as) United States
`US RE41,065 E
`(10) Patent Number:
`a2) Reissued Patent
`Schnuretal.
`(45) Date of Reissued Patent:
`Dec. 29, 2009
`
`
`USO0RE41065E
`
`(54) ALKYNL AND AZIDO-SUBSTITUTED4-
`ANILINOQUINAZOLINES
`
`:
`(73) Assignees: Pfizer, Inc., New York, NY (US); OSI
`Pharmaceuticals, Inc., Melville, NY
`(US)
`
`1/1995
`635498
`EP
`1/1995
`0635498 Al
`EP
`1/1995
`0 635 507 Al
`EP
`4/1975
`466233
`SU
`Inventors: Rodney Caughren Schnur, Noank, CT
`(75)
`
`(US); Lee Daniel Arnold, Mt. Sinai, NY=WO WO 92/20642 I1/1992
`
`(US)
`WO
`92/20642 Al
`11/1992
`WO
`WO 93/04047 Al
`3/1993
`WO
`1995/03283
`2/1995
`wo
`WO 95/15758
`6/1995
`wo
`95/15758 Al
`6/1995
`wo
`1996/1518
`5/1996
`WO
`1996/28430
`9/1996
`wo
`1997/32856
`9/1997
`WO
`1998/13354
`4/1998
`WO
`2004/072049 Al
`8/2004
`WO
`1997/30035
`8/2007
`
`(21) Appl. No.: 12/038,530
`
`(22)
`
`Filed:
`
`Feb. 27, 2008
`
`Related U.S. Patent Documents
`
`Reissue of:
`(64) Patent No.:
`Issued:
`Appl. No.:
`Filed:
`
`5,747,498
`May5, 1998
`08/653,786
`May 28, 1996
`
`USS. Applications:
`
`(63) Continuation-in-part of application No. PCT/IB95/00436,
`filed on Jun. 6, 1995.
`
`(51)
`
`Int. Cl.
`CO7D 239/94
`CO7D 239/70
`AGIK 31/317
`AG6IP 17/06
`AG6IP 35/00
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S.C wie 514/266.1; 544/293; 544/283
`(58) Field of Classification Search ........0..0...... 544/293;
`514/266.1
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`(Continued)
`
`Primary Examiner—Venkataraman Balasubramanian
`(74) Attorney, Agent, or Firm—Woodcock Washburn LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to compoundsof the formula
`
`fo"
`ar Bn
`R KY
`N
`ad
`
`a
`
`Sy
`
`RY | 2A
`we
`N
`
`and to pharmaceutically acceptable salts thereof, wherein
`R', R?, R*, R*, n and m are as defined herein. The com-
`pounds of formula IJ are useful in the treatment of hyperpro-
`liferative diseases, such as cancer. The invention further
`relates to processes of making the compounds of formula I
`and to methods of using such compoundsin the treatment of
`hyperproliferative diseases.
`
`18 Claims, No Drawings
`APOTEX EX. 1056-001
`
`APOTEX EX. 1056-001
`
`

`

`US RE41,065 E
`
`Page 2
`
`OTHER PUBLICATIONS
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`Roche Ltd.& Anr. vs. CIPLA Ltd. , Replication on Behalf of
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`ces A and B, Mar. 26, 2009.
`
`APOTEX EX. 1056-002
`
`APOTEX EX. 1056-002
`
`

`

`US RE41,065 E
`
`Page 3
`
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`man—La Roche Ltd.v. CIPLA Ltd.
`, Rejoinder to the Reply
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`Hoffman—La Roche Ltd., & Anr. vs. Cipla Limited.
`
`* cited by examiner
`
`APOTEX EX. 1056-003
`
`APOTEX EX. 1056-003
`
`

`

`US RE41,065 E
`
`1
`ALKYNL AND AZIDO-SUBSTITUTED 4-
`ANILINOQUINAZOLINES
`
`Matter enclosed in heavy brackets [ ] appears in the
`original patent but forms no part of this reissue specifica-
`tion; matter printed in italics indicates the additions
`made byreissue.
`This application is a continuation-in-part of PCT interna-
`tional application number PCT/IB95/00436, filed Jun. 6,
`1995, which designates the United States.
`BACKGROUND OF THE INVENTION
`
`This invention relates to 4-(substituted phenylamino)
`quinazoline derivatives which are useful in the treatment of
`hyperproliferative diseases, such as cancers, in mammals.
`Manyof the current treatment regimes for cancer utilize
`compounds which inhibit DNA synthesis. Such compounds
`are toxic to cells generally but their toxic effect on the rap-
`idly dividing tumorcells can be beneficial. Alternative
`approaches to anti-cancer agents which act by mechanisms
`other than the inhibition of DNA synthesis have been
`explored in order to enhancethe selectivity of action against
`cancercells.
`
`Tt is knownthat a cell may becomecancerousby virtue of
`the transformation of a portion of its DNA into an oncogene
`(i.e. a gene which, on activation, leads to the formation of
`malignant tumor cells). Many oncogenes encode proteins
`which are aberrant tyrosine kinases capable of causing cell
`transformation. Alternatively, the overexpression of a nor-
`mal proto-oncogenic tyrosine kinase mayalso result in pro-
`liferative disorders, sometimes resulting in a malignant phe-
`notype.
`Receptor tyrosine kinases are large enzymes which span
`the cell membrane and possess an extracellular binding
`domain for growth factors such as epidermal growth factor, a
`transmembrane domain, and an intracellular portion which
`functions as a kinase to phosphorylate specific tyrosine resi-
`dues in proteins and hence to influence cell proliferation. It
`is known that such kinases are frequently aberrantly
`expressed in common human cancers such as breast cancer,
`gastrointestinal cancer such as colon, rectal or stomach
`cancer, leukemia, and ovarian, bronchial or pancreatic can-
`cer. It has also been shown that epidermal growth factor
`receptor (EGFR) which possesses tyrosine kinaseactivity is
`mutated and/or overexpressed in many human cancers such
`as brain, lung, squamouscell, bladder, gastric, breast, head
`and neck, oesophageal, gynecological and thyroid tumors.
`Accordingly, it has been recognized that inhibitors of
`receptor tyrosine kinases are useful as a selective inhibitors
`of the growth of mammalian cancer cells. For example,
`erbstatin, a tyrosine kinase inhibitor selectively attenuates
`the growth in athymic nude mice of a transplanted human
`mammary carcinoma which expresses epidermal growth
`factor receptor tyrosine kinase (EGFR)but is without effect
`on the growth of another carcinoma which does not express
`the EGFreceptor.
`Various other compounds, such as styrene derivatives,
`have also been shownto possess tyrosine kinase inhibitory
`properties. More recently five European patent publications,
`namely EP 0 566 226 Al, EP 0 602 851 Al, EP 0 635 507
`Al, EP 0 635 498 Al and EP 0 520 722 Al have disclosed
`that certain quinazoline derivatives possess anti-cancer prop-
`erties which result from their tyrosine kinase inhibitory
`properties. Also PCT publication WO 92/20642 discloses
`bis-mono and bicyclic aryl and heteroaryl compounds as
`tyrosine kinase inhibitors.
`
`10
`
`15
`
`20
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`Although the anti-cancer compounds described above
`make a significant contribution to the art there is a continu-
`ing search in thisfield of art for improved anti-cancer phar-
`maceuticals.
`
`SUMMARY OF THE INVENTION
`
`This invention relates to compounds of the formula
`
`a |
`= B3n
`ee SYRt
`ea | Sy
`RQ)-“iS
`
`and to pharmaceutically acceptable salts and prodrugs
`thereof, wherein:
`mis 1, 2, or 3;
`each R' is independently selected from the group consist-
`ing of hydrogen, halo, hydroxy, hydroxyamino,
`carboxy, nitro, guanidino, ureido, cyano,
`trifluoromethyl, and -(C,-C, alkylene)-W-(phenyl])
`wherein W is a single bond, O, S or NH;
`or each R'
`is independently selected from R° and
`(C,-C,)-alkyl substituted by cyano, wherein R? is
`selected from the group consisting of R®, —OR®,
`—NR®R®, —C(O)R’, —NHOR*®, —OC(O)R®, cyano,
`A and —YR°; R® is C,-C, alkyl; R®° is independently
`hydrogen or R°; R’ is R°, —OR® or —NR‘R®; A is
`selected from piperidino, morpholino, pyrrolidino,
`4-R°-piperazin-1-yl,
`imidazol-1-yl, 4-pyridon-1-yl,
`-
`(C,-C, alkylene)(CO,H), phenoxy, phenyl,
`phenylsulfanyl, C.-C, alkenyl, and -(C,-C, alkylene)
`C(O)NRSR°; and Y is 8, SO, or SO,; wherein the alkyl
`moieties in R°, —OR® and —NR‘R® are optionally
`substituted by one to three substituents independently
`selected from halo and R’, and wherein the alkyl moi-
`eties of said optional substituents are optionally substi-
`tuted by halo or R®, with the proviso that two heteroat-
`omsare not attached to the same carbon atom,and with
`the further proviso that no more than three R® groups
`may comprise a single R’ group;
`or each R' is independently selected from —NHSO,R°,
`phthalimido-(C,-C,,)-alkylsulfonylamino, benzamido,
`benzenesulfonylamino,
`3-phenylureido,
`2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and
`R!°-(C,-C,)-alkanoylamino wherein R'° is selected
`from halo, —OR®, C.-C, alkanoyloxy, —C(O)R’, and
`—NR°R®; and wherein the foregoing R’ groups are
`optionally substituted by 1 or 2 substituents indepen-
`dently selected from halo, C,-C, alkyl, cyano, meth-
`anesulfonyl and C,—C, alkoxy;
`or two R’ groups are taken together with the carbons to
`which they are attached to form a 5—8 membered ring
`that includes 1 or 2 heteroatomsselected from O, S and
`N;
`R?is hydrogen or C,-C, alkyl optionally substituted by 1
`to 3 substituents independently selected from halo,
`C,-C, alkoxy, —NR°R®, and —SO,R°;
`nis 1 or 2 and each R® is independently selected from
`hydrogen, halo, hydroxy, C,-C, alkyl, —NR°R®, and
`C,-C, alkoxy, wherein the alkyl moieties of said R*
`APOTEX EX. 1056-004
`
`APOTEX EX. 1056-004
`
`

`

`US RE41,065 E
`
`3
`groups are optionally substituted by 1 to 3 substituents
`independently selected from halo, C,—C, alkoxy,
`—NR&R®, and —SO,R°*; and,
`R*is azido or -(ethynyl)-R*’ wherein R'’ is hydrogen or
`C,-C, alkyl optionally substituted by hydroxy, —OR®,
`or —NR&R®.
`Preferred compoundsof formula I include those wherein
`R?is hydrogen and R*is -(ethynyl)-R".
`Other preferred compounds of formula I include those
`wherein m is 1 or 2;
`each R!is independently selected from the group consist-
`ing of hydrogen, hydroxy, hydroxyamino, carboxy,
`nitro, carbamoyl, ureido, R° optionally substituted with
`halo, —OR®, carboxy, —C(O)NR°R®, A or —NR®R®;
`—OR?*optionally substituted with halo, —OR®, —OC
`(O)R®, —NR°R®, or A; —NR®R®, —C(OJR® RP,
`—SR°, phenyl-(C,—C,)-alkoxy, cyano, phenyl,
`—NHR*optionally substituted with halo or R? wherein
`said R® is optionally substituted by R?; —NHOR®,
`—SR®*, C,-C, alkylsulfonylamino, phthalimido-
`(C,-C,)-alkylsulfonylamino, 3-phenylureido,
`2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halo-
`(C,-C,)-alkanoylamino, hydroxy-(C,—-C,)-
`alkanoylamino,
`(C,—C,)-alkanoyloxy-(C,—-C,)-
`alkanoylamino,
`(C,—C,)-alkoxy-(C,—-C,)-
`alkanoylamino, (C,—C,)-alkoxycarbonyl-(C,—C,)-
`alkanoylamino, carbamoyl-(C,—-C,)-alkanoylamino,
`N-(C,-C,)-alkylcarbamoyl-(C,—C,)-alkanoylamino,
`N,N-di-[(C,—-C,)-alkyl]carbamoyl-(C,-C,)-
`alkanoylamino, amino-(C,—C,)-alkanoylamino,
`(C,-C,)-alkyl-amino-(C,-C,)-alkanoylamino, and di-
`(C,-C,)-alkyl-amino-(C,—C,,)-alkanoylamino, and
`wherein said phenyl or phenoxyor anilino substituent
`in the foregoing R’ groups is optionally substituted
`with one or two substituents independently selected
`from halo, C,—C, alkyl and C,-C, alkoxy;
`each R?is independently selected from hydrogen, methyl,
`ethyl, amino, halo and hydroxy; and,
`R* is ethynyl.
`Other preferred compounds of formula I include those
`wherein each R’ is independently selected from hydrogen,
`hydroxy, hydroxyamino, nitro, carbamoyl, ureido, R*
`optionally substituted with halo, —OR®, carboxy, or —C(O)
`NH,; —OR?optionally substituted with halo, —OR°, —OC
`(O)R®, —NR®R®, or A; —NR°R®, —C(OYNROR®, —SR?,
`phenyl-(C,—C,,)-alkoxy wherein said phenyl moiety is
`optionally substituted with 1 or 2 substituents independently
`selected from halo, R° or —OR?.
`Other preferred compounds of formula I include those
`wherein R? is hydrogen and R*is azido.
`Other preferred compounds of formula I include those
`wherein R?is halo and R' is hydrogen or —OR?.
`Other preferred compounds of formula I include those
`wherein R’is methoxy.
`Specific preferred compounds of formula I include the
`following:
`(6,7-dimethoxyquinazolin-4-yl)-(3-ethynylpheny])-amine;
`(6,7-dimethoxyquinazolin-4-yl)-[3-(3'-hydroxypropyn-1-yl)
`phenyl ]-amine;
`[3-(2'-(aminomethy1)-ethynyl)phenyl ]-(6,7-
`dimethoxyquinazolin-4-yl)-amine;
`(3-ethynylpheny1)-(6-nitroquinazolin-4-yl)-amine;
`(6,7-dimethoxyquinazolin-4-yl)-(4-ethynylpheny])-amine;
`(6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-
`methylphenyl)-amine;
`(6-aminoquinazolin-4-yl)-(3-ethynylpheny1)-amine;
`(3-ethynylpheny1)-(6-methanesulfonylaminoquinazolin-4-
`yl)-amine;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`(3-ethynylpheny1)-(6,7-methylenedioxyquinazolin-4-yl)-
`amine;
`(6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-
`methylphenyl)-amine;
`(3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine;
`(3-ethynylpheny!)-[6-(4'-toluenesulfonylamino)quinazolin-
`4-yl]-amine;
`(3-ethynylpheny1)-{6-[2'-phthalimido-eth-1'-yl-
`sulfonylamino]quinazolin-4-yl}-amine;
`(3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine;
`(7-aminoquinazolin-4-yl)-(3-ethynylpheny1)-amine;
`(3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine;
`(6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
`(7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
`[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-
`ethynylphenyl)-amine;
`(3-azidopheny1)-(6,7-dimethoxyquinazolin-4-yl)-amine;
`(3-azido-5-chloropheny])-(6,7-dimethoxyquinazolin-4-yl)-
`amine;
`(4-azidopheny])-(6,7-dimethoxyquinazolin-4-yl)-amine;
`(3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-
`amine;
`(6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine
`(6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-
`phenyl)-amine;
`(6,7-dimethoxy-quinazolin-4-y1)-[3-(propyn-1'-yl)-pheny1]-
`amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-
`methyl-phenyl)-amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-
`fluoro-phenyl)-amine;
`[6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-
`phenyl)-amine;
`[6-(2-chloro-ethoxy)-7 -(2-methoxy-ethoxy)-quinazolin-4-
`yl]-G-ethynyl-phenyl)-amine;
`[6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-
`phenyl)-amine;
`2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-
`quinazolin-6-yloxy]-ethanol;
`[6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-
`yl]-G-ethynyl-phenyl)-amine;
`[7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-
`yl]-G-ethynyl-phenyl)-amine;
`[7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-
`yl]-G-ethynyl-phenyl)-amine;
`2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-
`quinazolin-7-yloxy]-ethanol;
`2-[4-(-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-
`quinazolin-6-yloxy]-ethanol;
`2-[4-(-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-
`quinazolin-7-yloxy]-ethanol;
`[6-(2-acetoxy-ethoxy)-7-(2 -methoxy-ethoxy)-quinazolin-4-
`yl]-G-ethynyl-phenyl)-amine;
`(3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4methy1-
`piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine;
`(3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-
`4-yl)-ethoxy)-quinazolin-4-yl]-amine;
`(6,7-diethoxyquinazolin-1 -yl)-(3-ethynylphenyl)-amine;
`(6,7-dibutoxyquinazolin-1-yl)-(3-ethynylpheny1)-amine;
`(6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-
`amine;
`(6,7-diethoxy quinazolin-1-yl)-(3-ethynyl-2-methyl-
`phenyl)-amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-
`methyl-phenyl)-amine;
`(3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-
`ethoxy)-quinazolin-1-yl]-amine;
`
`APOTEX EX. 1056-005
`
`APOTEX EX. 1056-005
`
`

`

`US RE41,065 E
`
`5
`[6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-
`ethynylphenyl)-amine; and
`2-[4-(-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-
`quinazolin-7-yloxy]-ethanol.
`Other specific preferred compounds of formula I include
`the following:
`(6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-pheny1)-amine;
`(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-
`phenyl)-amine;
`(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-
`phenyl)-amine;
`(6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-
`phenyl)-amine;
`(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-
`phenyl)-amine;
`(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-
`phenyl)-amine;
`(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine;
`(6-aminocarbonylmethy]l-7-methoxy-quinazolin-4-yl)-G-
`ethynylphenyl)-amine;
`(6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine;
`(6-aminocarbonylmethy1-7-ethoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine;
`(6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine;
`(6-aminocarbonylmethy1-7-isopropoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine;
`(6-aminocarbonylmethy1-7-propoxy-quinazolin-4-yl)-G-
`ethynylphenyl)-amine;
`(6-aminocarbonylmethy]l-7-methoxy-quinazolin-4-yl)-G-
`ethynylphenyl)-amine;
`(6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-@3-
`ethynylphenyl)-amine; and
`(6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-3-
`ethynylphenyl)-amine.
`Other specific preferred compounds of formula I include
`the following:
`(6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
`(3-ethynylpheny1)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-
`ethoxy)-quinazolin-1-yl]-amine;
`[6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-
`ethynylphenyl)-amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-
`ethynylphenyl)-amine;
`(6,7-dimethoxyquinazolin-1-yl)-(3-ethynylpheny])-amine;
`(3-ethynylpheny1)-(6-methanesulfonylamino-quinazolin-1-
`yl)-amine; and,
`(6-amino-quinazolin-1 -yl)-(3-ethynylphenyl)-amine.
`The invention further relates to a pharmaceutical compo-
`sition for the treatment of a hyperproliferative disorder in a
`mammal which comprises a therapeutically-effective
`amount of the compoundof claim 1 and a pharmaceutically
`acceptable carrier.
`The invention further relates to a method of treating a
`hyperproliferative disorder in a mammal which comprises
`administering to said mammal a therapeutically-effective
`amount of the compoundofclaim 1.
`In a preferred embodiment, the methodoftreating hyper-
`proliferative disorders includes those wherein said hyperpro-
`liferative disorder is cancer.
`In another preferred embodiment, the method oftreating
`hyperproliferative disorders includes those wherein said
`hyperproliferative disorder is said cancer is brain,
`lung,
`squamous cell, bladder, gastric, pancreatic, breast, head,
`neck, oesophageal, gynecological or thyroid cancer.
`
`10
`
`20
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`In another preferred embodiment, the methodoftreating
`hyperproliferative disorders includes those wherein said
`hyperproliferative disorder is noncancerous.
`In another preferred embodiment, the methodoftreating
`hyperproliferative disorders includes those wherein said
`hyperproliferative disorder is a benign hyperplasia of the
`skin or prostate.
`The invention further relates to a process for preparing a
`compound ofthe formula
`
`a |
`= Bn
`ve SYRt
`a | Sy
`Q)-36
`
`or a pharmaceutically acceptable salt or prodrug thereof,
`wherein:
`
`mis 1, 2, or 3;
`each R' is independently selected from the group consist-
`ing of hydrogen, halo, hydroxy, hydroxyamino,
`carboxy, nitro, guanidino, ureido, cyano,
`trifluoromethyl, and -(C,-C, alkylene)-W-(phenyl)
`wherein W is a single bond, O, S or NH;
`or each R'
`is independently selected from R° and
`(C,-C,)-alkyl substituted by cyano, wherein R? is
`selected from the group consisting of R°, —OR®,
`—NR®R®, —C(O)R’, —NHOR*®, —OC(O)R®, cyano,
`A and —YR°; R® is C,-C, alkyl; R®° is independently
`hydrogen or R°; R’ is R°, —OR® or —NR‘R®; A is
`selected from piperidino, morpholino, pyrrolidino,
`4-R°-piperazin-1-yl,
`imidazol-1-yl, 4-pyridon-1-yl,
`-
`(C,-C, alkylene)(CO,H), phenoxy, phenyl,
`phenylsulfanyl, C.-C, alkenyl, and -(C,-C, alkylene)
`C(O)NRSR°; and Y is 8, SO, or SO,; wherein the alkyl
`moieties in R°, —OR® and —NR‘R® are optionally
`substituted by one to three substituents independently
`selected from halo and R’, and wherein the alkyl moi-
`eties of said optional substituents are optionally substi-
`tuted by halo or R®, with the proviso that two heteroat-
`omsare not attached to the same carbon atom,and with
`the further proviso that no more than three R® groups
`may comprise a single R’ group;
`or each R' is independently selected from —-NHSO,R°,
`phthalimido-(C,-C,,)-alkylsulfonylamino, benzamido,
`benzenesulfonylamino,
`3-phenylureido,
`2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and
`R!°-(C,-C,)-alkanoylamino wherein R'° is selected
`from halo, —OR®, C.-C, alkanoyloxy, —C(O)R’, and
`—NR‘R®; and wherein the foregoing R' groups are
`optionally substituted by 1 or 2 substituents indepen-
`dently selected from halo, C,-C, alkyl, cyano, meth-
`anesulfonyl and C,—C, alkoxy;
`or two R! groups are taken together with the carbons to
`which they are attached to form a 5—8 membered ring
`that includes 1 or 2 heteroatomsselected from O, S and
`N;
`R?is hydrogen or C.-C, alkyl optionally substituted by 1
`to 3 substituents independently selected from halo,
`C,-C, alkoxy, —NR®R®, and —SO,R*;
`nis 1 or 2 and each R?*is independently selected from
`hydrogen, halo, hydroxy, C,-C, alkyl, —NR°R®, and
`APOTEX EX. 1056-006
`
`APOTEX EX. 1056-006
`
`

`

`7
`C,-C, alkoxy, wherein the alkyl moieties of said R*
`groups are optionally substituted by 1 to 3 substituents
`independently selected from halo, C,—C, alkoxy,
`—NR&R®, and —SO,R°*; and,
`R* is azido or -(ethynyl)-R" wherein R" is hydrogen or
`C,-C, alkyl optionally substituted by hydroxy, —OR®,
`or —NR‘R®; which comprises
`a) treating a compoundofthe formula
`OH
`
`R)yi
`
`Sy
`
`2 or
`
`A
`N
`
`(Rj
`
`“SH
`
`2
`
`A
`N
`
`wherein R' and m are as defined above, with CCl, and
`(C.-C, ,aryl);P, optionally supported on an inert
`polymer, wherein the aryl moieties of said
`(C.-C, ,aryl), P are optionally substituted by C,—C,
`alkyl; and
`b) treating the product of step a) with a compound of
`the formula
`
`2
`|
`HN—X( y
`
`J
`
`Bs
`
`US RE41,065 E
`
`8
`
`SCHEME
`
`x
`
`a Oo
`
`N
`|
`Hy
`
`N
`
`2
`
`+
`
`ta),
`
`SS
`
`?),;
`KAN
`Y
`qt
`4
`
`
`cs
`Ry
`NM A UeN
`
`Y
`
`NA NX
`wu
`
`Sy N
`3
`
`Bm
`
`cr .
`RPMy A xLk
`
`Rt
`
`10
`
`15
`
`25
`
`30
`
`x
`
`no NA ™
`wal
`FrBm
`Sy
`SS
`wherein R?, R? andnare as defined above, and J is Y or
`35
`R*, wherein R* is as defined above and wherein Y is
`1
`NH,, Br, I or trifluoromethanesulfonyloxy, with the
`proviso that when J is Y then the productof step b) must
`further be treated with an alkyne where Y is Br, I or
`trifluoromethanesulfonyloxy, or an azide where Y is
`NH,.
`Preferred processes for preparing the compoundoffor-
`mula I include those wherein each aryl group is selected
`from phenyl], naphth-1-yl and naphth-2-y1.
`Other preferred processes for preparing the compound of
`formula I include those wherein each Ar in (Cz-C,,aryl)3P
`is phenyl.
`Other preferred processes for preparing the compound of
`formula I include those wherein said (C,—C, ,aryl),P is sup-
`ported on an inert polymer.
`Other preferred processes for preparing the compound of
`formula I include those wherein said inert polymer is a
`divinylbenzene-cross-linked polymerof styrene.
`The term “halo”, as used herein, unless