PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 7 :
`C07D 487/04, 47U04, A61K 31/415,
`3U44, 3U505, 3U55, A61P 7/02 // (C07D
`487/04, 231:00, 239:00) (C07D 487/04,
`231:00, 237:00) (C07D 487/04, 223:00,
`231:00) (C07D 47U04, 211:00, 231:00)
`
`Al
`
`(11) International Publication Number:
`
`WO 00/39131
`
`(43) International Publication Date:
`
`6 July 2000 (06.07.00)
`
`(21) International Application Number:
`
`PCT/US99/30316
`
`(22) International Filing Date:
`
`17 December 1999 (17.12.99)
`
`(74) Agent: FERGUSON, Blair, F.; Du Pont Pharmaceuticals
`Company, Legal Patent Records Center, 1007 Market Street,
`Wilmington, DE 19898 (US).
`
`(30) Priority Data:
`601113,628
`601127,633
`
`23 December 1998 (23.12.98)
`2 April 1999 (02.04.99)
`
`US
`US
`
`(71) Applicant: DU PONT PHARMACEUTICALS COMPANY
`[US/US]; Chestnut Run Plaza, 974 Centre Road, Wilming(cid:173)
`ton, DE 19807 (US).
`
`(72) Inventors: FEVIG, John, M.; 987 Church Road, Lincoln
`University, PA 19352 (US). CACCIOLA, Joseph; 105
`Pattie Drive, Newark, DE 19702 (US). CLARK, Charles,
`G.; 4 Glenview Place, Cherry Hill, NJ 08034 (US). LAM,
`Patrick, Yuk, Sun; 6 Ridgeway Drive, Chadds Ford, PA
`19317 (US). PINTO, Donald, J., P.; 39 Whitson Drive,
`Newark, DE 19702 (US). PRUITT, James, R.; 237 Skycrest
`Drive, Landenberg, PA 19350 (US). ROSSI, Karen, A.;
`120A Embery Court, Newark, DE 19711 (US).
`
`(81) Designated States: AL, AU, BR, CA, CN, CZ, EE, HU, IL,
`IN, JP, KR, LT, LY, MK, MX, NO, NZ, PL, RO, SG, SI,
`SK, TR, UA, VN, ZA, Eurasian patent (AM, AZ, BY, KG,
`KZ, MD, RU, TJ, TM), European patent (AT, BE, CH, CY,
`DE, DK, ES, Fl, FR, GB, GR, IE, IT, LU, MC, NL, PT,
`SE).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: NITROGEN CONTAINING HETEROBICYCLES AS FACTOR XA INHIBITORS
`
`(57) Abstract
`
`The present application describes nitrogen containing heterobicyclics and derivatives thereof, or pharmaceutically acceptable salt
`forms thereof, which are useful as inhibitors of factor Xa.
`
`CFAD EX 1003
`
`

`
`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.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Annenia
`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
`Gennany
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`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
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The fonner Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`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 00/39131
`
`PCT/US99/30316
`
`Nitrogen Containing Heterobicycles as Factor Xa Inhibitors
`
`TITLE
`
`FIELD OF THE INVENTION
`
`This invention relates generally to nitrogen containing heterobicycles, which are
`
`inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical
`
`compositions containing the same, and methods of using the same as anticoagulant agents
`
`for treatment and prevention ofthromboembolic disorders.
`
`5
`
`10
`
`BACKGROUND OF THE INVENTION
`
`W094/20460 describes angiotensin II compounds of the following formula:
`
`d$•Het
`
`x
`wherein X can be a number of substituents and Het can be a nitrogen-containing
`
`15
`
`heterobicycle. However, W094/20460 does not suggest Factor Xa inhibition or exemplify
`
`compounds like those of the present invention.
`
`W096/12720 describes phosphodiesterase type IV and TNF production inhibitors
`
`of the following formula:
`
`RI
`
`R''(l0N
`~y-13
`20 wherein X can be oxygen and R2 and R3 can a number of substituents including
`
`heterocycle, heterocycloalkyl, and phenyl. However, the presently claimed compounds do
`
`not correspond to the compounds ofW096/12720. Furthermore, W096/12720 does not
`
`!
`
`suggest Factor Xa inhibition.
`
`W098/52948 describes inhibitors of ceramide-mediated signal transduction. One
`
`25
`
`of the types of inhibitors described is of the following formula:
`
`

`
`WO 00/39131
`
`PCT /US99/30316
`
`R2
`I
`y~Z,
`i.'21
`~
`,
`N
`Y1
`'R1
`
`0
`
`wherein Y 1 can be N-R6, R6 can be unsubstituted aryl-alkyl or unsubstituted heterocyclic(cid:173)
`alkyl and R1 can be a substituted aryl group. W098/52948 does not mention factor Xa
`
`inhibition or show compounds like those of the present invention.
`
`5
`
`U.S. Patent Nos. 3,365, 459 and 3,340,269 illustrates anti-inflammatory inhibitors
`
`of the following formula:
`
`:~~'R'
`ti~
`
`wherein A is 2-3 carbon atoms, X can be 0, and R1 and R3 can be substituted or
`
`unsubstituted aromatic groups. Neither of these patents, however, exemplify compounds
`
`10
`
`of the present invention.
`
`Activated factor Xa, whose major practical role is the generation of thrombin by
`
`the limited proteolysis of prothrombin, holds a central position that links the intrinsic and
`
`extrinsic activation mechanisms in the final common pathway of blood coagulation. The
`
`generation of thrombin, the final serine protease in the pathway to generate a fibrin clot,
`
`15
`
`from its precursor is amplified by formation ofprothrombinase complex (factor Xa, factor
`
`V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can
`
`generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for
`
`the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in
`
`the amplification ofblood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of
`
`20
`
`factor Xa may be more efficient than inactivation ofthrombin in interrupting the blood
`
`coagulation system.
`
`Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially
`
`valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus
`
`desirable to discover new factor Xa inhibitors.
`
`25
`
`2
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`SUMMARY OF THE INVENTION
`
`Accordingly, one object of the present invention is to provide novel nitrogen
`
`containing heterobicycles that are useful as factor Xa inhibitors or pharmaceutically
`
`acceptable salts or prodrugs thereof.
`
`5
`
`It is another object of the present invention to provide pharmaceutical compositions
`
`comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of
`
`at least one of the compounds of the present invention or a pharmaceutically acceptable
`
`salt or prodrug form thereof.
`
`It is another object of the present invention to provide a method for treating
`
`10
`
`thromboembolic disorders comprising administering to a host in need of such treatment a
`
`therapeutically effective amount of at least one of the compounds of the present invention
`
`or a pharmaceutically acceptable salt or prodrug form thereof.
`
`It is another object of the present invention to provide novel bicyclic compounds
`
`for use in therapy.
`
`15
`
`It is another object of the present invention to provide the use of novel bi cyclic
`
`compounds for the manufacture of a medicament for the treatment of a thromboembolic
`
`disorder.
`
`These and other objects, which will become apparent during the following detailed
`
`description, have been achieved by the inventors' discovery that the presently claimed
`
`20
`
`bicyclic compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are
`
`effective factor Xa inhibitors.
`
`DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
`
`[ 1]
`
`Thus, in a first embodiment, the present invention provides a novel compound
`
`25
`
`selected from the group:
`
`3
`
`

`
`WO 00/39131
`
`PCT /US99/30316
`
`1r}:;N'A-B
`'-N
`G-tJ )s O
`z2
`N\
`17)-__;N'A-B
`N
`G-+1) s
`
`N"-
`
`0
`
`I
`
`/7~N'KB
`N"-
`N
`G-tJ ) s
`
`0
`
`N~
`17-y:;,N'A-B
`N"-
`N
`G--tJ ) s
`
`0
`
`0
`
`if)'KB
`
`"N
`G-tJ )s O
`z2
`N\o
`J()-__;N'KB
`N
`G--tJ ) s
`
`0
`
`JtPKB
`
`0
`
`N
`G-tJ )s
`
`I
`
`z2
`
`I
`
`z-)>
`
`A-8
`
`J( \
`N
`G--tJ ) s
`
`0
`
`z2
`
`I
`
`Jr~KB z-:(>
`
`0
`
`N
`G-+1 ) s
`
`5
`
`A-B
`
`0
`
`J( \
`N
`G~ )s
`
`4
`
`0
`
`ff:JKB
`
`0
`
`N
`
`G-tJ ) s
`
`z2
`
`I
`
`0
`
`Jr~KB
`
`0
`
`N
`G~ )s
`
`

`
`W0 00/39131
`WO 00/39131
`
`PCT/US99/30316
`PCT /US99/30316
`
`G
`
`0
`
`z2
`
`I
`
`N \
`
`\
`
`N'A-B
`
`0
`
`G
`
`N
`z1 ~
`I
`\
`N,A-B
`N~
`
`0
`
`G
`
`G
`
`0
`
`G
`
`z2 N\o
`
`N'A-B
`
`0
`
`z1
`\
`I
`N~
`
`G
`
`z-{o\\
`~(>--!'A-s
`G-tJ )s
`
`N
`
`0
`
`5
`
`5
`
`

`
`W0 00/3913]
`WO 00/39131
`
`PCT/US99/30316
`PCT /US99/30316
`
`-N
`\
`N,A-B
`
`0
`
`I
`
`z2
`N
`\
`N,A-B
`
`G
`
`G
`
`S(O)p
`\
`N
`'A-B
`
`0
`
`(O)p
`
`s\
`
`N
`A-B
`
`0
`
`G
`
`G
`
`z
`//
`N,
`N
`G-+1) s
`
`\
`N'A-B
`
`0
`
`-:(;
`-t;z'
`
`\
`N,A_.B
`
`z
`//
`N'-
`
`0
`
`N
`G-+1 )s
`
`JG
`
`N
`
`!l
`"
`G-+1 )s
`
`O
`
`N,
`A-B
`
`(O)p
`s
`
`j~~(;\_B
`
`0
`
`G-+1) s
`
`5
`
`6
`
`

`
`
`W0 00/39131W0 00/39131
`WO 00/39131
`
`PCT/US99/30316
`
`PCT/US99/30316PCT/US99/30316
`
`)
`
`0
`
`\
`
`N
`'A-B
`
`G
`
`7
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`I
`
`z2
`
`NrO
`
`N,
`A-B
`
`0
`
`oyo
`
`N,
`A-B
`
`0
`
`z2
`
`I ff;ro
`
`N
`G-tJ )5 O
`
`A-B
`
`G
`
`)s
`
`f):):o
`
`A-B
`
`N
`G-tJ)s
`
`0
`
`G
`
`8
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`N
`'--.
`N
`G-tJ )s
`
`t7f)
`
`z2
`
`0
`
`N
`'A-8
`
`0
`
`z
`//
`N'--.
`N
`
`\
`
`G~ )s
`
`0
`
`z2
`N~
`
`\
`
`N
`'A-8
`
`G
`
`)s
`
`N
`'--.
`N
`
`G~ )s
`
`0
`
`A-8
`
`0
`
`G
`
`0
`
`A-B
`
`1r:('r0
`
`z2
`
`I
`
`N
`'A-8
`
`0
`
`z
`//
`N"-
`
`N
`G-tJ) s
`
`z2
`I
`N
`
`yo
`
`N
`'A-B
`
`11-;('r0
`
`N
`"-
`
`N
`G-tJ) s
`
`0
`
`N
`'A-8
`
`0
`
`0
`
`oyo
`
`N
`'A-B
`
`0
`
`G
`
`0
`
`G
`
`G
`
`5
`
`or a stereoisomer or pharmaceutically acceptable salt thereof, wherein compounds of the
`
`above formulas are substituted with 0-2 R3;
`
`G is a group of formula I or II:
`
`10
`
`(;;~_
`~
`I
`
`9
`
`II
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`5
`
`IO
`
`ring Dis selected from -(CH2)3-, -(CH2)4-, -CH2N=CH-, -CH2CH2N=CH-, and a 5-6
`
`membered aromatic system containing from 0-2 heteroatoms selected from the
`
`group N, 0, and S, provided that from 0-1 0 and S atoms are present;
`
`ring D, when present, is substituted with 0-2 R;
`
`E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with
`
`0-1 R;
`
`R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(Ct-3 alkyl), N(Ct-3 alkyl)2,
`
`CH2NH2, CH2NH(C1_3 alkyl), CH2N(C1_3 alkyl)2, CH2CH2NH2,
`
`CH2CH2NH(C1_3 alkyl), and CH2CH2N(C1-3 alkyl)2;
`
`15
`
`alternatively, ring D is absent;
`
`when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and
`
`pyridazinyl, and ring Eis substituted with R" and R';
`
`20 R" is selected from F, Cl, Br, I, OH, Ct-3 alkoxy, CN, C(=NR8)NR7R9,
`
`NHC(=NR8)NR7R9, NR8CH(=NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, Ct-3
`
`alkyl-S, S(O)R3b, S(0)2R3a, S(0)2NR2R2a, and OCF3;
`
`R' is selected from H, F, Cl, Br, I, SR3, C02R3, N02, (CH2)tOR3, Ct-4 alkyl, OCF3, CF3,
`
`25
`
`C(O)NR7R8, and (CR8R9)tNR7R8;
`
`alternatively, R" and R' combine to form methylenedioxy or ethylenedioxy;
`
`Z is Nor CR la-
`'
`
`30
`
`zt is S, 0, or NR3;
`
`10
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`z2 is selected from H, Ct-4 alkyl, phenyl, benzyl, C(O)R3, and S(O)pR3c;
`
`Ria is selected from H, -(CH2)rRl',-CH=CH-Rl', NCH2Rl", OCH2Rl", SCH2Rl'',
`
`NH(CH2)z(CH2)tR I', O(CH2)2(CH2)tR l ', and S(CH2)z(CH2)tR 1 ';
`
`5
`
`R 1' is selected from H, C1_3 alkyl, F, Cl, Br, I, -CN, -CHO, (CF2)rCF3, (CH2)rOR2,
`
`NR2R2a, C(O)R2c, OC(O)R2, (CF2)rC02R2c, S(O)pR2b, NR2(CH2)rOR2,
`
`C(=oNR2c)NR2R2a, NR2C(O)R2b, NR2C(O)R3, NR2C(O)NHR2b, NR2C(0)2R2a,
`
`OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, S02NR2R2a, NR2S02R2b,
`
`10
`
`C3_6 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic
`
`system containing from 1-4 heteroatoms selected from the group consisting ofN,
`
`0, and S substituted with 0-2 R4a;
`
`RI" is selected from H, CH(CH20R2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(0)2R2b, and
`
`15
`
`S02NR2R2a;
`
`R2, at each occurrence, is selected from H, CF3, Ct-6 alkyl, benzyl, C3_6 carbocyclic
`
`residue substituted with 0-2 R4b, a C3_6 carbocyclic-CH2- residue substituted with
`
`0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms
`
`20
`
`selected from the group consisting ofN, 0, and S substituted with 0-2 R4b;
`
`R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3_6 carbocyclic
`
`residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing
`
`from 1-4 heteroatoms selected from the group consisting ofN, 0, and S substituted
`
`25
`
`with 0-2 R4b·
`'
`
`R2b, at each occurrence, is selected from CF3, Ct-4 alkoxy, Ct-6 alkyl, benzyl, C3_6
`
`carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic
`
`system containing from 1-4 heteroatoms selected from the group consisting ofN,
`
`30
`
`0, and S substituted with 0-2 R4b;
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`R2c, at each occurrence, is selected from CF3, OH, Ct-4 alkoxy, C1-6 alkyl, benzyl, C3_6
`
`carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic
`
`system containing from 1-4 heteroatoms selected from the group consisting ofN,
`
`0, and S substituted with 0-2 R4b;
`
`alternatively, R2 and R2a, together with the atom to which they are attached, combine to
`
`form a 5 or 6 membered saturated, partially saturated or unsaturated ring
`
`substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected
`
`from the group consisting of N, 0, and S;
`
`5
`
`10
`
`R3, at each occurrence, is selected from H, C14 alkyl, and phenyl;
`
`R3a, at each occurrence, is selected from H, Ci-4 alkyl, and phenyl;
`
`15
`
`R3h, at each occurrence, is selected from H, C14 alkyl, and phenyl;
`
`R3c, at each occurrence, is selected from C14 alkyl, and phenyl;
`
`A is selected from:
`
`20
`
`C3-10 carbocyclic residue substituted with 0-2 R4, and
`
`5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from
`
`the group consisting ofN, 0, and S substituted with 0-2 R4;
`
`B is selected from:
`
`25
`
`X-Y, C(=NR2)NR2R2a, NR2C(=NR2)NR2R2a,
`
`C3_10 carbocyclic residue substituted with 0-2 R4a, and
`
`5110 membered heterocyclic system containing from 1-4 heteroatoms selected from
`
`the group consisting ofN, 0, and S substituted with 0-2 R4a;
`
`30 Xis selected from C14 alkylene, -CR2(CR2R2h)(CH2)r, -C(O)-, -C(=NRl')-,
`
`-CR2(NRl"R2)-, -CR2(QR2)-, -CR2(SR2)-, -C(O)CR2R2a_, -CR2R2aqo), -S(O)p-,
`
`12
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`-S(O)pCR2R2a_, -CR2R2as(O)p-, -S(0)2NR2-, -NR2S(0)2-, -NR2S(0)2CR2R2a_,
`
`-CR2R2aS(0)2NR2-, -NR2S(0)2NR2-, -C(O)NR2-, -NR2C(O)-,
`
`-C(O)NR2CR2R2a_, -NR2C(O)CR2R2a_, -CR2R2aC(O)NR2-, -CR2R2aNR2C(O)-,
`
`-NR2C(O)O-, -OC{O)NR2-, -NR2C(O)NR2-, -NR2-, -NR2CR2R2a_, -CR2R2aNR2-,
`
`5
`
`0 -CR2R2ao- and-OCR2R2a_.
`'
`'
`'
`
`Y is selected from:
`CH2NR2R2a;
`CH2CH2NR 2R 2a;
`
`10
`
`C3_10 carbocyclic residue substituted with 0-2 R4a, and
`
`5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from
`
`the group consisting ofN, 0, and S substituted with 0-2 R4a;
`
`R4, at each occurrence, is selected from H, =O, (CH2)rOR2, F, Cl, Br, I, Ct-4 alkyl, -CN,
`
`15
`
`N02, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a,
`
`NR2C(O)NR2R2a, C(=NR2)NR2R2a, C(=NS(0)2R5)NR2R2a,
`
`NHC{=NR2)NR2R2a, C(O)NHC(=NR2)NR2R2a, S02NR2R2a, NR2S02NR2R2a,
`
`NR2S02-C1-4 alkyl, NR2S02R5, S(O)pR5, (CF2)rCF3, NCH2Rl'', OCH2Rl",
`SCH2Rl", N(CH2)2(CH2)tR1', O(CH2h(CH2)tR1', and S(CH2)2(CH2)1Rl';
`
`20
`
`alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4
`
`heteroatoms selected from the group consisting ofN, 0, and S;
`
`R4a, at each occurrence, is selected from H, =O, (CH2)rOR2, (CH2)r-F, (CH2)r-Br, (CH2)r
`
`25
`
`Cl, Cl, Br, F, I, C1-4 alkyl, -CN, N02, (CH2)rNR2R2a, (CH2)rC(O)R2c,
`
`~R2C(O)R2b, C(O)NR2R2a, (CH2)rN=CHOR3, C(O)NH(CH2)2NR2R2a,
`
`NR2C(O)NR2R2a, C{=NR2)NR2R2a, NHC(=NR2)NR2R2a, S02NR2R2a,
`
`NR2S02NR2R2a, NR2S02-C1-4 alkyl, C(O)NHSQz-C14 alkyl, NR2S02R5,
`
`S(O)pR5, and (CF2)rCF3;
`
`30
`
`13
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4
`
`heteroatoms selected from the group consisting ofN, 0, and S substituted with 0-1
`
`R5·
`'
`
`5 R4h, at each occurrence, is selected from H, =O, (CH2)rOR3, F, Cl, Br, I, Ct-4 alkyl, -CN,
`
`N02, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a,
`
`C(O)NR3R3a, NR3C(O)NR3R3a, C(=NR3)NR3R3a, NR3C(=NR3)NR3R3a,
`
`S02NR3R3a, NR3S02NR3R3a, NR3S02-C1-4 alkyl, NR3S02CF3, NR3S02-
`
`phenyl, S(O)pCF3, S(O)p-Ct-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
`
`10
`
`R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6,
`
`and benzyl substituted with 0-2 R6;
`
`R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C14 alkyl, CN, N02,
`
`15
`
`(CH2)rNR2R2a,(CH2)rC(O)R2h, NR2C(O)R2h, NR2C(O)NR2R2a, C(=NH)NH2,
`
`NHC(=NH)NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S02C14 alkyl;
`
`R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6
`
`alkoxy, C14 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl,
`
`20
`
`C6-IO arylmethylcarbonyl, C14 alkylcarbonyloxy Ci-4 alkoxycarbonyl, C6-IO
`
`arylcarbonyloxy C14 alkoxycarbonyl, C1-6 alkylaminocarbonyl,
`
`phenylaminocarbonyl, and phenyl C14 alkoxycarbonyl;
`
`RB, at each occurrence, is selected from H, Ct-6 alkyl and (CH2)n-phenyl;
`
`25
`
`altematiyely, R7 and R8 combine to form a 5 or 6 membered saturated, ring which
`
`contains from 0-1 additional heteroatoms selected from the group consisting ofN,
`
`0, and S;
`
`30 R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
`
`14
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`n, at each occurrence, is selected from 0, I, 2, and 3;
`
`m, at each occurrence, is selected from 0, I, and 2;
`
`5
`
`p, at each occurrence, is selected from 0, I, and 2;
`
`r, at each occurrence, is selected from 0, 1, 2, and 3;
`
`s, at each occurrence, is selected from 0, 1, and 2; and,
`
`10
`
`t, at each occurrence, is selected from 0, I, 2, and 3.
`
`[2]
`
`In a preferred embodiment, the present invention provides a novel compound,
`
`15 wherein the compound is selected from the group:
`
`20
`
`15
`
`

`
`
`WO 00/39131WO 00/39131
`WO 00/39131
`
`PCT/US99/30316
`
`PCT/US99/30316PCT/US99/30316
`
`5
`
`0
`
`16
`
`

`
`WO 00/39131
`
`zj) 2 1
`
`~P \
`I
`N
`'A-B N ~
`G-tJ )s O G )s
`
`'-N
`
`PCT/US99/30316
`
`0
`
`0
`
`;lf)
`
`N
`'A-B
`
`N
`"-
`N
`G~ )s
`0 HN)
`
`0
`
`\
`
`N
`'A-B
`
`J(H
`yo
`l
`G-tJ ) s
`
`N
`A-B
`
`0
`
`N
`"
`
`N
`
`NH
`
`yo
`
`N
`A-B
`
`N
`
`N
`"
`G~ )s
`
`r):;Y0
`
`N
`A-B
`
`0
`
`oyo
`
`N
`A-B
`
`G
`
`G
`
`G
`
`wherein compounds of the above formulas are substituted with 0-2 R3;
`
`G is selected from the group:
`
`17
`
`5
`
`10
`
`

`
`WO 00/39131
`W0 00/39131
`
`,
`
`PCT/US99/30316
`PCT/US99/30316
`
`OCH3
`
`NH;
`
`Cl
`
`NH2
`
`CH2NH2
`
`CHZNHZ
`
`CH2NH2 /
`\ I
`
`F
`
`F
`
`CHZNHZ
`
`F©zCH2NH2 CH2NH2
`
`HZNHZC
`
`%}
`
`OCH3
`
`©%:r©
`
`H300
`
`OCH3
`
`\0CH3
`
`CH2NH2
`
`CH2NH2
`
`18
`18
`
`

`
`WO 00/39131
`WO 00/39131
`
`V
`
`PCT /US99/303 l 6
`PCT/US99/30316
`
`19
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`N
`,,.-:;:.
`
`,,.-:;:.
`
`0
`
`0
`
`N
`
`0
`
`s
`
`,,,::.
`
`s
`
`NH2
`~ I o
`N
`
`NH2
`
`o
`
`N
`H
`
`,,.-:;:.
`
`,,,::.
`
`N
`H
`
`N
`H
`
`ro ro ro I
`N No
`-o5 -o5 -ro
`-<NO
`--08 ,,.-:;:.
`--08 ,,,::.
`-v8 ,,.-:;:.
`ro y3 ro y5
`-ro ,,.-:;:.
`-o5 ,,,::. 00 ,,,::.
`
`N
`,,,::.
`
`,,,::.
`
`N
`,,,::.
`
`0
`
`N
`I
`
`5 A is selected from one of the following carbocyclic and heterocyclic systems which are
`
`substituted with 0-2 R4;
`
`phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,
`
`thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazo'tYI,
`
`pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3--oxadiazolyl,
`
`I 0
`
`1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,
`
`1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,
`
`\,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl,
`
`indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl,
`
`benzisothiazolyl, and isoindazolyl;
`
`15
`
`Bis selected from: H, Y, and X-Y;
`
`20
`
`

`
`WO 00/39131
`
`PCT /US99/303 l 6
`
`Xis selected from C1.4 alkylene, -C(O)-, -C(=NR)-, -CR2(NR2R2a)-, -C(O)CR2R2a.,
`
`-CR2R2aC(O), -C(O)NR2-, -NR2C(O)-, -C(O)NR2CR2R2a., -NR2C(O)CR2R2a_,
`
`-CR2R2aqo)NR2-, -CR2R2aNR2C(O)-, -NR2C(O)NR2-, -NR2-, -NR2CR2R2a_,
`
`-CR2R2aNR2-, 0, -CR2R2ao-, and -OCR2R2a_;
`
`5
`
`Y is CH2NR2R2a or CH2CH2NR2R2a;
`
`alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems
`
`that are substituted with 0-2 R4a;
`
`I 0
`
`cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl,
`
`pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl,pyrrolyl, pyrrolidinyl,
`
`oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,
`
`oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
`
`1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
`
`15
`
`1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
`
`1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl,
`
`benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and
`
`isoindazolyl;
`
`20
`
`alternatively, Y is selected from the following bicyclic heteroaryl ring systems:
`
`•
`K is selected from 0, S, NH, and N; and,
`
`25
`
`sis 0.
`
`21
`
`

`
`WO 00/39131
`
`PCT /US99/303 l 6
`
`[3]
`
`In a more preferred embodiment, the present invention provides a novel compound,
`
`wherein the compound is selected from the group:
`
`5
`
`A..-B
`
`G
`
`H
`z1 N \
`J I
`N,A-B
`
`\
`
`~
`
`H z-[>
`
`A..-B
`
`\
`
`//
`N"-
`
`0
`
`N
`
`G~ )s
`
`N~
`N'A..-B
`
`\
`
`~--(
`
`N'A..-B
`
`10
`
`G
`
`0
`
`0
`
`G
`
`G
`
`22
`
`

`
`
`W0 00/39131W0 00/39131
`WO 00/39131
`
`
`
`..
`
`PCT/US99/30316
`
`PCT/US99/30316PCT/US99/30316
`
`-):;
`
`\
`N,A-B
`
`0
`
`z
`//
`N"-
`N
`G-tJ )s
`
`-j:;H
`
`0
`
`z
`//
`N"-
`N
`G-+1 )s
`
`\
`N,K9
`
`0
`
`-..:: N
`\
`N,A-B
`
`G
`
`0
`
`0
`
`z1
`I
`N0.
`G
`
`0
`
`5
`
`\
`
`//
`N
`"'-N
`G-tl) s
`
`ZN
`
`N
`'A-B
`
`0
`
`G
`
`23
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`HN~
`
`\
`
`N
`A-B
`
`NH yo
`
`N
`A-B
`
`5
`
`G
`
`G
`
`wherein compounds of the above formulas are substituted with 0-2 R3;
`
`G is selected from the group:
`
`10
`
`24
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`~NH2 ~Cl
`
`NH2
`
`Cl
`
`F
`
`H2N
`
`'o
`
`b
`
`H2N
`
`H2N
`
`\
`s
`
`b
`
`H2N
`
`H2N
`
`H2N
`
`5
`
`\
`0
`
`b
`
`\
`s
`
`b
`
`NH2
`
`-(:6
`
`NH2
`
`6-
`
`N
`H
`
`b
`
`s
`
`b
`
`N
`H
`
`25
`
`Ntcr Ntcr Nb(;(
`Nb)__ Nb)__ Nb)__
`--05 --05
`--08 b
`---65 b
`
`0
`
`b
`
`·--{)[)
`-ro b
`
`

`
`WO 00/39131
`
`PCT /US99/30316
`
`[ 4]
`
`In an even more preferred embodiment, the present invention provides a novel
`
`compound, wherein:
`
`5
`
`G is selected from:
`
`::o-
`::a__
`N~ I h- Co-
`:Xr- H2N
`Ntcr Ntcr
`
`N~ I h-
`
`~ I h-
`
`H2N
`
`~ I h-
`N
`
`'\
`0
`
`~
`
`[5)
`
`In a still more preferred embodiment, the present invention provides a novel
`
`compound, wherein;
`
`A is sel1ected from phenyl, pyridyl, and pyrimidyl, and is substituted with ().2 R4; and,
`
`B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl,
`
`and is substituted with 0-1 R4a;
`
`26
`
`10
`
`15
`
`20
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`R2, at each occurrence, is selected from H, CH3, CH2CH3, cyclopropylmethyl, cyclobutyl,
`
`and cyclopentyl;
`
`R2a, at each occurrence, is Hor CH3;
`
`5
`
`alternatively, R2 and R2a, together with the atom to which they are attached, combine to
`
`form pyrrolidine substituted with 0-2 R4b;
`
`R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, Ct-4 alkyl, (CH2)rNR2R2a,
`
`IO
`
`and (CF 2)rCF 3;
`
`R4a is selected from C1-4 alkyl, CF3, (CH2)rOR2, (CH2)rNR2R2a, S(O)pR5, S02NR2R2a,
`
`and l-CF3-tetrazol-2-yl;
`
`15
`
`R4h, at each occurrence, is selected from H, CH3, and OH;
`
`R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
`
`X is CH2 or C(O);
`
`Y is selected from pyrrolidino and morpholino; and,
`
`r, at each occurrence, is selected from 0, 1, and 2.
`
`20
`
`25
`
`[ 6]
`
`In a further preferred embodiment, the present invention provides a novel
`
`compound, wherein;
`
`A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-
`
`30
`
`phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-
`
`methoxyphenyl; and,
`
`27
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`Bis selected from the group: 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 1-
`
`pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N(cid:173)
`
`dimethylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, l-methyl-2-
`
`imidazolyl, 2-methyl-1-imidazolyl, 2-( dimethylaminomethyl}-1-imidazolyl, 2-(N-
`
`5
`
`( cyclopropylmethyl)aminomethyl)phenyl, 2-(N-( cyclobutyl)aminomethyl)phenyl,
`
`2-(N-( cyclopentyl)aminomethyl)phenyl, and 2-(N-(3-
`
`hydroxypyrrolidinyl)methyl)phenyl
`
`10
`
`[7]
`
`In an even further preferred embodiment, the present invention provides a novel
`
`compound selected from:
`
`1-[ 4-Methoxyphenyl]-3-cyano-6-[2'-methylsulfonyl-3-fluoro-[ 1, 1 ']-biphen-4-yl]-1,4-
`
`dihydropyrazolo-[ 4,3-d]-pyrimidine-5,7-dione;
`
`15
`
`1-[ 4-Methoxyphenyl]-3-(methoxycarbonyl}-6-[2'-aminosulfonyl-3-fluoro-[ 1, l ']-biphen-4-yl]-l ,6-
`
`dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2 '-aminosulfonyl-3-fluoro-[l, l ']-biphen-4-yl]-1,6-
`
`20
`
`dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-(methoxycarbonyl}-6-[2'-aminosulfonyl-[1, 1 ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`25
`
`1-[ 4-Methoxyphenyl]-6-[2'-aminosulfonyl-[1, 1']-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-
`
`pyrimidin-7-one-3-carboxylic acid;
`
`1-[ 4-Methoxyphenyl]-3-( aminocarbonyl)-6-[2'-aminosulfonyl-[1, 1 ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`30
`
`1-[ 4-Methoxyphenyl]-3-cyano-6-[2'-aminosulfonyl-[1, 1']-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-
`
`d]-pyrimidin-7-one;
`
`28
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`1-( 4-Methoxyphenyl]-3-( aminomethyl)-6-[2'-aminosulfonyl-[1, 1 ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-( 4-Methoxyphenyl]-3-( ethoxycarbonyl)-6-[ 4-(2-methylimidazol-l '-yl)phenyl]-1,6-
`
`5
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-(aminocarbonyl)-6-[ 4-(2-methylimidazol-l '-yl)phenyl]-l ,6-
`
`dihydropyrazolo-[4,3-dJ-pyrimidin-7-one;
`
`10
`
`1-[ 4-Methoxyphenyl]-3-( ethoxycarbonyl)-6-[2'-N-pyrrolidinylmethyl-[1, l 'J-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-( ethoxycarbonyl)-6-[2'-N-pyrrolidinylmethyl-[1, l ']-biphen-4-yl]-1,4,5,6-
`
`tetrahydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`15
`
`1-[ 4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2' -N-pyrrolidinylmethyl-[ 1, l ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-cyano-6-[2' -N-pyrrolidinylmethyl-[l, l ']-biphen-4-yl]-1,6-
`
`20
`
`dihydropyrazolo-[4,3-dJ-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl ]-3-( ethoxycarbonyl)-6-[2-fluoro-4-(2-dimethylaminomethylimidazol-1 ' -
`
`yl)phenyl]-1,6-dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`25
`
`1-[2-Aminomethylphenyl]-3-( ethoxycarbonyl)-6-[2'-methylsulfonyl-[ 1, l ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`l-[3-Aminoiminomethylphenyl]-3-methyl-6-[2'-aminosulfonyl-[ 1, l ']-biphen-4-yl]-1,4,5,6-
`
`tetrahydropyrazolo-[3,4-c ]-pyridin-7-one;
`
`30
`
`l-[2-Aminomethylphenyl]-3-methyl-6-[2'-aminosulfonyl-[ 1, 1 ']-biphen-4-yl]-1,4,5,6-
`
`tetrahydropyrazolo-[3,4-c ]-pyridin-7-one;
`
`29
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`1-[3-Aminobenzisoxazol-5 '-yl]-3-methyl-6-[2'-aminosulfonyl-[1,l ']-biphen-4-yl]-1,4,5,6-
`
`tetrahydropyrazolo-[3,4-c ]-pyridin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-cyano-6-[2 '-N ,N-dimethylaminomethyl-[l, I ']-biphen-4-yl]-1,6-
`
`5
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-cyano-5-methyl-6-[2' -N,N-dimethylaminomethyl-[ 1, 1 ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`10
`
`l-[2-Aminomethylphenyl]-3-cyano-6-[2'-methylsulfonyl-3-fluoro-[l, 1 ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2'-aminosulfonyl-[ 1, 1 ']-biphen-4-yl]-1,6-
`
`dihydropyrazolo-[3 ,4-dJ-pyridazin-7-one;
`
`15
`
`1-[ 4-Methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2'-N-pyrrolidinylmethyl-[ 1, 1 ']-biphen-4-yl]-
`
`1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one,
`
`1-(3-Aminobenzisoxazol-5' -yl]-3-trifluoromethyl-6-[ 4-( l-methylimidazol-2 '-yl)phenyl]-
`
`20
`
`1,6-dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-( 4-Methoxyphenyl]-3-( ethoxycarbonyl)-6-[2'-hydroxymethyl-3-fluoro-[1,1 ']-biphen-4-
`
`yl)-1,6-dihydropyrazolo-[ 4,3-:dJ-pyrimidin-7-one;
`
`25
`
`1-( 4-Methoxyphenyl]-3-( ethoxycarbonyl)-6-[2'-N-pyrrolidinylmethyl-3-tluoro-[1, l ']-
`
`biphen-4-yl]-1,6-dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-[ 4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2'-N-pyrrolidinylmethyl-3-tluoro-[1, 1 '](cid:173)
`
`biphen-4-yl]-1,6-dihydropyrazolo-[ 4,3-dJ-pyrimidin-7-one;
`
`30
`
`1-[ 4-Methoxyphenyl ]-3-( aminocarbonyl)-6-[2 '-(3-(R )-hydroxy-N-pyrrolidinylmethyl)-3-
`
`fl uoro-[ 1,1']-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
`
`30
`
`

`
`WO 00/39131
`
`PCT /US99/30316
`
`1-[ 4-Methoxyphenyl]-3-(N-formylaminomethyl)-6-[2 '-methylsulfonyl-3-fluoro-[ I, l '](cid:173)
`
`biphen-4-yl]-1,6-dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-(3-Aminobenzisoxazol-5' -yl]-3-( ethoxycarbonyl)-6-[2'-hydroxymethyl-[1, l ']-biphen-4-
`
`5
`
`yl]-1,6-dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`1-[3-Aminobenzisoxazol-5'-yl]-3-(ethoxycarbonyl)-6-(2'-N-pyrrolidinylmethyl-[l,l '](cid:173)
`
`biphen-4-yl]-l,6-dihydropyrazolo-[ 4,3-d]-pyrimidin-7-one;
`
`10
`
`1-( 4-Methoxyphenyl]-3-trifluoromethyl-7-[2'-methylsulfonyl-[1, 1 ']-biphen-4-yl]-4,5,6, 7-
`
`tetrahydropyrazolo-[3,4-c ]-azepin-8-one;
`
`1-[ 4-Methoxyphenyl]-3-trifluoromethyl-7-[2'-aminosulfonyl-3-fluoro-[1, 1 ']-biphen-4-yl]-
`
`4,5 ,6, 7-tetrahydropyrazolo-[3,4-c ]-azepin-8-one;
`
`15
`
`1-[ 4-Methoxyphenyl]-3-trifluoromethyl-7-[2' -N-pyrrolidinylmethyl-[ 1, 1 ']-biphen-4-yl]-
`
`4,5,6,7-tetrahydropyrazolo-[3,4-c ]-azepin-8-one;
`
`1-[3-Aminobenzisoxazol-5 '-yl]-3-trifluoromethyl-7-[2 '-N-pyrrolidinylmethyl-(1, l ']-
`
`20
`
`biphen-4-yl]-4,5 ,6, 7-tetrahydropyrazolo-[3,4-c ]-azepin-8-one;
`
`1-(3-Aminobenzisoxazol-5 '-yl]-3-trifluoromethyl-7-[2'-N-dimethylaminomethyl-[1, 1 '](cid:173)
`
`biphen-4-yl ]-4,5, 6, 7-tetrahydropyrazolo-[3 ,4-c ]-azepin-8-one;
`
`25
`
`1-[3-Aminobenzisoxazol-5 '-yl]-3-trifluoromethyl-7-[2'-N-isopropylaminomethyl-[1, 1 ']-
`
`biphen-4-yl]-4,5 ,6, 7-tetrahydropyrazolo-[3 ,4-c ]-azepin-8-one;
`
`1-[3-Aminobenzisoxazol-5 '-yl]-3-trifluoromethyl-7-[2 '-(3-(R)-hydroxy-N(cid:173)
`
`pyrrolidinyl)methyl-[ 1, l ']-biphen-4-yl]-4,5,6, 7-tetrahydropyrazolo-[3,4-c ]-azepin-
`
`30
`
`8-one;
`
`31
`
`

`
`WO 00/39131
`
`PCT/US99/30316
`
`1-[3-Aminobenzisoxazol-5 '-yl]-3-trifluoromethyl-7-[2' -(3-(R)-hydroxy-N(cid:173)
`
`pyrrolidinyl)methyl-3-fluoro-[ 1, I ']-biphen-4-yl]-4,5,6, 7-tetrahydropyrazolo-[3, 4-
`
`c ]-azepin-8-one;
`
`5
`
`1-(3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-7-[2' -N-pyrrolidinylmethyl-3-fluoro-
`
`[l, I ']-biphen-4-yl]-4,5,6, 7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
`
`1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-7-[2' -N-dimethylaminomethyl-3-fluoro(cid:173)
`
`[ I, I ']-biphen-4-yl]-4,5,6, 7-tetrahydropyrazolo-[3 ,4-c ]-azepin-8-one;
`
`10
`
`1-[3-Aminobenzisoxazol-5 '-yl]-3-trifluoromethyl-7-[2 '-N-isopropylaminomethyl-3-
`
`fluoro-[ 1, 1 ']-biphen-4-yl]-4,5 ,6, 7-tetrahydropyrazolo-[3 ,4-c ]-azepin-8-one;
`
`1-[ 4-Methoxyphenyl]-3-trifluoromethyl-7-[ 4-(2-dimethylaminomethylimidazol-1 '-yl)-3-
`
`15
`
`fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
`
`1-[ 4-Methoxyphenyl]-3-trifluoromethyl-7-[ 4-(imidazol-l '-yl)-3-fluorophenyl]-4,5,6, 7-
`
`tetrahydropyrazolo-[3,4-c ]-azepin-8-one;
`
`20
`
`1-[2-Aminomethylphenyl]-3-trifluoromethyl-7-(2'-methylsulfonyHl,1 ']-biphen-4-yl]-
`
`4,5 ,6, 7-tetrahydropyrazolo-[3 ,4-c ]-azepin-8-one;
`
`1-[3-Aminobenzisoxazol-5' -yl]-3-methyl-6-[2'-N-pyrrolidinylmethyl-[1, l ']-biphen-4-yl]-
`
`1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c ]-pyridin-7-one;
`
`25
`
`1-[3-Aminobenzisoxazol-5 '-yl]-