PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`lntemanonal Bureau
`
`
`
`.
`
`I
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(51) International Patent Classification 7 :
`
`(11) International Publication Number:
`
`W0 Oil/18740
`
`
`
`C07D 215/54, A61K 31/47, C07D 401/12, A1
`417/12, 215/56, 401/04, 491,10, 405/12,
`
`413/12 // (C07D 491/10, 317:00, 211:00)
`
`
`
`.
`.
`.
`(43) International Publication Date:
`
`.
`6 April 2000 (06.04.00)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`22 September 1999 (22.09.99)
`
`(30) Priority Data:
`09/162,289
`
`29 September 1998 (29.09.98)
`
`PCT/US99/22056
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, BE,
`
`ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD,
`
`MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
`SE, SG, SI, SK, SL, TJ, TM, TR,
`'I'I‘, TZ, UA, UG, UZ,
`US
`VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE, LS, MW,
`
`SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM, AZ, BY,
`
`KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, CH,
`(71) Applicant: AMERICAN CYANAMID COMPANY [US/US];
`CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
`
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`Five Giralda Farms, Madison, NJ 07940—0874 (US).
`
`GW, ML, MR, NE, SN, TD, TG).
`(72) Inventors; WlSSNER, Allan; 31 Wood Avenue, Ardsley, NY
`
`10502 (US). TSOU, Hwei—Ru; 7 Beverly Place, New City,
`
`NY 10956 (US). BERGER, Dan, Maarten; 6 lrion Drive, Published
`New City, NY 10956 (US). FLOYD, Middleton, Brawner,
`With international search report.
`Jr.; 5 Babbling Brook Drive, Suffem, NY 10901 (US).
`Before the expiration of the time limit for amending the
`
`HAMANN, Philip, Ross; 9 Alice Street, Gemerville, NY
`claims and to be republished in the event of the receipt of
`10923 (US). ZHANG, Nan; 9 New Street, Apartment 2C,
`amendments.
`Eastchester, NY 10709 (US). FROST, Philip; 4 Emerson
`
`Court, Morris Township, NJ 07960 (US).
`
`(74) Agents: MILOWSKY, Arnold, 8.; American Home Products
`
`Corporation, Patent Law Dept.—2B, One Campus Drive,
`
`Parsippany, NJ 07054 (US) et a1.
`
`(54) Title: SUBSTITUTED 3—CYANOQUINOLINES AS PROTEIN TYROSINE KINASES INHIBITORS
`
`This invention provides compounds of formula (1),
`wherein R1, Gl, G2, R4, Z, X and n are defined herein, or a
`pharmaceutically acceptable salt thereof, which are useful
`as antineoplastic agents and in the treatment of polycystic
`kidney disease.
`
`(CH2)n_X
`z/
`
`R
`
`1
`
`CEN
`
`\
`
`/
`
`N
`
`G
`
`1
`
`G2
`
`['1]
`
` (57) Abstract
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`cote d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germ any
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People‘s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`N0
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`80
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`

`WO 00/18740
`
`PCT/US99/22056 '
`
`-1-
`
`SUBSTITUTED 3-CYANOOUINOLINES AS PROTEIN TYROSINE KINASES INHIBITORS
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to certain substituted 3-cyano quinoline compounds as
`
`well as the pharmaceutically acceptable salts thereof. The compounds of the present
`
`invention inhibit the action of certain growth factor receptor protein tyrosine kinases
`
`(PTK) and other protein kinases thereby inhibiting the abnormal growth of certain
`
`cell types. The compounds of this invention are therefore useful for the treatment of
`
`certain diseases that are the result of deregulation of these PTKs. The compounds of
`
`this invention are anti—cancer agents and are useful for the treatment of cancer in
`
`mammals.
`
`In addition, the compounds of this invention are useful for the treatment
`
`of polycystic kidney disease in mammals. This invention also relates to the
`
`manufacture of said 3—cyano quinolines, their use for the treatment of cancer and
`
`polycystic kidney disease, and the pharmaceutical preparations containing them.
`
`Protein tyrosine kinases are a Class of enzymes that catalyze the transfer of a
`
`phosphate group from ATP to a tyrosine residue located on a protein substrate.
`
`Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth
`
`factor receptor proteins function as tyrosine kinases and it is by this process that they
`
`effect signaling. The interaction of growth factors with these receptors is a necessary
`
`event in normal regulation of cell growth. However, under certain conditions, as a
`
`result of either mutation or overexpression, these receptors can become deregulated;
`
`the result of which is uncontrolled cell proliferation which can lead to tumor growth
`
`and ultimately to the disease known as cancer [Wilks A.F., Adv. Cancer Res, 60, 43
`
`(1993) and Parsons, J.T.; Parsons, S.J., Important Advances in Oncology, DeVita
`
`V.T. Ed., J.B. Lippincott Co., Phila., 3 (1993) ]. Among the growth factor receptor
`
`kinases and their proto—oncogenes that have been identified and which are targets of
`
`the compounds of this invention are the epidermal growth factor receptor kinase
`
`(EGF-R kinase, the protein product of the erbB oncogene), and the product produced
`
`by the erbB—2 (also referred to as
`
`the neu or HER2) oncogene. Since the
`
`phosphorylation event is a necessary signal for cell division to occur and since
`
`overexpressed or mutated kinases have been associated with cancer, an inhibitor of
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`WO 00/18740
`
`PCT/US99/22056 —
`
`-2-
`
`this event, a protein tyrosine kinasc inhibitor, will have therapeutic value for the
`
`treatment of cancer and other diseases characterized by uncontrolled or abnormal cell
`
`growth. For example, overexpression of the receptor kinase product of the erbB—2
`
`oncogene has been associated with human breast and ovarian cancers [Slamon, D. J.,
`
`et. al., Science, 244, 707 (1989) and Science, 235 , 1146 (1987)]. Deregulation of
`
`EGF—R kinase has been associated with epidermoid tumors [Reiss, M., et. al., Cancer
`
`Res, 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res. 7, 459
`
`(1987)], and tumors involving other major organs [Gullick, W.J., Brit. Med. Bull, 47,
`
`87 (1991)]. Because of the importance of the role played by deregulated receptor
`
`kinases in the pathogenesis of cancer, many recent studies have dealt with the
`
`development of specific PTK inhibitors as potential anti—cancer therapeutic agents
`
`[some recent reviews: Burke. T.R., Drugs Future, 17, 119 (1992) and Chang, C.J.;
`
`Geahlen, R.L., J. Nat. Prod., 55, 1529 (1992)]. The compounds of this invention
`
`inhibit the kinase activity of EGF—R and are therefore useful for treating certain
`
`disease states, such as cancer, that result, at least in part, from deregulation of this
`
`receptor. The compounds of this invention are also useful for the treatment and
`
`prevention of certain pre—cancerous conditions, such as the growth of colon polyps,
`
`that result, at least in part, from deregulation of this receptor.
`
`It is also known that deregulation of EGF receptors is a factor in the growth of
`
`epithelial cysts in the disease described as polycystic kidney disease [Du J., Wilson P.
`
`D., Amer. J. Physiol., 269(2 Pt 1), 487 (1995); Nauta J., et al., Pediatric Research ,
`
`37(6), 755 (1995); Gattone V.H., et al., Developmental. Biology, 169(2), 504 (1995);
`
`Wilson P.D., et al., Eur. J. Cell Biol, 61(1), 131, (1993)]. The compounds of this
`
`invention, which inhibit the catalytic function of the EGF receptors, are consequently
`
`10
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`20
`
`25
`
`useful for the treatment of this disease.
`
`The mitogen-activated protein kinase (MAPK) pathway is a major pathway in
`
`the cellular signal transduction cascade from growth factors to the cell nucleus. The
`
`pathway involves kinases at two levels: MAP kinase kinases (MAPKK), and their
`
`substrates MAP kinases (MAPK). There are different isoforms in the MAP kinase
`
`30
`
`family.
`
`(For review, see Rony Seger and Edwin G. Krebs, FASEB, Vol. 9, 726, June
`
`1995). The compounds of this invention can inhibit
`
`the action of two of these
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`

`

`WO 00/18740
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`PCT/US99/22056
`
`-3-
`
`kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAP kinase. MEK is
`
`activated by phosphorylation on two’ serine residues by upstream kinases such as
`
`members of the raf family. When activated, MEK catalyzes phosphorylation on a
`
`threonine and a tyrosine residue of ERK. The activated ERK then phosphorylates
`
`and activates transcription factors in the nucleus, such as fos and jun, or other cellular
`
`targets with PXT/SP sequences. ERK, a p42 MAPK is found to be essential for cell
`
`proliferation and differentiation. Over—expression and/or over-activation of Mek or
`
`ERK has been found to be associated with various human cancers (For example,
`
`Vimala S. Sivaraman, Hsien-yu Wang, Gerard J. Nuovo, and Craig C. Malbon, J.
`
`Clin. Invest. Vol. 99, No. 7April 1997).
`
`It has been demonstrated that inhibition of
`
`MEK prevents activation of ERK and subsequent activation of ERK substrates in
`
`cells, resulting in inhibition of cell growth stimulation and reversal of the phenotype
`
`of rats—transformed cells (David T. Dudley, Long Pang, Stuart J. Decker, Alexander J.
`
`Bridges, and Alan R. Saltiel, PNAS, Vol. 92, 7686, August 1995). Since, as
`
`demonstrated below, the compounds of this invention can inhibit the coupled action
`
`of MEK and ERK , they are useful for the treatment of diseases such as cancer which
`
`are characterized by uncontrolled cell proliferation and which, at least in part, depend
`
`on the MAPK pathway.
`
`Epithelial Cell Kinase (ECK) is a receptor protein tyrosine kinase (RPTK)
`
`belonging to the EPH (Erythropoietin Producing Hepatoma)
`
`family. Although
`
`originally identified as an epithelial
`
`lineage-specific tyrosine kinase, ECK has
`
`subsequently been shown to be expressed on vascular endothelial cells, smooth
`
`muscle cells, and fibroblasts. ECK is a type I transmembrane glycoprotein with the
`
`extracellular ligand-binding domain consisting of a cysteine—rich region followed by
`
`three fibronectin type III repeats. The intracellular domain of ECK possesses a
`
`tyrosine kinase catalytic domain that initiates a signal transduction cascade reflecting
`
`the ECK function. ECK binds and is subsequently activated by its counter—receptor,
`
`Ligand for Eph-Related Kinase (LERK)—l, which is an immediate early response
`
`gene product readily inducible in a lineage-unrestricted manner with proinflammatory
`
`cytokines such as IL—1 or TNF.
`
`Soluble LERK—l has been shown to stimulate
`
`angiogenesis in part by stimulating ECK in a murine model of corneal angiogenesis.
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`WO 00/18740
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`PCT/US99/22056
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`-4-
`
`Unlike their normal counterparts,
`
`tumor cells of various lineages constitutively
`
`express LERK—l and this expression can further be upregulated by hypoxia and
`
`proinflammatory cytokines. Many of these tumor cells also express ECK at higher
`
`levels than their normal counterparts, thereby creating an opportunity for autocrine
`stimulation via ECK : LERK—l interaction. The increased expression of both ECK
`
`and LERK—l has been correlated with the transformation of melanomas from the
`
`noninvasive horizontal phase of growth into very invasive vertically growing
`
`metastatic melanomas. Together,
`
`the ECK : LERK—l
`
`interaction is believed to
`
`promote tumor growth via its tumor growth promoting and angiogenic effects. Thus,
`
`the inhibition of the ECK tyrosine kinase activity mediating signaling cascade
`
`induced by its binding and cross—linking to LERK—l may be therapeutically beneficial
`
`in cancer,
`
`inflammatory diseases, and hyperproliferative disorders. As is shown
`
`below, the compounds of this invention inhibit the tyrosine kinase activity of ECK
`
`and are therefore useful for the treatment of the aforementioned disorders.
`
`Growth of most solid tumors is dependent on the angiogenesis involving
`
`activation, proliferation and migration of vascular endothelial cells and their
`
`subsequent differentiation into capillary tubes. Angiogenization of tumors allows
`
`them access to blood-derived oxygen and nutrients, and also provides them adequate
`
`perfusion. Hence inhibiting angiogenesis is an important therapeutic strategy in not
`
`only cancer but also in a number of chronic diseases such as
`
`rheumatoid arthritis,
`
`psoriasis, diabetic retinopathy, age-related macular degeneration, and so on. Tumor
`
`cells produce a number of angiogenic molecules. Vascular Endothelial Growth Factor
`
`(VEGF) is one such angiogenic factor. VEGF, a homodimeric disulfide-linked
`
`member of the PDGF family, is an endothelial cell-specific mitogen and is known to
`
`cause profound increase in the vascular endothelial permeability in the affected
`
`tissues. VEGF is also a senescence-preventing survival factor for endothelial cells.
`
`Almost all nucleated tissues in the body possess the capability to express VEGF in
`
`response to various stimuli
`
`including hypoxia, glucose deprivation, advanced
`
`glycation products,
`
`inflammatory cytokines, etc. Growth-promoting angiogenic
`
`effects of VEGF are mediated predominantly via its signaling receptor Kinase insert
`
`Domain containing Receptor (KDR).
`
`The expression of KDR is low on most
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`WO 00/18740
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`PCT/US99/22056 7
`
`-5-
`
`endothelial cells; however, activation with angiogenic agents results in a significant
`
`upregulation of KDR on endothelial cells. Most angiogenized blood vessels express
`
`high levels of KDR. KDR is a receptor protein tyrosine kinase with an extracellular
`
`VEGF-binding domain consisting of 7
`
`immunoglobulin-like domains
`
`and a
`
`cytoplasmic domain containing the catalytic tyrosine kinase domain split by a kinase—
`
`insert region.
`
`Binding to VEGF causes dimerization of KDR resulting in its
`
`autophosphorylation and initiation of signaling cascade. Tyrosine kinase activity of
`
`KDR is essential for mediation of its functional effects as a receptor for VEGF.
`
`Inhibition of KDR-mediated functional effects by inhibiting KDR’s catalytic activity
`
`is considered to be an important therapeutic strategy in the treatment of angiogcnizcd
`
`disease states including cancer. As is shown below, the compounds of this invention
`
`inhibit the tyrosine kinase activity of KDR and are therefore useful for the treatment
`
`of the aforementioned disease states.
`
`In addition to the above utilities some of the compounds of this invention are
`
`useful for the preparation of other compounds of this invention.
`
`The compounds of this invention are certain substituted 3-cyano quinolines.
`
`Throughout this patent application, the quinoline ring system will be numbered as
`
`indicated in the formula below; the numbering for the quinazoline ring system is also
`shown:
`
`5
`
`4
`
`5
`
`4
`
`7
`
`8
`
`/
`
`N
`
`1
`
`2
`
`7
`
`8
`
`e)
`
`2
`
`N
`
`1
`
`10
`
`15
`
`20
`
`No 3~cyano quinolines have been reported that have biological activity as
`
`inhibitors of protein tyrosine kinases. A 3-Cyano quinoline with a 4—(2—methyl
`
`anilino)
`
`substituent having gastric (HVKU—ATPase inhibitory activity at high
`
`concentrations has been described [lfe R.J., et 211., J. Med. Chem, 35(18), 3413
`
`25
`
`(1992)].
`
`There are quinolines that do not have the 3-cyano substituent and, unlike the
`
`compounds of this invention, are unsubstituted at the 4-position but are reported to be
`
`inhibitors of protein tyrosine kinases [Gazit A., et a1., J. Med. Chem, 39(11), 2170
`
`

`

`WO 00/18740
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`PCT/US99/22056
`
`—6—
`
`(1996)]. A series of quinolines that have a 3—pyridyl substituent and no substituent at
`
`the 4—position have been described as inhibitors of platelet derived growth factor
`
`receptor kinase [Dolle RB, et a1, J. Med. Chem, 372, 2627 (1994) and Maguire
`
`M.P., et al., J. Med. Chem, 372, .129 (1994)]. The patent applications WO 96/09294
`
`and WO-9813350 describe inhibitors of protein tyrosine kinases that
`
`include 4—
`
`anilino quinolines with a large variety of substituents on positions 5—8 but which must
`
`also have a hydrogen or fluorine atom at position 3. The US patent 5,480,883
`
`describes quinoline derivatives that are inhibitors of protein tyrosine kinases but these
`
`derivatives do not have the unique combination of substituents, including the 3-cyano
`
`group, contained in the compounds of the present invention. The applications WO—
`
`9802434 and WO-9802438 describe quinoline derivatives that are tyrosine kinase
`
`inhibitors but these quinolines do not have the important 3-cyano substituent .
`
`In addition to quinolines, certain quinazoline derivatives that are similar, in
`
`some respects,
`
`to the compounds of this invention are known to be inhibitors of
`
`protein tyrosine kinases. The application EP—520722 describes 4-anilinoquinazolines
`
`that contain simple substituents such as chloro, trifluoromethyl, or nitro groups at
`
`positions 5 to 8. The application EP—566226 is similar but with a much larger variety
`
`of substituents now allowed at positions 5 to 8. The application WO-9609294
`
`describes compounds with similar substituents at positions 5 to 8 and with the
`
`substituent at to 4-position consisting of some polycyclic ring systems. Some simple
`
`substituted quinazolines are also described in the applications WO—9524190, WO—
`
`9521613, and WO—9515758. The applications EP-602851 and WO—9523141 cover
`
`similar quinazoline derivatives where the aryl group attached at position 4 can be a
`
`variety of heterocyclic ring structures. The application EP-635498 describes certain
`
`quinazoline derivatives that have alkenoylamino and alkynoylarnino groups among
`
`the substituents at position 6 and a halogen atom at position 7. The application
`
`WO-9519774 describes compounds where one or more of the carbon atoms at
`
`positions 5-8 can be replaced with heteroatoms resulting in a large variety of bicyclic
`
`systems where the left-hand ring is a 5 and 6—membered heterocyclic ring;
`
`in
`
`addition, a variety of substituents are allowed on the left-hand ring. The application
`
`EP—682027-A1
`
`describes
`
`certain pyrrolopyrimidine
`
`inhibitors of PTKs. The
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`PCT/US99/22056
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`-7-
`
`application WO—951997O describes compounds in which the left-hand aromatic ring
`
`of thc basic quinazoline structure has been replaced with a wide variety of different
`
`heterocyclic rings so that
`
`the resulting inhibitors are tricyclic. The application
`
`EP-635507 describes quinazolines where an additional 5 or 6—membered heterocyclic
`
`ring with optional substitution is fused at positions 5 and 6.
`
`In addition to the aforementioned patent applications,
`
`a number of
`
`publications describe 4-anilinoquinazolines: Fry, D.W., et. al., Science, 265, 1093
`
`(1994), Rewcastle G.W., et. al., J. Med. Chem, 38, 3482 (1995), and Bridges, A.J.,
`
`et. al., J. Med. Chem, 39 , 267, (1996). There are no publications that describe 3—
`
`10
`
`cyano quinolines as PTK inhibitors.
`
`DESCRIPTION OF THE INVENTION
`
`This invention provides a compound of formula 1:
`
`(CH2)n-X
`/
`
`R1
`
`2
`
`\ CEN
`/
`
`N
`
`G1
`
`(32
`
`R4
`
`1
`
`wherein:
`
`X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one
`
`or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or
`
`phenyl ring wherein the pyridinyl, pyrimidinyl, or phenyl
`
`ring may be
`
`optionally mono- di—, or tri—substituted with a substituent selected from the
`
`group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
`
`atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1—6 carbon atoms,
`
`halomethyl, alkoxymethyl of 2—7 carbon atoms, alkanoyloxymethyl of 2—7
`
`carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1—6 carbon atoms,
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`WO 00/18740
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`PCT/US99/22056 V
`
`—8—
`
`hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon
`
`atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,
`
`thiophenoxy,
`
`benzoyi, benzyl, amino, alkylamino of 1—6 carbon atoms, dialkylamino 0f 2 to
`
`12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon
`
`5
`
`atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3—8 carbon
`
`atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalky of 3—8 carbon
`
`atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon
`
`atoms, N,N—dia1ky1aminoalkyl of 3—10 carbon atoms, N—alkylaminoalkoxy of
`
`2-9 carbon atoms, N,N—dia1ky1aminoalkoxy of 3-10 carbon atoms, mercapto,
`
`10
`
`and benzoylamino;
`
`Z is -NH—, -O-, —S—, or -NR- ;
`
`R is alkyl of 1—6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
`
`G1, G2, R1, and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon
`
`atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2—6 carbon atoms, alkenyloxy
`
`15
`
`of 2—6 carbon atoms, alkynyloxy of 2—6 carbon atoms, hydroxymethyl,
`
`halomethyl, alkanoyloxy of 1—6 carbon atoms, alkenoyloxy of 3-8 carbon
`
`atoms, alkynoyloxy of 3—8 carbon atoms, alkanoyloxyrnethyl of 2-7 carbon
`
`atoms, alkenoyloxymethyl of 4—9 carbon atoms, alkynoyloxymethyl of 4—9
`
`carbon atoms, alkoxymethyl of 2—7 carbon atoms, alkoxy of 1—6 carbon atoms,
`
`20
`
`alkylthio of
`
`1-6
`
`carbon atoms,
`
`alkylsulphinyl of
`
`1-6
`
`carbon atoms,
`
`alkylsulphonyl of 1—6 carbon atoms, alkylsulfonamido of 1—6 carbon atoms,
`
`alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2—6 carbon
`
`atoms, hydroxy,
`
`trifluoromethyl,
`
`trifluoromethoxy, cyano, nitro, carboxy,
`
`carboalkoxy of 2—7 carbon atoms, carboalkyl of 2—7 carbon atoms, phenoxy,
`
`25
`
`phenyl,
`
`thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4
`
`carbon atoms, alkylamino of 1—6 carbon atoms, dialkylamino of 2 to 12
`
`carbon
`
`atoms,
`
`N—alkylcarbamoyl,
`
`N,N—dialkylcarbamoy1,
`
`N—alkyl-N—
`
`alkenylamino of 4 to 12 carbon atoms, N,N—dialkeny1amino of 6-12 carbon
`
`atoms, phenylamino, benzylamino,
`
`30
`
`

`

`WO 00/18740
`
`PCT/US99/22056 ’
`
`-9-
`
`/(C(R6)2)p\
`R7'(C(R6)2)p_N\
`/N‘(C(R6)2)k'Y'
`(C(R6)2)p
`
`, Rng‘CH'M‘(C(R6)2)k‘Y'
`
`R7-(C(R5)2)g-Y-
`
`, R7'(C(R6)2)p'M‘(C(Re)2)k‘Y' 1°r Het'(C(R6)2)q'W‘(C(Rs)2)k‘Y'
`
`with the proviso that either G1 or G2 or both G1 and G2 must be a radical
`
`selected from the group
`
`/(C(R6)2)p\
`R7-(C(R6)2)p—N\
`/N’(C(R6)2)k'Y'
`(C(R6)2)p
`
`, Rng-CH-M—(C(R5)2)k-Y-
`
`R'7-(C(R6)2)g-Y-
`
`, R7'(C(R6)2)p'M_(C(R6)2)k'Y'
`
`,
`
`HGt'(C(R6)2)q‘W‘(C(Rs)2)k'Y-,
`
`0r
`
`.
`H
`Rg-N— ’
`
`Y is a divalent radical selected from the group consisting of
`
`9
`”(CH2)a— —0— ,and “N—
`6
`
`1
`
`10
`
`15
`
`20
`
`R7 is -NR6R6, J, -OR6, —N(R6)3 2 0r —NR6(OR6);
`
`9
`R'7 is —NR6(OR6), —N(R6)3 * alkenoxy of 1—6 carbon atoms, alkynoxy of 1—6 carbon
`
`atoms, N-alkyl-N‘alkenylamino of 4 to 12 carbon atoms, N,N—dialkenylamino of 6—12
`
`carbon atoms, N—alkyl—N—alkynylamino of 4 to 12 carbon atoms, N—alkenyl—N-
`
`alkynylamino of 4 to 12 carbon atoms, or N,N—dialkynylamino of 6-12 carbon atoms
`
`With the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen
`
`atom through a saturated carbon atom;
`
`M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p-OR6;
`
`W is >NR6, —O— or is a bond;
`
`Het
`
`is
`
`a heterocycle
`
`selected from the
`
`group
`
`consisting of morpholine,
`
`thiomorpholine,
`
`thiomorpholine
`
`S—oxide,
`
`thiomorpholine
`
`S,S—dioxide,
`
`

`

`WO 00/18740
`
`PCT/US99/22056 7
`
`-10-
`
`piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3—triazole, 1,2,4—
`
`triazolc,
`
`thiazole,
`
`thiazolidine,
`
`tetrazole, piperazine,
`
`furan,
`
`thiophene,
`
`tetrahydrothiophene,
`
`tetrahydrofuran,
`
`dioxane,
`
`1,3-dioxolane
`
`,
`
`(OCHZCHZO)r
`
`tetrahydropyran, and
`
`N
`H
`
`;
`
`5
`
`wherein the heterocycle is optionally mono- or di—substituted on carbon or
`
`nitrogen with R6, optionally mono- or di—substituted on carbon with hydroxy,
`
`-N(R6)2’ or —OR6, optionally mono or di—substituted on carbon with the
`
`mono—valent radicals ~(C(R6)2)SOR6 0r —(C(R6)2)SN(R6)2, or optionally
`
`mono or di-substituted on a saturated carbon with divalent radicals -O— or
`
`10
`
`-0(C<R6)2>SO-;
`
`R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2—6 carbon atoms, alkynyl of 2-
`
`6 carbon atoms, cycloalkyl of 1—6 carbon atoms, carboalkyl of 2-7 carbon
`
`atoms, carboxyalkyl
`
`(2-7 carbon atoms), phenyl, or phenyl optionally
`
`15
`
`substituted with one or more halogen, alkoxy of 1-6 carbon atoms,
`
`trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2—6
`
`carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon
`
`atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon
`
`atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl,
`
`20
`
`thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of
`
`1—6 carbon atoms, or alkyl of 1—6 carbon atoms;
`
`R2, is selected from the group consisting of
`
`

`

`WO 00/18740
`
`PCT/US99/22056 '
`
` R3
`R3: RM:
`R3
`R3
`
`R3
`
`R3
`
`R3
`
`R3
`
`R3 0
`
`R3
`
`R3
`
`9
`
`3
`
`R3
`
`’
`
`0
`
`0
`
`R3
`
`0
`R3/
`
`PG r?
`
`R3 _
`R3
`
`R3
`
`’
`
`’
`
`(C(R3)2)p
`
`N/Rs
`s
`
`I R
`
`O
`
`0
`
`,
`
`R
`
`O
`
`3
`0 R3
`
`o
`Rg-s—s—<C<R3)2>r—<
`
`R
`
`3
`
`.
`
`/(C(R5)2)u
`REi—N\
`
`(C(R5)2)v
`
`0
`
`l
`
`R5
`
`o
`
`0
`
`)
`
`’Re
`
`O
`
`/<C(R5>2)u
`o\
`
`(C(R5)2)v
`
`O
`
`R5
`
`l
`
`o
`
`,(C(Rs)2)u
`s
`\ (C(R5>2)v
`
`[
`
`R5
`
`,
`
`1
`
`o
`
`0
`
`o
`
`o
`
`,
`
`[N]
`
`o
`
`N
`
`E j
`5'
`R6
`
`

`

`WO 00/18740
`
`PCT/US99/22056
`
`-12-
`
`R
`
`R5
`
`:—<
`
`\
`so
`
`2
`
`R5 ’
`
`J-2)S(CH
`
`(CH2)
`
`fife.»W4
`
`J‘ (CH2)
`
`0 \
`
`Q‘é—fHQ
`R5
`R5
`
`\CH2
`Q‘Z—<R5
`
`\
`
`002C5—fJH2
`
`R5
`
`0020
`
`R5
`R5
`
`R5
`
`R5
`
`H2
`Q
`
`\
`
`o
`
`\
`
`pH2
`
`0020
`
`’
`
`R3 is independently hydrogen, alkyl of 1—6 carbon atoms, carboxy, carboalkoxy of
`
`1-6 carbon atoms, phenyl, carboalkyl of 2—7 carbon atoms,
`
`/
`R7'(C(R6)2)p—N\
`
`(C(Re)2)p
`\N
`/N(C(Re)2)r’
`(C(Re)2)p
`
`7_(C(R6)2)s'
`
`,
`
`R7-(C( R6)2)p'M—(C(R6)2)r'
`
`RBRQ'CH'M_(C(R6)2)r'
`
`’0’ Het'(C(R6)2)q‘W‘(C(Re)2)r‘
`
`;
`
`with the proviso that at least one of the R3 groups is selected from the group
`
`10
`
`

`

`WO 00/18740
`
`PCT/US99/22056 7
`
`_ 13 _
`
`/
`R7‘(C(R6)2)p—N\
`
`(C(R6)2)p
`\
`/N‘(C(R6)2)r
`(C(R6)2)p
`
`R'7‘(C(Rs)2)s'
`
`.
`
`R7—(C(Re)2)p-M—(C(R6)2)r-
`
`RBRQ‘CH'M_(C(R6)2)r”
`
`,0" Het“(C(R6)2)q'W'(C(R6)2)r'
`
`;
`
`R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of
`
`1—6 carbon atoms, phenyl, carboalkyl of 2—7 carbon atoms,
`
`/(C(R6)2)p\
`R7'(C(R6)2)p—N\
`/N_(C(R6)2)r‘
`(C(R6)2)p
`
`R7_(C(R6)2)s'
`
`,
`
`R7—(C<R6)2)p‘M_(C(R6)2)r'
`
`.
`
`RSRQ'CH'M_(C(R6)2)r'
`
`,or Het'(C(R6)2)q'w_(C(R6)2)r‘
`
`;
`
`R8, and R9 are each, independently, —(C(R6)2)rNR6R6, or -(C(R6)2)r 0R6;
`
`J is independently hydrogen, chlorine, fluorine, or bromine;
`
`10
`
`Q is alkyl of 1—6 carbon atoms or hydrogen;
`
`a = O or 1;
`
`g = 1-6;
`
`k = 0—4;
`
`H is 0— 1;
`
`15
`
`p=24
`
`CFO-4;
`
`r = 1—4;
`
`s = 1-6;
`
`u : 0-4 and V = 0-4 , wherein the sum of 11+v is 2-4;
`
`20
`
`or a pharmaceutically acceptable salt thereof,
`
`provided that
`
`

`

`WO 00/18740
`
`PCT/US99/22056 '
`
`_14_
`
`when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such
`
`alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom
`
`through a saturated carbon atom;
`
`and further provided that
`
`when Y is -NR6— and R7 is -NR6R6, —N(R6)3 *’ or —NR6(OR6), then g = 2—6;
`
`when M is —O- and R7 is —OR6, then p = 1-4;
`
`when Y is -NR6—, then k = 2-4;
`
`when Y is —O— and M or W is —O-, then k = 1—4;
`
`when W is not a bond with Het bonded through a nitrogen atom, then q = 2—4;
`
`and when W is a bond with Het bonded through a nitrogen atom and Y is -O-
`
`or -NR6—, then k = 2—4 .
`
`The pharmaceutically acceptable salts are those derived from such organic and
`
`inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic,
`
`hydrochloric, hydrobromic, phosphoric, nitric,
`
`sulfuric, methanesulfonic,
`
`and
`
`similarly known acceptable acids.
`
`The
`
`alkyl portion of
`
`the
`
`alkyl,
`
`alkoxy,
`
`alkanoyloxy,
`
`alkoxymethyl,
`
`alkanoyloxymethyl, alkylsulphinyl, alkylsulphonyl, aminoalkyl, N—alkylaminoalkyl,
`
`N,N-dia1kylaminoalkyl,
`
`N—alkylaminoalkoxy,
`
`N,N—dialkylaminoalkoxy,
`
`alkyl—
`
`sulfonamido,
`
`carboalkoxy,
`
`carboalkyl,
`
`carboxyalkyl,
`
`carboalkoxyalkyl,
`
`alkanoylamino, N—alkylcarbamoyl, and N,N—dialkylcarbamoyl substituents include
`
`both straight chain as well as branched carbon chains. The alkenyl portion of the
`
`alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido, substituents include
`
`both straight chain as well as branched carbon chains and one or more sites of
`
`unsaturation and all possible configurational
`
`isomers. The alkynyl portion of the
`
`alkynyl, alkynoyloxyrnethyl, alkynylsulfonamido, alkynyloxy, substituents include
`
`both straight chain as well as branched carbon chains and one or more sites of
`
`unsaturation. Carboxy is defined as a —C02H radical. Carboalkoxy of 2—7 carbon
`
`atoms is defined as a —C02R“ radical, where R" is an alkyl radical of 1-6 carbon
`
`atoms. Carboxyalkyl is defined as a HOzC-R"'— radical where R‘” is a divalent alkyl
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 00/18740
`
`PCT/US99/22056
`
`-15-
`
`radical of 1—6 carbon atoms. Carboalkoxyalkyl is defined as a R"02C—R'”- radical
`
`where R'” is a divalent akyl radical and where R" and R'” together have 2-7 carbon
`
`atoms. Carboalkyl is defined as a -COR“ radical, where R" is an alkyl radical of 1-6
`
`carbon atoms. Alkanoyloxy is defined as a —OCOR" radical, where R" is an alkyl
`
`radical of 1-6 carbon atoms. Alkanoyloxymcthyl is defined as R"C02CH2— radical,
`
`where R" is an alkyl radical of 1—6 carbon atoms. Alkoxymethyl
`
`is defined as
`
`R"OCH2— radical, where R" is an alkyl radical of 1—6 carbon atoms. Alkylsulphinyl is
`
`defined as R"SO-
`
`radical, where R" is an alkyl radical of
`
`1—6 carbon atoms.
`
`Alkylsulphonyl is defined as R"SOz- radical, where R" is an alkyl radical of 1—6
`
`10
`
`15
`
`carbon atoms. Alkylsulfonamido,
`
`alkenylsulfonamido,
`
`alkynylsulfonamido are
`
`defined as R"SO2NH— radical, where R" is an alkyl radical of 1—6 carbon atoms, an
`
`alkenyl radical of 2-6 carbon atoms, or an alkynyl radical of 2-6 carbon atoms,
`
`respectively. N—alkylcarbamoyl is defined as R“NHCO— radical, where R" is an alkyl
`
`radical of 1-6 carbon atoms. N,N—dialkylcarbamoyl is defined as R" R'NCO- radical,
`
`where R" is an alkyl radical of 1-6 carbon atoms, R' is an alkyl radical of 1-6 carbon
`
`atoms and R‘, and R" may be the same or different . When X is substituted, it is
`
`preferred that it is mono— , di— , or tri—substituted, with monosubstituted being most
`
`preferred. It is preferred that of the substituents R1 and R4, at least one is hydrogen
`
`and it is most preferred that both be hydrogen. It is also preferred that X is a phenyl
`
`20
`
`ring, Z is —NH—, and n = 0.
`
`Het is a heterocycle, as defined above which may be optionally mono- or di—
`
`substituted with R6 on carbon or nitrogen, optionally mono— or di—substituted on
`
`carbon with hydroxy, -N(R6)2, or -OR6, optionally mono or di-substituted on carbon
`
`with with —(C(R6)2)SOR6 or —(C(R6)2)SN(R6)2 , and optionally mono or
`
`di—
`
`25
`
`30
`
`substituted on a saturated carbon with divalent radicals -O- or —O(C(R6)2)SO-
`
`(carbonyl and ketal groups , respectively); in some cases when Het is substituted with
`
`—O— (carbonyl), the carbonyl group can be hydrated. Het may be bonded to W when q
`
`= 0 via a carbon atom on the heterocyclic ring, or when Het is a nitrogen containing
`
`heterocycle which also contains a saturated carbon-nitrogen bond, such heterocycle
`
`may be bonded to carbon, Via the nitrogen when W is a bond. When q = 0 and Het is
`
`

`

`W0 00/1 8740
`
`PCT/US99/22056
`
`—16—
`
`a nitrogen containing heterocycle which also contains an unsaturated carbon—nitrogen
`
`bond, that nitrogen atom of the heterocycle may be bonded to carbon when W is a
`
`bond and the resulting heterocycle will bear a positive charge. When Het
`
`is
`
`substituted with R6, such substitution may be on a ring carbon, or in the case of a
`
`nitrogen containing heterocycle, which also contains a saturated carbon-nitrogen,
`
`such nitrogen may be substituted with R6 or in the case of a nitrogen containing
`
`heterocycle, which also contains an unsaturated carbon-nitrogen, such nitrogen may
`
`be substituted with R6 in with case the heterocycle will bear a positive charge.
`
`Preferred
`
`heterocycles
`
`include
`
`pyridine,
`
`2,6-disubstituted morpholine,
`
`2,5—
`
`disubstituted
`
`thiomorpholine,
`
`2-substituted
`
`imidazole,
`
`substituted
`
`thiazole,
`
`thiazolidine, N-substituted imidazole, N-subsitituted 1,4-piperazine, N—subsitituted
`
`piperadine, dioxane, 1,3—dioxolane, and N—substituted pyrrolidine.
`
`The compounds of this invention