Compound B is administered a a capsule composition twice daily.

[00218} in another embodiment, about 10 mg Compound S is administered as a capsule composition twice daily.

[00219} In another embodiment, about 20 rug Compound B is administered 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.

[002221 In another embodiment, about 50 mg Compound B is administered as a capsule composition twice daily. | 223) In another embodiment, about 60 mg Compound B is administered as a capsule composition twice daily.

{00224] la another embodiment, about 70 mg Compound B is administered as a capsule composition twice daily,

[00225} in another embodiment, about 80 mg Compound B is administered as a capsule composition twice daily.

{00226} in another embodiment, about SH mg Compound B is admmistered as a capsule composition twice daily.

f 00227) In another embodiment, about 1.00 rag Compound 8 is admmistered as a capsule composition twice daily,

Q0228i in another embodiment. Compound A is administered as a capsule consisting of Si¾e 0 capsules filied with 10, 30 or 40 nig of drug substance only. There are no additional exciptents 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 ener a! Ad ministration

[002291 In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of the FBK.S of Formula I or II and a pharmaceutically acceptable carrier, exeipient or diluent. In certain other specific embodiments, administration is by the oral route.

Administration of the compounds^' of Formula 1 or la. or their phannaceUiicaliy acceptable salts_* in pure farm or in an appropriate pharmaceutical composition, can be earned out via any of the accepte modes of adnrinisirasio or agents for serving similar utilities. Thus, the Compound of Formula I or II ean be. administered m " die same or separate vehicles.

Administration cm be, for example, orally, .nasally, parenteral ly (intravenous, ratramuseular, or subcutaneous), topically, tratisderoaliy, intravagimd y, infmvesicali , iniracistemaliy, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets^ -suppositories, .pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages.

[00230} The compositions will include a conventional phannaeeutseai carrier or exeipieut and a Compound of Formula I or II as the/an. ac tive agent.

[00231 j Adjuvant include preserving, wetting, suspending, sweetening, flavoring, perftJtning, emulsifying, and. dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, ehlarobmanoi, phenol, sorbie acid, and the like. It may also be desirable to include isotonic agents, tor 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 exampl ,, aluminum monostearate and gelatin.

100232] 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 die like, such as, for example, citric acid, sorts-tan nlcnioUnnaie, triethanolamine oleate, butylated hydroxytoluene, etc.

j 00233 j The choice of formulation depends on various factors such as the mode of dru administration (e.g., ibr oral administration, formulations in the ibrm of tablets, pills or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for -drugs that show poor bioavailability based upon the principle that bioavailabilit can ^'be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat, No. 4, 107,288 deseribes a . harmaceutical formulation having particles in the size range from 10 to 1 ,000 ^'ran in which the active material is supported on a cross inked matrix of macromoleeules. 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 nra) in the presence of a surface modifier and then dispersed in a liquid medium; to give pharmaceutical formulation that exhibits remarkably high bioavailability. [00234] Compositions- suitable for parenteral injection may comprise physiologically acceptable sterile aqueous. r nonaqueous: solutions, dispersions, suspensions or emulsions, and sterile powders for ^constitution, into sterile injectable solutions or dispersions.

Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol,. polyols (propylenegiyeol, polyethyie.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 lecithin, by the maintenance of the required particle size in the ease of di spersions and by the use of surfactants,

{00235] One speci fic route of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of severit 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 exciplent (or carrier) such as sodium, citrate or dicaicium phosphate or (a) .fillers or extenders, as tor example, starches, lactose, sucrose, glucose, marmiioi, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidones. Sucrose, and gum acacia, (c) hismectants, a for example, glycerol, (d)^' disintegrating agents, as for example, agar-agar,, calcium carbonate, potato or tapioca tarch, alginie acid, croscarme^'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 monastearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentoniJe, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buttering agents.

[00237} Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others^' well known in the art They may contain pacifying agents, nd can. als be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions thai can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated- form, i appropriate, with, one or more of the above-mentioned exeipients,

[00238] l iquid dosage forms for oral administration include phannaceuticaliy acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissol ving, dispersing, etc., a eompoisrld(s) of the invention, or a

pharmaceutically acceptable, salt thereof,. and optional, pharmaceutical adjuvants in a carrier, such as, for example, water, .saline, -aqueous dextrose, glycerol, ethanol and the like;

stabilizin agents and ettiulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbo ate, ethyl acetate, benfc l alcohol, -.benzyl benxoate, propyienegiyeo!,

1 ,3-butyieneglycol, dime thylfomiantide; .oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydfofutfury! alcohol,

p lvethyieneglycols and fatty acid esters of sprbitan; or mixtures^' of these substances, and the like, to thereby form a solution, or suspension.

(002391 Suspensions, in addition to the active co.iripo.unds, may cont in suspending agents, as for exaoipie, ethoxyiated isostea^'ryl alcohol s¾ pojyoxyethyiene sorbitol and .sorbiian esters, rokroctystalline cellulose, aluramum roetahydroxkle, bentonite, agar-agar and tragaca th, -or mixtures of these substances, and the like.

f0fl24O] 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 exeip ents or carders such as cocoa butter, poiyethylenegtycoi 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} 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 propellaiits as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being .within the -scope of this invention.

(00242] Compressed^' gases may be used t disperse a compound of this invention in aerosol form. Inert gases suitable fo this purpose are nitrogen, carbon, dioxide, etc.

(002431 Generally,, depending oft the intended mode of .administration, the

pharmaceutically acceptable compositions will contain about 1 % to about 99% b weight of a eoinpound(s) of the invention, or a pharmaceutically 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% an about 75% by weight of a conipound(s) of the invention, or a pharmaceutically 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 ski lied in this art; for example, see Remington ^'s Pharmaceutical Sciences, 18th Ed,, (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, m any event, contain an effective amount of a compound of the invention, or a pharmaceutically acceptable .salt thereof, for treatment of a disease-stii e in aceordaB.ee with the teachings of this invention.

{00245] In the pharmaceutical compositions disclosed herein, the compounds of Formula I 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 activit of the specific compound employed, the metabolic stability and length of action of the. compound, the age, body weight, genera! health, sex, diet, mode and time of administration . rate of excretion, drug combination., the severity of the particular disease-states, and the host undergoing therapy. The compounds of Formula I or 0 can be administered to a patient at dosage levels in the range of about 0, 1 to about 1 ,000 mg per day, or in the range. f 100 mg to 800 mg per day, orin the range of 200 to 700 ing per day, or hi the range of 300 t 600 mg per day,

(00246 j For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per .kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can- depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a ^'particular "patient is well known to one of ordinary skill in the art. I f formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the Other pharmaceutically active agent(s) within approved dosage ranges. Compounds of Formula 1 or 1.1 may alternatively be -used sequentially with known phannaceutically acceptable ageni(s) when a combination formulation is inappropriate.

(0024?) 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 effective amount produces :an improved clinical benefit, rate (CBR ~ CR (complete remission) PR (partial remission) + SO (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%, 80%, or more. I some embodiments, the therapeutic effect is an increase in overall response rate, in some embodiments, the increase in overall response rate is about 10%, 20%,.30-%,^:40%, 50%, 60%, 80% or .more,

(00248] in s me embodiments^ a comparable clinical benefit rate (CBR = CR (complete remission) + P (partia! remission) ÷ SD ^' (stable disease) 6 cycles) is obtained with treatment of a) Compound A or B or a plmmiaeeufieally 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 a t 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, the improvement of clinical benefit fa e is at least about 70%. in seme embodiments, the improvement Of clinical benefit ^' rate is at least- about 80%.

[00249] In some embodiments, a comparable clinical benefit rate (CBR— CR (complete remission) ÷ P (partial remission) 4· SD (stable disease) 6 months) is obtained with treatment of a) Compound Λ or B or a pharmaceutically 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 ss at least about 30%, in some embodiments, the improvement of clinical benefit rate 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, the improvement of clinical benefit rate is at least about 70%. In some embodiments, the improvement of clinical benefit rate is at least about 80%.

Ceneral Synthesis

Synthesis of Compounds of Formula I

| ft250) The starting niateriais and reagents used in preparing, these compounds arc either available from commercial suppliers siieh a Aldrich Chemical Co. (Milwaukee, Wis.), or B ache (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, Volume 1 -17 (John Wiley and Sons, 1991 ); Rod's Chemistry of Carbon

Compounds, Volumes 1 -5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-4 (John Wiley and Sons, 1991), Marc 's Advanced. Organic

Chemistry, (John Wiley and Sons, 4^,!! Edition) ami Larch's: Comprehensive Organic

Transformations (VICHY Publishers/me., 1 89). These schemes are merely illustrative of some methods by which the compounds of this inveniion can he synthesized, and various modifications to those schemes can be made nd will be suggested to one^■ skilled in. the art having referred to this disclosure. The starting materials and the intermediates of the reaction- may be including hut not.

limited to filtration, distillation, crystallization, chromatogra hy and the like. Such materials may be 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 ^co, to about 125 ¾ and most specifically at about room for ambient) tenipen.it.are, e.g., about 20 ¾. Unless otherwise stated .(as in the case of a

hydr genatiort), all reactions are performed under an atmosphere of nitrogen.

00252} Prodrugs -can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound,. These modified functional groups regenerate original iunctional groups by routine manipulation or in vivo. Amides^' and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion, of prodrugs is provided in T, Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S..

Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward 8, Roche, American Pharmaceutical Association and Pergamon Press, 1 87. both of whic h 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 or quatemized nitrogen atoms in their structure- Compounds ^•of Formula I that may be prepared through the syntheses described herei may exist as single stereoisomers, rscemates, and -as mixtures of enantiomers and diastereoroers. The compounds may also exist as geometric isomers. Ail such single stereoisomers, raeemates and mixtures thereof, and geometric isomers are intended to be within, the scope of this invention,

(00254 | Some of the compounds of the.- invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in th euol f rm;- where an amide is present, the molecule may exist as theimidic acid; and where an enamine is present, the molecule ma exist a 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 ail 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-pyndmyl, also described as its structure:

14.

Both 2-hydroxy-pyridiayi and the above structure 14 include, and are equivalent to, pyridin- 2(^'i.H)-one and its structure 15:

15.

Regardless of which structure- or which terminology is used, each tamomer is included within the scope of the Invention,

{00256] For example, one tautomer of Compound Λ is Compound A-l :

Compound A-l

(^'0.P257J Another tauto er of Compound Λ is Compound Λ-2:

Compound Λ-2

Compound A-2 is named N43-.{[(2Z)-3-[{2^hloro-5-raethoxyphenyi)amino]quinoxaim~

J60258] As would be understood by a skilled practitioner, tautomeric forms can interconvert

} 0259) Moreover, intermediates leading to Compounds of Formula I, as well as

Compounds of Formula I themselves, can be recovered ess uncharged or zwttteriome molecules, or catioriic salts such a sodium or potassium, depending on the substitutions on the B ring and on reaction conditions. All such zwitierkmic forms are within the scope of the invention, and to the extent that one structure i used to depict a zwittersooie compound, it includes all such xwiiteriomc forms.

{66266] For example, one zwitterk ie form of Compound A is Compound A-3

Compound A-3

[06261] Another z tterionic depiction of Compound A is Compound A~

Compound Λ-4

|¾0262| Another z vitterioiisc depiciioii of Compound A is Compound ,A-5.

Compound A-5

[0 263J As would be understood by a skilled practitioner, tautomeric forms can

{0026 ] Moreover, mtercon version can also exist between ihe uncharged tautomeric forms and the xwUterionic forms.

02ΐ>5| Regardless οί which structure or which ienninoiogy is used, each taiitomcr or K ktcriort is included within the scope of the invention. Thus, as used herein, the structure

and the associated terms "Compound A" and ^< -(3- {[(3- ([2-cHoro-5- {methaxy)pheny.]am_:m^

encompass all possible tautomeric and x htcric c forms of the compound.

(00- 6 ) The present invention also includes -oxide derivatives and protected derivatives of compounds of forrruda f. For example, -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 group containing a - nitrogen aiomfs), these groups can be protected with a suitable "protecting group" or "protective group " A comprehensive list of suitable protective groups can he found in T.W, Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991 , the disclosure of which is incorporated herein by reference in its entirety. The protec ted derivatives of compounds of Formula I can be prepared by methods well known in the ait.

|08267 j Methods for the preparation and/or separation and isolation of, single

stereoisomers .from racemic mixtures or son-raeenue mixtures of stereoisomers are well known in the art. For example, optically active ( )- and (S)- isomers may be prepared using chirai sytuhoits or chirai reagents, or resolved using conventional techniques. Enaniiomers (R~ and S-tsosncrs} may be resolved by methods known, to. one of ordinary skill in. the art. for example by; .formation of diastereoisomerie salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated; for example, by crystallization, selective reaction of one enantiomer with an enaiitionier- spec ific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified esiamiomers; or gas-liquid or liquid

chromatography in a chirai environment, for example on a chirai support, such as silica with a bound chirai Hgand or i the presence of a chirai solvent, it will be 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, speci ic 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 trans formation. For a mixture of enantipmers, enriched in a particular enantiomer, the major component enantiomer may be ^'further enriched (with concomitant loss in yield.). by ree ystailization.

[00268] In addition, the compounds of the present invention can exist in unsolvated as well as soivated forms with pharmaceutically acceptable solvents such as water, ethanoS, 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 thai follow, unless otherwise speci fied, the final, form -of the compound was assumed ^'to be the uncharged molecule in the absence of analytical techniques mat would_, have determ ined otherwise. Compounds of Formula 1 can be prepared using methods known to on of ordinary ski ll in the art: or starting from the Compound of formula 1 as depicted in ^'Scheme 1 below. Compounds of formula l ean be prepared starting from compound 1 by fusion -of appropriate reagents at 180 "C in the presence of a base such as KJCOJ and metallic copper Is known to provide intermediates of formula 1 (see S. H.

Dandegaonker and C, K, esta, , Med. Cfwm. 1965, 8, 884),

Scheme I

[00270} Referring 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-dichioroq:uino aliiie) and an appropriately substituted sulfonamide of formula 2

in the art), a base sueh s R.5CO3, 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 -and washed with water and brine. The organic layers are combined and dried over a drying agent such as sodium, sulfate, filtered, and concentrated under -vacuum to provide a compound of formula 3.

{00271 j 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), die reaction is allowed to cool, 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 umoxaiine derivatives are known_. to one skilled in the art and include, but are not limited. to S. -V. Utvmenko, V. t. Savich, D. D. Bpbrovmk, Chem.. Hei&rocycl Compd. (Engl. Transl), 1994, 50, 340 and W. C. Lamina, R D. Martmaft, ,/. Med Chem. 1981, 24, 93.

[00273] Compounds of Formula .1 where B is phenyl substituted with ^¾i where R^J8 is alkylamino or diaikylamino or B is heieroaryl substituted with R^' where R* i s amino, alkylamino, or diaikylammo. and all other groups are as defined in the Summary of the Invention can be prepared according to Scheme 2. Scheme 2

f n Scheme 2, LG is a leaving group such as chloro. 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 R^ja 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 R^¾ and ^} are

L - (.R⁷)C{0)-C Valkyk^e-N^'(R^¾j(R^ where R\ R⁷\ and R^7,! 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:

iii. -Nil' ^lC{0)NR^{{ (}¾^{! ih} where R' ^ia, R^{! u} _? and R^¾ are as defined in the Summary of the invention: iv. - ^{1 '}Ο(0)Ο1¾.^{! :}"^s where R^L> and R^tAi are as defined in the Summary .of the

Invention;

v. -K{R^J¾)C(O rC aikyiene-N(R^l¾fc)C(0)^:R^SSa where Rⁱ⁸, K \ and ^, are as

defined in t s? Summary, of the Invention;

vi. -Nf ^^jCiOJ-C C^-aik ie!ie-CCOjR^^'" where K^<s and R~**^a as defined m.ihe

Summary of t e Invention;

vtL - ^SCOl C C_ft-idky! oe-NiR²^}^'* where ²\ R"^!a,. and R^:u' are as defined in the Summary of the Invention;

■viii. -N(R²²}C(0) C^aIkyiene- {R^2a)-N(R^2¾)(R^&), where R²², R"⁴ and are as_. defined in the Summary of the invention;

IX. - R'^"V.XO;}~Ct.Cf_ralkyieiie-OR^"¾ where R^""⁴ and R?⁴* are as defined in the Summary of the■Invention; and where the alkytene in R^J and R^Jil are independently optionally substituted as described in the Suramar of the invention can be prepared accordin to .Scheme 4 by reacting wiih an intermediate of formula 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), or 9(g):

9(a) iiOC(0)"C Cr4¾!.ky!ene- (R^T;i)(R^?¾) where R^a is R^?a or a -proieciimg group, such as Boe or Fnioe;

9(b) HOC(0)R^¾;

9(c) HOC(03NR^T,sR^SJb;

9(d) I:iOC(0OR^i3¾;

9(e) HOC(0)-CrC_is-aik¥lene.N(R^!S¾!)C(O)Rⁱ*^a;

9(g) LO-$( ;fe:-C|.Q-alkylerie- ^'(R^1!b)R^a where R" is R^it;i or a N-protectmg group, such as Boe or Fraoe.

Scheme 4

8 100277] In Schem 4, R in Scheme 4 is -C(0)i * -CiQJ R^ ^{1 ih}, -t'C0)OR^J*\ -C(O)- Ci -C₆-ailvylene-N(R^;^}C{0)R^t¾, -CfO)-C C^alkylene-C(0}R^2i!3, or - (0)₂-C₅.C alkylene- N(R^{" !f,})R^a. The reaction is carried out under standard amide coupling conditions known to one of ordinary skill in the art. In particular, the reaction is earned out in the presence of a coupling ageot such, as BATU, a base such as DIBA, and in a solvent such as &MV. Where applicable, the N-proteciin grou is then removed using procedures known to one of ordin ry¹ skill in the art, such as treating with acid where PG is Boc.

[00278] Proceedin as described for Scheme 4, compounds of the invention where B is phenyl substituted with R^J* or B is heteroaryi substituted with R^J where R** and R^? are

i. -CCOjN 'R"³;

ri. -C(Q) ( ⁱ¾-Ci .6-aikYS.ene--Nf R^S0;>}Rⁱⁱ*;

hi. -C(0}R^{i *} where R^!~ is an -substiiut.ed heterocycloalfcyl;

iv. -C( )N(R^u)H(^{' , ½})(R ^b);

v. -C(0) (R^½)-C}-Q-alkylene-C(0)OR^56a; er

vi. -C(0]N(R^{; '}i-Ci-Q-aikyien -CiOi ''"; or

can be prepared by exchangin the starting materials as necessary. la particular, the intermediate of formula ! 1

Π

is used instead of 8.

{00279} Compounds of Formula I where B is phenyl substituted with R^j:! or B i heteroary! substituted with R⁵ where R³* and R ^' are - HCiOJCifc R^ ^ where R^¾ and R⁷'¹ are as defined in the Summary of the Invention can be prepared, according to Scheme 5. 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 DIHA, in a .solvent such as ACN.

iil()280| Compounds of Formula ί ean 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 c»f acetic -ac- in a solvent such as DMA and by heating.

cedure 1

{00281 J into a l-dram vial was placed 2 >R¾nio-A-(3-(A^:-(3-i3,S-dtmethox - phe«ylamino)qumoxaUa-2"yl) &ulfaraoyl) phenyl) acetamide (86 mg, 0- 15 nuno ), prepared usin procedures similar to those in Example 171 ,aiong with 2 ml. of aeetoniid!e. Eight equivalents ( 1 ,2 nimol) of the desired amine, aniline, hydrazine o alkoxyan iiie were added followed fay the addition of Hu g's Base (41 ML 0.25 mmol). The reaction then was stirred at 5_.0 "C for one hour (overnight for aniline reagents]. Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture. A Waters

Fractioalynx preparative reverse-phase HPLC equipped with a Waters SunFire Prep CI 8, CCD S μ , 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 raM ammonium .acetate in water/acetoaitrile was used to carry out the purification.

Procedure 1

1_.60282) Into a 2 -dram vial were added 3-amino-A^?*(3-(3,5-dimethox.y- he yfam ^quinoxalin^- ^henzenesuli^namide (54 nig, 0.12 mmo!), prepared usin procedures similar to those described in Example 15, DMA (2 mL) and the desired earbuxvlic acid (0.17 mniol), DIB A (70 pt, 0.4 mmol) followed by HATU {53 mg,0.M mmol) were added to the via! and the reaction mixture stirred at 50 "C overnight. Preparative reverse-phase FI LC was- sed to isolate the desired product directly from the crude reaction mixture, A Waters Fractioniynx preparative reverse-phase HPLC; equipped wit -a. Waters SunFire Prep C IS, OC'D 3 uM, 30 X 70 mm column and running a 5-100 % gradient with a binary solvent system of 25 mM ammonium acetate in water aeetonkrile; was used- to carry- out the purification.

General Animation Procedure hi

|TO2S3f A CE - microwave reaction vessel was charged- mihN-i^N^''

ehioroquino.xa!in-2-yl}siiSia.mo> )phenyl)-2-( (30 mg, 0.071 mmol), prepared using procedures similar to those described in Example 374, the desired aniline ( i 6 rag, 0.14. mraol, 2 eq), and 0.5 mL of dimethySaeetamide. The vessel was sealed and the reaction mixture. was heated under microwave radiation for 70 rain at 140 ^i!C in a CEM Discover mierowave instrument. The solvent was then removed by roiary-evaporatioti. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NR+OAc/ACN to the desired product.

l Animation Procedure ! b

(00284) A CEM microwave reaction vessel was charged with /v-(3 3- chloroquirt0xali.u-2-yi.)si ia^^ (62 mg„ 0.147 mmol), prepared usin procedures simil r to those ia Example 374. the desired aniline (0.56? mraoL 4 e¾),-and 1.0 mL of toluene_* ^'The vessel was sealed and the reaction mixture wa eated under microwave radiation for 60 mm at ISO *C in a CEM Discover microwave instrument. The solvent was removed on rotary-evaporator. Purification of the final product was done, by preparatory HPLC with. NM OAC/ACN as eluem to yield the desired produet.

General Acvlatioii Procedure 2

(002851 ^-(3-(?v-{3-(3 -diMethoxy-pheny1aram

•:sulfamoyi)phenyi)azetidine-3-carbox{)mide (125 mg, .0.23 mrnol), prepared usin procedures similar to those described in- -Example 372_» was dissolved into 5 mL DCE in a 10 ml. r imd- bottom flask, DIEA (1.17 mrnol 5.0 equiv.) was then added with stirring followed by aeid chloride (0,47 ^'mraol, 2.0 equ^'rv.). 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 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 eluents 25 mM aqueous NiitOAe/CAE. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep CI S, OCD 5 Μ, 30 X 70 rfira column and funning a 5- Ϊ Θ0 % gradient with a binary .solvent-System -of ^' 5 m ammonioin acetate iti water/acetcmitri !e; was used to carry out tlie purification.

on. Procedure I

100286] To a solution ot^ -iS-C -iS-^^-dtmethox - hen lamim^qttin alin^- yi)sidfaraoyi)pheiiyl)axetidioe-3-earboxamide ( i 10 mg, 0.19 mmol), prepared using

procedures similar to those described in.. Example 372, in 3 mL oftXlE and 200 L of_.DMF, aldehyde (0.77 mmol, 4.0 eq.)was added s owly followed by tetramethylammomnm triaeetoxybo-rohydride- ( 1 . 1.6 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 n a rotary evaporator. The crude material was then re- dissolved in. methanol. Purification of the final product was accomplished by. reparatory - reverse-phase HPLC with the eluents 25 mM aqueous N¾OAc/CA . A Waters

Froctionlynx preparative reverse-phase HPLC;_. equipped wit a Waters SunFire Prep C 8, CCD 5 μΜ, 30 X 70 mm column and running a 5-1.00 %. -gradient with a binary solvent system of 25 ruM ammonium

purification.

ocedure h\

}0O287{ Into a small i dram vial was added S- - ^chlororS_^metho y- heii lamifttt - quinoxalin-2-y|)sul¾moyl)ben¾oic acid (61 mg, 0, 13 mmoL 1 .1 equiv), prepared using procedures described for Example 100. The acid was dissolved in DMA ( I mL) and D1EA (42 uL, 0.24 mmol, 2 equiv) was added then added to the -solution. The amine reagent (1 ml. of 0.12 M solution in DMA) was added to -solution with stirring fallowed by HATU (64 mg, 0.17 mMoi. 1.4 equiv). The reaction was stirred overnight at room temperature. Upon completion as indicated by LCMS analysis, 2 mL of methanol was added to the solution. Preparative reverse-phase HPLC wa 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∞ ammonium acetate m te 'aceiouitriJe ~ was used to., cany out the- 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- butylcarbamate (he. where R\ within . HR'R," ^' contained a Boc-proteeted amine group). The de-protection was carried oot after HPLC purification of the Boe-protee-ted precursor. {00289} into

phenylamino)q«moxaUn>2-yl)suliamoyl)hen¾ok acid (61 nig, 0.13 mffiot LI equiv). The acid was dissolved in ! mL of DMA and D!EA (42 uL, 0.24 tumoi, 2 equiv) was added then added to the solution. The mono- Boc-proteeted diamine reagent I rnL of 0.12 M solution in DMA, 1 equiv) was^' -added to solution with stirring followed by HATH (64 rng. 0.17 mmoi, 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 di desired product directly from. this, crude .reaction solution, A Waters Fracrio ynx_. preparative reverse-phase HPLC; equipped, with a Waters SunFire Pre C 18, OCD .5 μΜ , 30 ^'X 70 mm col omn and ainniiig: a 5- 100 % gradient with a binary solvent system of 25 rn ammonium acetate^' in ^: watef aeetoniaiid was used to cany 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 --starting material was detected. The deproteeted product precipitated out of solution as an HCl salt, and; was collected by filtration, washed with ether and dried under vacuum..

Synthesis of Compound A

| 2*>0| Crude Compound A can be prepared as described below -and depicted below in Scheme 7.

77

}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. Sytttbesis-of -}3-C{3-f(2-chloro*-5-mertH> v he»yl)amitH) «i.n

yI}s«iiitmoyl)pheoylj-2-niethyIaianinamide (crude);

1002941

To 0,42 kg of 2-amino-2- methylpropartoic acid, was added 3,7^■volumes of acetoaitrile, 0,0 volume .of

dimemylfbanamide, and 0.62 kg o oxalyl chloride. The reaction .mixture w s stirred at 20 °C until completion of the reaction. The mixture was then, filtered, arid the filter cake was washed twice with i volume of aeeiooiirile and dried . unde 'vacuu .

(00295J To I kg of 3-aim^'no- - -(C2. hloro-5-meUH>x>^henyl)a mo]quinoxdm-2- yl )· benzenesulfbnamide hydrochloride was added S volumes of dimethylfor amide and 0.385 kg of 2-meihylalanyi chloride hydrochloride at 5*C. After completion of the reaction, the .mixture was heated to 50 °G and a solution of 2HF04 (1 A kg), water (1.6.5 volumes) and ethanoi (7.i 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 10 volumes of water ami dried under vacuum.

Synthesis of Compound, of ^'Formula H

100296] Compounds of Formula H can be made by the syn hetic procedures described below. The startin materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, GaUX). or are prepared by methods known to those skilled in th art following procedures set forth in references such as Pieser and Fteser's Reagents for Organic Synthesis, Volumes 1- 1.7 (John Wiley and Sons, S 991 ), Rodd^'s Chemistry of Carbon Compounds, Volumes .1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions. Volumes 1-4 (John Wiley and Sons, 1991 ), March's Advanced Organic

Chemistry, (John Wiley and Sons, 4^lh Edition), a d LarOcfc's Comprehensive Organic

Transformations (VCH. Publishers inc., 1989), These schemes are merely illustrative of some methods b 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 ha ving referred to this .disclosure. The starting materials and the intermediates of the reaction may be i solated and purified if desired using conven tional techniques, including but. nest limited to filtration, distillation,. -crystallization, chromatography, aad the like. Such materials may be characterized 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 R^f is optionally substituted alkyl, R" is hydrogen or optionally substituted -alky!-,. K^* is methyl or ethyl, R^c> 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 ll^l 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 Mi

j00314] An intermediate of formula 14 is prepared by reacting an intermediate of formula 13 with a primary amine R^fNHj in a solvent such as water and with heating. 14 is then treated with iodine monoehioride in a solvent such as methanol, at around 0 "C and allowed to. react for approximately overnight or less as needed for the reaction to go to completion to form 15. After completion the residue is triturated with acetone. The intermediate 15 is^' then reacted in a solvent, such as DMA, with^■ethyl scryiate in the presence of a base, such as triethylamine, and in the presence of a catalyst, such as PdfOAc^'lj, and {+)8iN AP. The reaction is heated to approximately 100 "C and allowed to react for approximately overnigh or less as needed for the reaction to go to completion to form 16, 1.6 ts then optionally ^■purified by column chroinatography. A Comp und of formula I can then be prepared from. 16 by using the same reaction conditions as described in Scheme 1 (starting- at^' She point of the preparation of 5 from 4),

(00315) A compound of the invention where is optionally substituted alkyi, R is methyl or ethyl. K^' is phenyl or heteroaryl each of w hich is optionally substituted with 1 , 2, 3. 4, r 5 R^' groups - (as - efined in the Summary of the Invention), and R~ is hydrogen, can

..alternatively be prepared according to Sche^'me 1.1. 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

j 00 191 The primar objectives of this study are to evaluate the co-primary efficacy endpoinis; of ( 1 ) objective tumor re.spon.se rate (OKK.) (confirmed complete response [CR] or confnmed partial response PR)); and 2} rate f a-monih (183 days) progression-free survival (PFS6), int. su ects receiving Compound Λ for advanced or recurrent EC aad to evaluate the safety and tokrabllUy of Compound Λ 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 p½nnacodvnaniie- profiles of Compound A. The exploratory objectives of this study are to evaluate the correlation of the pre-existing status of

PB /PTEN patiiway eomponents/trsodolators (eg, P1K3CA mutatiPti/iamplifteatton, PTE.N deficiency.} with clinical outcome in subjects treated with Compound A as well as to (i) evaluate assessment of circulating tumor DMA for KRAS, FIK3CA, BllAF mutations at the time of trea tment and impact of mutations detected in the circulation with clinical outcome: (si) identify surrogate biornarkers associated with clinical activity of Compound A; and (iii) estimate the OUR 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

Stud 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), a pr ximately 80 subjects were to be enrolled to obtain 71 evaiuabSe subjects per protocol. Stage I enrolled 3? evaluable subjects. If at least four subjects had achieved an objective response (a confirmed PH. 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 evaluable subjects (including both stages) ^"have been enrolled.

J00321] As of amendment 3 (Part 2), ^'approximately 45 additional patients will be enrolled to obtain a total of approximately 75 per protocol evaluable 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 inclusion/exclusion criteria.

[003221 During the course of the study, subjects' tumor samples (archival and/or from new biopsies) will be analyzed for biornarkers thai ma 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. Inclusimi _ι Criteria

The subject has a histologically continued diagnosis of EC (endometrioid, serous, clear cell adenocarcinoma, adenosquamous carcinoma, or mixed histology, an grade} ihat is advanced (ie, persistent, locally advanced) or recurrent, and is incurable by standard therapies, and has received one platinum-based chemotherapy regimen for EC.

The subject is at least 18 years old.

The subject has an Eastern._. Cooperative: Oncology Group (ECOG) performance, -.status of 0 or L

The subject has at least one lesion that is measurable on computerized tomography (CT) or magnetic resonance imaging ( .RI) scan determined by investigator per RECIST Version 1. ί ,

a) 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 tw sequential CT or M.RI scans performed after the completion of radiation, or

o Histopathologic evidence of persistent disease, > fX⁾ days after the 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 nun x 20 rani 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 sod marrow function as follows:

a) Absolute neutrophil count 1500/nmr

b) Platelets > ΙΟΟ,όΟΟ/ηηη'

c) Hemoglobin > -9 g dL

d) Bilifu^'bm -< 1.5 ¾ the upper limit of nonnal (IILK)

e) Serum creatinine < 1,5 x UL , calculated creatinine clearance > 60 mUmin, or glomerular filtration rate > 40 m.L/min

0 Alanine aminotransferase (ALT.) and aspartate aminotransferase (AST) < 2.5 x ULN The subject is capable of understanding the informed consent and complying with the protocol and has signed the informed consent docu ent 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

Pharmacodynamics

[ 336] Blood, tumor tissue, and non-ltimor tissue (collected at. the same time as tumor tissue) wiil. be obtained from consented subjects for analysis of a ariety of established and .exploratory pharmacodynamic markers- on. a defined schedtde throughout the study,

[00337}^' When possible, pharaiaeodynamic sample collection will coincide with scheduled PK time points,

[003.38] Detailed instructions for pharmacodynamic sample preparation and shipping will be provided, to the study sites in a separate Pharmacodynamic 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 (e¾g., vascular, endothelial growth .factor Λ fVEGF-A], glucose, and insulin), drag-induced changes in phosphorylation of signal transduction proteins and lipids (e.g., pEGFR, pAKT. pERK, pGS . and PIP3), as well as assess ment of the contribution Of complementin genet ic changes in targe t modulators (e.g., PTE , RAS, e- ET, HER2, and L B-^'l) on efficacy

Statistical Methods

f 00340] The co-primary efficacy .endpoints are: 1) ORR, defined as the proportion of subjects for whom the best response is a confirmed CR or confirmed PR, and 2) PESO, defined as- the proportion of subjects who survive and are progression free at least 183 days after the date of the first dose of study ding, Deienmfmtion of response and progression will b based on -evaluation per RECiST Version L I ,

ftH)341J Prior to amendment 3 (Part 1), the- study was designed to test the- following hypotheses:

ORR is≤ 5% and proportion with PFS6 is < 15%

H.v ORR is > 20¾ or proportion with PFS6 is > 3.0%

{00342[ Tlie sample size estimate of 71 subjects eva!uable 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%,

1003431 Based on the stopping rule defined in the original protocol (2-stage design), the study met the futility criteria for tlie 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 ammatase inhibitor will be treated with either Compound A or Compound B in combination with letrozole as follows.

(00353) Treatment Arm 1 subjects will receive:

» Compound A (ablets, orally administered once daily (qd) and

« Letrozo!e 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 lite second dose 10-12 hours after the first (morning) dose.

♦ Letrozole tablets, orally administered qd, 30 minutes after the first (morning) dose of Compound B.

Phase 1

003551 Subjects will be alternately assigned to Arm I and Arm.2. A ^*3*3^* dose-escalation ^'design w ill be employed to determine, the MTD of the Compound A tablet formulation in combination with letrozole and of the Com^'pouftd B capsule formulation i combination with ietfoi'.ole. Subjects will receive the standard dose of 2.5 mg letrozole qd (i.e.,. there will be no. dose escalation of letrozole). Cohorts of subjects will be accrued in each arm to increasing doses of Compound A in combination with l.etrozole (Arm 1) or of Compound B in combination with letrozole (Arm 2) until more than 1 of 3 subjects or > 33% of 3 to 6 (or more) subjects at a . dose level experience, a. delimi ing toxicity (DLT) in the first 28 days of study treatment. Dose escalation in Ann 2 will not proceed beyond an Compound B dose of 50 mg bid (the MTD from single-agent Phase I Stud Compound B-OOl ), The _.single-agent MTD for the Compound A tablet formulation has not been determined.

[00356J If 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 for safety and ioiembillly. The MTD in each arm will be defined based on six subjects. The decision to dose escalate w hki each treatment ami 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 PK data will be considered in the decision to 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 other signs of progression in the brain for > 1 month alter completion of local therapy. ny corticosteroid use for brain metastases mast have been discontinued without the subsequent appearance of symptoms for > 4 weeks before the first study treatment in order to be eligible,

) The subject has io start cytotoxic cheroodieriipy due to rapid PD involving major organs,) The subject has prothrombi time/ international Normalized Ratio (PT/ I l) or partial thromboplastin time (PTT) test results at screening that are above 1.3 ^χ 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 (using Bazctl or Fridericia formula}.

* he subject has a diagnosis of uncontrolled diabetes me!littts {glycosylated

hem.ogbb.ra Ale [HbAl c] > 8% thai is not attributed to another temporary preexisting condition such as prior treatment with corticosteroids lor brain metastases} or fasting plasma glucose (FPG) > 1615 mg/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 durin the study.

* The subjec t is known to be positive for the human immunodeficiency 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

(0 36⁾9) The total duration -of the study is approximately 24 months: Investigational Regiment Do$e oate/Duratio.n

100370) Compound A will ^'be supplied as 100-. 150-, and 200-mg tablets and will be adrtitiiistered orally qd. The starting dose of Compound A will be 200 nig.

|0 3?1] Compound B will be supplied as 10-, 3.0-, 40-, and 50- g capsules and Will be administered orally bid. The 11 rst 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 mg capsules or 100. 1.50, and 200 m tablets. Compound A will be administered at a dose of 600 mg once daily (capsule)^' or 400 mg once daily (tablet)..

Combination Drug(s)

(00372) Leiffizol is commercially available as 2.5-m tab-lets. One 2,5-mg-_. tablet of Setrozole will be administered orally qd, 30 -minutes alter the Compound A dose or the morning dose of Compound B.

Safety

100373] Safety will be assessed by evaluation of adverse, events CAEs), vital signs, electrocardiogram (breast eaneerG), laboratory tests, and concomitant. medication. 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 Assessmea is

[00374] Tumor response will be assessed In Phase 1 a id Phase 2 asing Rbreast caneeriST Version 1 A (Eisenhauer et al. 2009): Subjects will be assessed using an Mill, 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 anticancer therapy, or death. Responses, will be confirmed by repeat assessments at least 4 weeks after the response criteria are met.

(0037S) Evaluation of tumor markers is not required in this study, if a subject has a tumor marker tha t is being followed and that has been shown to fee indicati ve 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. Results

[00392] An analysis of preliminary data from the phase I part of the study is presented below based upon information torn 20 of 21 patients that enrolled in phase I . The baseline characteristics -of the ersrollees are summarized in the following tables.

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

[003971 in su mary. 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 ÷ ierxomle 2,5 mg- QD

» Arm 2; Compound B SO ma 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 white remaining within the spirit and scope of the invention.. It will be obvious to one of skill in. the :att 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 he determined with reference to the following appended claims, along with the full 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 die same extent as i f each individual patent, patent application or publication were s individually^■■denoted.

Claims

What is claimed is:

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

R^3a is -N(R⁷)C(0)-Ci-C⁶-alkylene-N(R^7a)(R^7b) where R⁷ is hydrogen and R^7a and R^7b 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 R^3a 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.