(12) United States Patent
`Pinto et al.
`
`I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US006967208B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,967,208 B2
`Nov. 22, 2005
`
`(54) LACTAM-CONTAINING COMPOUNDS AND
`DERIVATIVES THEREOF AS FACTOR XA
`INHIBITORS
`
`(75)
`
`Inventors: Donald J. P. Pinto, Churchville, PA
`(US); Mimi L. Quan, Yardley, PA
`(US); Michael J. Orwat, New Hope,
`PA (US); Yun-Long Li, Wilmington,
`DE (US); Wei Han, Yardley, PA (US);
`Jennifer X. Qiao, Princeton, NJ (US);
`Patrick Y. S. Lam, Chadds Ford, PA
`(US); Stephanie L. Koch, Newark, DE
`(US)
`
`(73) Assignee: Bristol-Myers Squibb Pharma
`Company, Princeton, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 139 days.
`
`(21) Appl. No.: 10/245,122
`
`(22) Filed:
`
`Sep. 17, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2003/0191115 Al Oct. 9, 2003
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/324,165, filed on Sep. 21,
`2001, and provisional application No. 60/402,317, filed on
`Aug. 9, 2002.
`
`(51)
`
`Int. Cl.7 .................... C07D 471/16; A61K 31/437;
`A61P 7/02
`(52) U.S. Cl. ........................ 514/303; 546/119; 546/120
`(58) Field of Search .......................... 514/303; 546/119,
`546/120
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,340,269 A
`3,365,459 A
`3,423,414 A
`5,998,424 A
`6,020,357 A
`6,060,491 A
`6,187,797 Bl
`6,191,159 Bl
`6,271,237 Bl
`6,339,099 Bl
`6,369,227 Bl
`6,399,644 Bl
`6,403,620 Bl
`6,407,256 Bl
`6,413,980 Bl
`6,426,346 Bl
`6,429,205 Bl
`6,436,985 B2
`6,500,855 Bl
`6,548,512 Bl
`6,548,525 B2
`6,569,874 Bl
`6,602,895 B2
`6,630,468 B2
`6,673,810 B2
`
`9/1967 Blatter .................... 260/294.7
`1/1968 Blatter ....................... 260/296
`1/1969 Blatter ....................... 260/296
`12/1999 Galemmo et al.
`.......... 514/269
`2/2000 Pinto et al. ................. 514/406
`5/2000 Pruitt et al. . . . . . . . . . . . . . . . . . 514/355
`2/2001 Pruitt et al.
`2/2001 Pinto .......................... 514/406
`8/2001 Galemmo et al.
`.......... 514/256
`1/2002 Lam et al.
`4/2002 Lam et al.
`6/2002 Wexler et al.
`6/2002 Galemmo, Jr. et al.
`6/2002 Pinto
`7/2002 Fevig et al.
`7/2002 Pruitt et al.
`8/2002 Jacobson et al.
`8/2002 Pinto
`12/2002 Lam et al.
`4/2003 Pinto et al.
`4/2003 Galemmo, Jr. et al.
`5/2003 Pruitt et al.
`8/2003 Galemmo, Jr. et al.
`10/2003 Pinto
`1/2004 Lam et al.
`
`6,689,770 B2
`6,706,730 B2
`6,716,841 B2
`6,750,225 B2
`2002/0025963 Al
`2003/0018023 Al
`2003/0069237 Al
`2003/0069258 Al
`2003/0078255 Al
`2003/0181466 Al
`2003/0212054 Al
`2003/0232804 Al
`2004/0038980 Al
`2004/0063772 Al
`2004/0073029 Al
`
`2/2004 Wexler et al.
`3/2004 Pinto
`4/2004 Jacobson et al.
`6/2004 Pinto et al.
`2/2002 Lam et al.
`1/2003 Pinto et al.
`4/2003 Fevig et al.
`4/2003 Lam et al.
`4/2003 Pinto
`9/2003 Zhou et al.
`11/2003 Quan et al.
`12/2003 Pinto et al.
`2/2004 Lam et al.
`4/2004 Quan et al.
`4/2004 Pruitt et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`W09420460
`W09612720
`W09828269
`W09828282
`W09852948
`W09857934
`W09857937
`W09857951
`W09932454
`W09932477
`W09950255
`W00039108
`W00039131
`W00059902
`W00105784
`W00119798
`W00132628
`WO 02/074765
`W02003048158
`W02003049681
`W02003099276
`W02004083174
`W020040831747
`
`1/1994
`5/1996
`7/1998
`7/1998
`11/1998
`12/1998
`12/1998
`12/1998
`7/1999
`7/1999
`10/1999
`7/2000
`7/2000
`10/2000
`1/2001
`3/2001
`5/2001
`9/2002
`6/2003
`6/2003
`12/2003
`9/2004
`9/2004
`
`OTHER PUBLICATIONS
`
`F. E. Nielsen et al., "Phosphorus Pentoxide in Organic
`Synthesis-I", Tetrahedron, vol. 38, No. 10, pp. 1435-1441,
`1982, RN:83325-18-2.
`
`(Continued)
`
`Primary Examiner-Bruck Kifle
`(74) Attorney, Agent, or Firm-David H. Vance; Jing S.
`Belfield
`
`(57)
`
`ABSTRACT
`
`The present application describes lactam-containing com(cid:173)
`pounds and derivatives thereof of Formula I:
`
`P4-P-M-M4
`
`or pharmaceutically acceptable salt forms thereof, wherein
`ring P, if present is a 5-7 membered carbocycle or hetero(cid:173)
`cycle and ring M is a 5-7 membered carbocycle or hetero(cid:173)
`cycle. Compounds of the present invention are useful as
`inhibitors of trypsin-like serine proteases, specifically factor
`Xa.
`
`103 Claims, No Drawings
`MYLAN EXHIBIT 1007
`
`

`

`US 6,967,208 B2
`Page 2
`
`OIBER PUBLICATIONS
`
`Kumar et al., "Ketene dithioacetals. Part II. Reaction of
`3-cyano-4-methylthio-2(1H)-pyridones with hydrazine
`and quanidine: synthesis of novel substituted and fused
`pyrazolo[ 4,3-c ]pyridone
`and
`pyrido[ 4,3-d]pyrimidine
`derivatives", Journal of the Chemical Society, Perkin Trans-
`
`actions I: Organic and Bio-Organic Chemistry 1978, No. 8,
`pp. 857-862 (abstract).
`
`Elodi et al., "Optimization of conditions for the catalytic
`effect of the factor IXa-factor VIII Complex:Probable role
`of the complex in the amplification of blood coagulation",
`Thromb. Res., vol. 15, pp. 617-629, 1979.
`
`

`

`US 6,967,208 B2
`
`1
`LACTAM-CONTAINING COMPOUNDS AND
`DERIVATIVES THEREOF AS FACTOR XA
`INHIBITORS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`5
`
`2
`
`The present application claims the priority of U.S. Pro(cid:173)
`visional Application No. 60/324,165, filed Sep. 21, 2001; 10
`and the priority of U.S. Provisional Application No. 60/402,
`317, filed Aug. 9, 2002. The present application claims the
`priority benefits of these prior applications, all of which are
`fully incorporated herein by reference.
`
`wherein Y 1 can be N-R6 , R6 can be unsubstituted aryl(cid:173)
`alkyl or unsubstituted heterocyclic-alkyl and R1 can be a
`substituted aryl group. W098/52948 does not mention fac-
`15 tor Xa inhibition or show compounds like those of the
`present invention.
`
`FIELD OF THE INVENTION
`
`U.S. Pat. Nos. 3,365,459, 3,340,269, and 3,423,414 illus(cid:173)
`trate anti-inflammatory inhibitors of the following formula:
`
`This invention relates generally to lactam-containing
`compounds and derivatives thereof 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 of thromboembolic disorders.
`
`20
`
`25
`
`BACKGROUND OF THE INVENTION
`
`W094/20460 describes angiotensin II compounds of the
`following formula:
`
`30
`
`R~3 A
`N
`
`I
`N
`'-R2
`
`R
`
`X
`
`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, exemplifies compounds of the
`present invention.
`
`W099/32477 reports Factor Xa inhibitors of the follow-
`35 ing formula:
`
`wherein X can be a number of substituents and Het can be
`a nitrogen-containing heterobicycle. However, W094/
`20460 does not suggest Factor Xa inhibition or exemplify
`compounds like those of the present invention.
`
`W096/12720 depicts phosphodiesterase type IV and TNF
`production inhibitors of the following formula:
`
`40
`
`45
`
`wherein the inhibitors contain at least three aryl or hetero(cid:173)
`cyclic groups (i.e., C, B, and R3
`) separated by two linking
`groups (i.e., E and D). Compounds of this sort are not
`considered to be part of the present invention.
`
`W000/39131 describes heterobicyclic Factor Xa inhibi-
`50 tors of which the following is an example formula:
`
`55
`
`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 60
`correspond to the compounds of W096/12720.
`Furthermore, W096/12720 does not suggest Factor Xa
`inhibition.
`
`wherein Z is C or N, G is a mono- or bicyclic group, A is a
`cyclic moiety and B is a basic group or a cyclic moiety.
`Compounds specifically described in W000/39131 are not
`considered to be part of the present invention.
`
`W098/52948 details inhibitors of ceramide-mediated sig- 65
`nal transduction. One of the types of inhibitors described is
`of the following formula:
`
`W098/28269, W098/28282, W099/32454, U.S. Pat. No.
`6,020,357, and U.S. Pat. No. 6,271,237 describe Factor Xa
`inhibitors of the following formula:
`
`

`

`wherein ring M is a heterocycle, Z is a linker, A is a ring, B
`is a basic or cylic group, D is a basic moiety, and Eis a ring. 10
`Compounds specifically described in W098/28269, W098/
`28282, W099/32454, U.S. Pat. No. 6,020,357, and U.S. Pat.
`No. 6,271,237 are not considered to be part of the present
`invention.
`W098/57951 describes Factor Xa inhibitors of the fol(cid:173)
`lowing formula:
`
`Compounds specifically described in W099/50255 and U.S.
`Pat. No. 6,191,159 are not considered to be part of the
`present invention.
`W000/59902 describes Factor Xa inhibitors of the fol-
`15 lowing formula:
`
`r.:YYM
`~
`
`3
`
`US 6,967,208 B2
`
`4
`
`-continued
`Rfa Z--/B
`
`Ml JI
`
`'-.N
`
`Rib
`
`Rlb
`
`5
`
`/E'-.. ))s
`
`G
`
`D
`
`r.:YYM
`~
`
`wherein ring M can be a variety of heterocycles and rings
`D-E represent a heterobicyclic group. Compounds specifi(cid:173)
`cally described in W098/57951 are not considered to be part
`of the present invention.
`W098/57934 and U.S. Pat. No. 6,060,491 describe Factor
`Xa inhibitors of the following formula:
`
`20
`
`wherein ring M can be a variety of rings all of which are
`substituted with Z-A-B, Z is a linker, A is a ring, B is a
`sulfonyl-containing heterobicycle, and rings D-E represent
`25 a heterobicyclic group or a 6-membered ring. Compounds
`specifically described in W000/59902 are not considered to
`be part of the present invention.
`WOOl/32628 describes cyano-pyrroles, cyano(cid:173)
`imidazoles, cyano-pyrazoles, and cyano-triazoles that are
`30 Factor Xa inhibitors. Compounds specifically described in
`WOOl/32628 are not considered to be part of the present
`invention.
`WOOl/05784 describes Factor Xa inhibitors of the fol(cid:173)
`lowing formulas:
`
`35
`
`wherein ring M is a 6-membered heteroaryl, Z is a linker, A
`is a ring, B is a basic or cylic group, Dis a basic moiety, and
`E is a ring. Compounds specifically described in W098/
`57934 and U.S. Pat. No. 6,060,491 are not considered to be
`part of the present invention.
`W098/57937 and U.S. Pat. No. 5,998,424 describe Factor
`Xa inhibitors of the following formula:
`
`40
`
`45
`
`R -~M
`
`E~
`
`~
`
`wherein ring M is a variety of rings, ring D is an aromatic
`ring, and R and E are non-basic groups. Compounds spe(cid:173)
`cifically described in W098/57937 and U.S. Pat. No. 5,998,
`424 are not considered to be part of the present invention.
`W099/50255 and U.S. Pat. No. 6,191,159 describe pyra(cid:173)
`zoline and triazoline Factor Xa inhibitors of the following
`formulas:
`
`wherein Z is C or N, G is a mono- or bicyclic ring M, A is
`a linker, B is a basic or cyclic group. Compounds specifi(cid:173)
`cally described in WOOl/05784 are not considered to be part
`55 of the present invention.
`W000/39108 describes Factor Xa inhibitors of the fol(cid:173)
`lowing formula:
`
`wherein ring M can be a variety of heterocycles and rings
`65 D-E represent a heterobicyclic group. Compounds specifi(cid:173)
`cally described in W000/39108 are not considered to be part
`of the present invention.
`
`

`

`5
`WOOl/19798 describes factor Xa inhibitors of the fol(cid:173)
`lowing formula:
`
`US 6,967,208 B2
`
`6
`The present invention provides a novel method of treating
`a patient in need of thromboembolic disorder treatment,
`comprising: administering a compound of the present inven(cid:173)
`tion or a pharmaceutically acceptable salt form thereof in an
`5 amount effective to treat a thromboembolic disorder.
`The present invention provides a novel method, compris(cid:173)
`ing: administering a compound of the present invention or a
`pharmaceutically acceptable salt form thereof in an amount
`effective to treat a thromboembolic disorder.
`The present invention provides novel lactam-containing
`compounds and derivatives thereof for use in therapy.
`The present invention provides the use of novel lactam(cid:173)
`containing 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 lactam-containing
`compounds of Formula I:
`
`P4-P-M-M4
`
`wherein P4 , P, M, and M4 are defined below, or pharmaceu-
`25 tically acceptable salt or prodrug forms thereof, are effective
`factor Xa inhibitors.
`
`A---Q-0-E---G-J-X
`wherein A, D, G, and X can be phenyl or heterocycle.
`However, none of the presently claimed compounds are
`exemplified or suggested in WOOl/19798.
`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 10
`pathway of blood coagulation. The generation of thrombin,
`the final serine protease in the pathway to generate a fibrin
`clot, from its precursor is amplified by formation of pro(cid:173)
`thrombinase complex (factor Xa, factor V, Ca2
`+ and
`phospholipid). Since it is calculated that one molecule of 15
`factor Xa can generate 138 molecules of thrombin (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 of blood coagulation. Thromb.
`Res. 1979, 15, 617-629), inhibition of factor Xa may be 20
`more efficient than inactivation of thrombin in interrupting
`the blood coagulation system.
`Therefore, efficacious and specific inhibitors of factor Xa
`are needed as potentially valuable therapeutic agents for the
`treatment of thromboembolic disorders. It is thus desirable
`to discover new factor Xa inhibitors. In addition, it is also
`desirable to find new compounds with improved pharmaco(cid:173)
`logical characteristics compared with known factor Xa
`inhibitors. For example, it is preferred to find new com(cid:173)
`pounds with improved factor Xa inhibitory activity and 30
`selectivity for factor Xa versus other serine proteases (i.e.,
`trypsin). It is also desirable and preferable to find com(cid:173)
`pounds with advantageous and improved characteristics in
`one or more of the following categories, but are not limited
`to: (a) pharmaceutical properties (e.g., solubility, 35
`permeability, and amenability to sustained release
`formulations); (b) dosage requirements (e.g., lower dosages
`and/or once-daily dosing); (c) factors which decrease blood
`concentration peak-to-trough characteristics ( e.g., clearance
`and/or volume of distribution); (d) factors that increase the 40
`concentration of active drug at the receptor ( e.g., protein
`binding, volume of distribution); ( e) factors that decrease the
`liability for clinical drug-drug interactions (e.g., cytochrome
`P450 enzyme inhibition or induction); (f) factors that
`decrease the potential for adverse side-effects ( e.g., phar- 45
`macological selectivity beyond serine proteases, potential
`chemical or metabolic reactivity, and limited CNS
`penetration); and, (g) factors that improve manufacturing
`costs or feasibility ( e.g., difficulty of synthesis, number of
`chiral centers, chemical stability, and ease of handling).
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`[1] In an embodiment, the present invention provides a
`novel compound of Formula I:
`
`P4-P-M-M4
`
`or a stereoisomer or pharmaceutically acceptable salt
`thereof, wherein;
`M is a 3-10 membered carbocycle or a 4-10 membered
`heterocycle, consisting of: carbon atoms and 1-3 het(cid:173)
`eroatoms selected from 0, S(O)P, N, and NZ2
`;
`ring M is substituted with 0---3 R 1
`a and 0-2 carbonyl
`groups, and there are 0-3 ring double bonds;
`P is fused onto ring M and is a 5, 6, or 7 membered
`carbocycle or a 5, 6, or 7 membered heterocycle,
`consisting of: carbon atoms and 1-3 heteroatoms
`selected from 0, S(O)p, and N;
`ring P is substituted with 0---3 R 1
`a and 0-2 carbonyl
`groups, and there are 0-3 ring double bonds;
`alternatively, ring Pis absent and P 4 is directly attached to
`ring M, provided that when ring Pis absent, P 4 and M 4
`are attached to the 1,2, 1,3, or 1,4 positions of ring M;
`one of P 4 and M 4 is -Z-A-B and the other -G1-G;
`G is a group of Formula Ila or Ilb:
`
`88-I
`-B8
`
`Ila
`
`Ilb
`
`ring D, including the two atoms of Ring E to which it is
`attached, is a 5-6 membered ring consisting of: carbon
`
`50
`
`SUMMARY OF THE INVENTION
`Accordingly, the present invention provides novel lactam(cid:173)
`containing compounds and derivatives thereof that are use-
`ful as factor Xa inhibitors or pharmaceutically acceptable 55
`salts or prodrugs thereof.
`The present invention provides pharmaceutical composi(cid:173)
`tions 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.
`The present invention provides a method for treating
`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 65
`invention or a pharmaceutically acceptable salt or prodrug
`form thereof.
`
`60
`
`

`

`US 6,967,208 B2
`
`7
`atoms and 0-2 heteroatoms selected from the group
`consisting of N, 0, and S(O)P;
`ring D is substituted with 0---2 R and there are 0-3 ring
`double bonds;
`E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, 5
`and pyridazinyl, and is substituted with 1-2 R;
`alternatively, ring D is absent and ring E is selected from
`phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
`pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,
`triazolyl, thienyl, and thiazolyl, and ring E is substi- 10
`tuted with 1-2 R;
`alternatively, ring D is absent and ring E is selected from
`phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
`pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, 15
`triazolyl, thienyl, and thiazolyl, and ring E is substi(cid:173)
`tuted with 1 R and with a 5-6 membered heterocycle
`consisting of: carbon atoms and 1-4 heteroatoms
`selected from the group consisting of N, 0, and S(O)p,
`wherein the 5-6 membered heterocycle is substituted
`with 0-1 carbonyl and 1-2 R and there are 0-3 ring
`double bonds;
`R is selected from H, C1_4 alkyl, F, Cl, Br, I, OH, OCH3,
`OCH 2CH 3, OCH(CH 3) 2, OCH 2CH2CH3, CN,
`C(=NR 8 )NR 7 R 9
`, NHC(=NR 8 )NR 7 R 9
`, ONHC 25
`(=NR8 )NR7 R9
`, NR 8 CH(=NR7
`), NH2 , NH(C 1 _3
`alkyl), N(C1_3 alkyl)2, C(=NH)NH2, CH2NH2,
`CH2NH(C1_3 alkyl), CH2N(C1_3 alkyl)2, CH2CH2NH2,
`CH2CH2NH(C1_3 alkyl), CH2CH2N(C1_3 alkyl)2,
`(CR8 R9),C(O)H, (CR8 R9),C(O)R2C, (CR8 R9),NR7R8
`, 30
`(CR8 R9),C(O)NR7R8
`, (CR8 R9),NR7 C(O)R7
`, (CR8R9
`),
`OR3, (CR8 R9),S(O) NR7 R8
`, (CR8 R9),NR7S(O)PR7
`(CR8 R9),SR3, (CR8 R{,),S(O)R3, (CR8 R9),S(0)2R3, and
`OCF3 ;
`alternatively, when 2 R groups are attached to adjacent 35
`atoms, they combine to form methylenedioxy or eth(cid:173)
`ylenedioxy;
`A is selected from:
`C3_10 carbocycle substituted with 0---2 R4
`, and
`5-12 membered heterocycle consisting of: carbon 40
`atoms and 1-4 heteroatoms selected from the group
`consisting of N, 0, and S(O)P and substituted with
`0-2 R4
`;
`provided that A is other than a dihydro-benzopyran;
`B~
`
`20
`
`,
`
`~
`
`50
`
`55
`
`provided that Z and B are attached to different atoms on
`A and that the A-X-N moiety forms other than a
`N-N-N group;
`provided that B is other than triazolone, quinolone, or
`isoquinolone, wherein the triazolone, quinolone, and
`isoquinolone groups are substituted or unsubstituted;
`Q1 is selected from C=O and S02;
`ring Q is a 4--8 membered monocyclic or bicyclic ring 60
`consisting of, in addition to the N-Q1 group shown,
`carbon atoms and 0---2 heteroatoms selected from NR4C,
`0, S, S(O), and S(0)2, wherein:
`014 2 double bonds are present within the ring and the
`ring is substituted with 0-2 R4a;
`alternatively, ring Q is a 4-8 membered monocyclic or
`bicyclic ring to which another ring is fused, wherein:
`
`65
`
`8
`the 4--7 membered ring consists of, in addition to the
`shown amide group, carbon atoms and 0-2 heteroa(cid:173)
`toms selected from NR4C, 0, S, S(O), and S(0)2 and
`0-2 double bonds are present within the ring;
`the fusion ring is phenyl or a 5-6 membered heteroaro(cid:173)
`matic consisting of carbon atoms and 1-2 heteroat(cid:173)
`oms selected from NR4C, 0, S, S(O), and S(0)2;
`ring Q, which includes the 4--7 membered ring and the
`fusion ring, is substituted with 0-3 R4a;
`alternatively, two non-adjacent atoms of one of the rings
`of ring Q are bridged with 1-2 atoms selected from:
`carbon atoms, NR4C, 0, S, S(O), and S(0)2, provided
`bonds other than 0-0, S(O)P-0, S(O)P-S(O)P,
`N-0, and N-S(O)P are present;
`Xis absent or is selected from ----(CR2R2a)1_4- , -CR2
`(CR2R 2b)(CH 2),-, -C(O)-, -C(=NR1c)-,
`-CR2(NR1cR2)-, -CR2(0R2)-, -CR2(SR2)-,
`-C(O)CR 2R 2a-, -CR 2R 2aC(O), -S(O)-,
`-S(0)2-, -SCR2R2a-, -S(O)CR2R2a-, -S(0)2
`CR2R2a-, -CR2R2aS(O)-, -CR2R2aS(0)2-,
`-S(0) 2NR 2CR 2R 2 a-,
`-NR 2S(0) 2- ,
`-CR 2R2aNR 2S(0)2-, -NR2S(0)2CR 2R2a-,
`-NR2C(O)-, -C(O)NR2CR2R2a-, -NR2C(O)
`CR2R2a_, -CR2R2aNR2C(O)-, -NR2CR2R2a_,
`and -OCR2R2a-;
`G1 is absent or is selected from (CR3R3a)1_5 , (CR3
`R3a)o_2CR3=CR 3(CR 3R 3a)o-2, (CR 3R 3a)o_2C-C
`(CR3R3a)o-2, (CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uc
`(O)O(CR 3R 3a)w, (CR 3R 3a)uOC(O)(CR 3R 3a)w,
`( CR 3R 3aL 0( CR 3R 3a)w, ( CR 3R 3aLN3\ CR 3R 3a)w,
`(CR3R3aLC(O)N3\CR3R3a)w, (CR3R3aLN3bC(O)
`(CR 3R 3a)w, (CR 3R 3a)uOC(O)N3b(CR 3R 3a)w,
`(CR3R3aL N3bC(O)O(CR3R3a)w, (CR3R3aLN3bC(O)
`N3\ CR 3R 3a)w, ( CR 3R 3aLN3bC(S )N3\ CR 3R 3a)w,
`(CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(O)(CR3R3a)w,
`(CR3R 3a)uS(OMCR3R 3a)w, (CR 3R 3a)uS(O)N3b
`(CR3R3a)w, (CR3R3aLN3bS(O)iCR3R3a)w, (CR3R3aL
`S( 0)2N3b( CR 3R 3a)w, (CR 3R 3a)uN3bS( 0)2N3b
`(CR3R3a)w, (CR3R3a)uNR3e(CR3R3a)w, (CR3R3a)uc
`(O)(CR 3R 3a)uC(O)(CR 3R 3a)w, (CR 3R3a)uNR3b
`(CR3R3a)uC(O)NR3\CR3R3a)w, (CR3R3a)uNR3bC(O)
`( CR 3R 3a)u C( Q )( CR 3R 3a)w, ( CR 3R 3a)u C( Q )( CR 3R 3a)u
`C(O)NR3\CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3aL
`C(O)NR3\CR3R3a)w, (CR3R3a)uS(O)NR 3bC(O)
`(CR3R3a)w, (CR3R3a)uC(O)NR3bS(O)iCR3R3a)w, and
`(CR3R3a)uS(0)2NR3bC(O)NR3bCR3R3a)w, wherein
`u+w total 0, 1, 2, 3, or 4, provided that G1 does not form
`an N-S, NCH2N, NCH20, or NCH2S bond with either
`group to which it is attached;
`Z is selected from a bond, ----(CR3R3e)1_4- , (CR3R3e)q0
`(CR3R3e)q1, (CR3R3e)~R3\CR3R3e)q1, (CR3R3e)qC
`( O)(CR 3R 3e\1, (CR 3R 3e)qC( 0)0( CR 3R 3e\1,
`(CR3R3e)qOC(O)(CR3R3e\1, (CR3R3e)qC(O)NR3b
`(CR 3R 3e)q1,
`( CR 3R 3e)qNR 3bC(O )( CR 3R 3e)q1,
`(CR3R3e)qOC(O)O(CR3R3e\1, (CR3R3e)qOC(O)NR3b
`(CR 3R 3e)q1, (CR 3R 3e)qNR 3bC(O)O(CR 3R 3e)q1,
`(CR3R3e)~R3bC(O)NR3\CR3R3e) 1, (CR3R3e) C(O)
`(CR3R3e) C(O)(CR3R3e\1, (CR3Rfe) NR3\CRJR3e)q
`C(O)NR3g(CR3R3e\1, (CR3R3e)qNR3iC(O)(CR3R3e)
`C(O)(CR3R3e)q1, (CR3R3e) C(O)(CR3R3e)qC(O)NR3g
`(CR3R3e)q1, (CR3R3e)qNR3gC(O)(CR3R3e) C(O)NR3b
`(CR3R3e\1, (CR3R3e)qS(CR3R3e\1, (CR3R3e)qS(O)
`(CR3R3e)q1, (CR3R3e)qS(O)iCR3R3e)q1, (CR3R3e)q
`S02NR3\CR3R3e) 1, (CR3R3e)_NR3bS0iCR3R3e\1,
`(CR3R3e)qS(O)NR1bC(O)(CR3R3e\1, (CR3R3e)qC(O)
`NR3bS(O)iCR3R3e)q1, and (CR3R3e)qNR3bS02NR3b
`(CR3R3e)q1, wherein q+ql total 0, 1, 2, 3, or 4, provided
`
`

`

`9
`that Z does not form a N-S, NCH2N, NCH20, or
`NCH2S bond with either group to which it is attached;
`provided that B-A-Z form other than a pyridone(cid:173)
`pheny l-CH2, pyridone-pyridyl-CH2, or pyridone(cid:173)
`pyrimidyl-CH2, wherein the pyridone, phenyl, pyridyl, 5
`and pyrimidyl groups are substituted or unsubstituted;
`Z2 is selected from H, S(0)2NHR3b, C(O)R3b, C(O)
`NHR 3b, C(O)OR3f, S(O)R31, S(0)2R31, C1_6 alkyl sub(cid:173)
`stituted with 0---2 R 1a, C2_6 alkenyl substituted with 0-2
`R 1a, C2_6 alkynyl substituted with 0-2 R 1a, ----(C0 _4
`alkyl)-C3_10 carbocycle substituted with 0---3 R 1a, and
`----(C0 _4 alkyl)-5-10 membered heterocycle substituted
`with 0-3 R 1
`a and consisting of: carbon atoms and 1-4
`heteroatoms selected from the group consisting of N,
`0, and S(O)P;
`R1a, at each occurrence, is selected from H, ----(CR3
`R3a)r-R1b, -(CR3R3a)r-CR3R1bR1b, -(CR3
`R3at-O----(CR3R3at-R1b, -C2_6 alkenylene-R1b,
`-C2_6 alkynylene-R1b, -(CR3R3a)r-C(=NR1b)
`NR3R1b NR3CR3R3aR1c OCR3R3aR1c SCR3R3aR1c 20
`NR 3(CR 3R3a)iCR 3R3a),R lb, C(O)NR2(CR 3R3a)~
`( CR 3R 3a),R 1b, CO2( CR 3R 3a)2( CR 3R 3a),R 1b,
`0( CR 3R 3a)i CR 3R 3a),R 1b, S( CR 3R 3a)i CR 3R 3a),R 1b,
`S(O)p(CR3R3a)~ld, O(CR3R3a)rR1d, NR3(CR3R3a)r
`R 1a, OC(O)NR3(CR3R3atR1a, NR3C(O)NR3(CR3 25
`R 3a)rR1a, NR3C(O)O(CR3R3a)rR1a, and NR3C(O)
`(CR3R3a)rR1a, provided that R 1
`a forms other than an
`N-halo, N-S, 0-0, or N-CN bond;
`alternatively, when two R 1
`a groups are attached to adja-
`cent atoms, together with the atoms to which they are
`attached they form a 5-7 membered ring consisting of:
`carbon atoms and 0-2 heteroatoms selected from the
`group consisting of N, 0, and S(O)p, this ring being
`substituted with 0---2 R4b and 0-3 ring double bonds;
`b is selected from H, C1_3 alkyl, F, Cl, Br, I, -CN,
`-N02, -CHO, (CF2)rCF3, (CR3R3a)rOR2, NR2R2a,
`C(O)R2b, C02R2b, OC(O)R2, (CF2)rC02R2a, S(O)p
`b, NR2(CH2)rOR2, C(=NR2c)NR2R2a, NR2C(O)
`R2
`b, NR2C(O)NHR2, NR2C(0)2R2a, OC(O)NR2R2a, 40
`R2
`C(O)NR2R2a, C(O)NR2(CH2)rOR2, S02NR2R2a,
`NR2S02R2, C(O)NR2S02R2, C3_6 carbocycle substi(cid:173)
`tuted with 0---2 R4b, and 5-10 membered heterocycle
`consisting of carbon atoms and from 1-4 heteroatoms
`selected from the group consisting of N, 0, and S(O)P, 45
`and substituted with 0---2 R4b, provided that R 1
`b forms
`other than an 0-0, N-halo, N-S, or N-CN bond;
`R1c is selected from H, CH(CH20R2)2, C(O)R2C, C(O)
`NR2R2a, S(O)R2, S(0)2R2, and S02NR2R2a;
`R1 a is selected from C3_6 carbocycle substituted with 0-2 50
`R4b and 5-10 membered heterocycle consisting of
`carbon atoms and from 1-4 heteroatoms selected from
`the group consisting ofN, 0, and S(O)P, and substituted
`with 0-2 R4b, provided that R 1 a forms other than an
`N-S bond;
`R2, at each occurrence, is selected from H, CF3, C1_6
`alkyl, benzyl, -(CH2)r-C3_10 carbocycle substituted
`with 0---2 R4b, and -(CH2)r-5-10 membered hetero(cid:173)
`cycle consisting of: carbon atoms and 1-4 heteroatoms
`selected from the group consisting of N, 0, and S(O)p, 60
`and substituted with 0-2 R4b;
`R2 a, at each occurrence, is selected from H, CF3, C1_6
`alkyl, benzyl, -(CH2)r-C3_10 carbocycle substituted
`with 0---2 R4b, and -(CH2)r-5-10 membered hetero(cid:173)
`cycle consisting of: carbon atoms and 1-4 heteroatoms 65
`selected from the group consisting of N, 0, and S(O)p,
`and substituted with 0-2 R4b;
`
`R1
`
`30
`
`35
`
`55
`
`US 6,967,208 B2
`
`10
`
`15
`
`R2
`
`10
`alternatively, R2 and R2 a, together with the atom to which
`they are attached, combine to form a 5 or 6 membered
`saturated, partially saturated or unsaturated ring sub(cid:173)
`stituted with 0-2 R4b and consisting of: 0-1 additional
`heteroatoms selected from the group consisting of N,
`0, and S(O)P;
`b, at each occurrence, is selected from CF3, C1_4 alkoxy
`substituted with 0-2 R4b, C1_6 alkyl substituted with
`0---2 R4 b, -(CH2)r-C3_10 carbocycle substituted with
`0---2 R4b, and -(CH2)r-5-10 membered heterocycle
`consisting of: carbon atoms and 1-4 heteroatoms
`selected from the group consisting of N, 0, and S(O)P,
`and substituted with 0-2 R4b;
`R2C, at each occurrence, is selected from CF3, OH, C1_4
`alkoxy, C1_6 alkyl, ----(CH2t-C3_10 carbocycle substi(cid:173)
`tuted with 0-2 R4b, and -(CH2)r-5-10 membered
`heterocycle containing from 1-4 heteroatoms selected
`from the group consisting of N, 0, and S(O)P, and
`substituted with 0-2 R4b;
`R 3, at each occurrence, is selected from H, CH3, CH2CH3,
`CH2CH2 CH3 , CH(CH3) 2 , CH2 CH2CH2 CH3 , CH2 CH
`(CH3 ) 2 , CH(CH3)CH2 CH3 , C(CH3 ) 3 , benzyl, and phe(cid:173)
`nyl;
`R 3 a, at each occurrence, is selected from H, CH3 ,
`CH2CH3 , CH2CH2 CH3 , CH(CH3) 2 , CH2CH2 CH2CH3 ,
`CH2CH(CH3) 2 , CH(CH3)CH2 CH3 , C(CH3 ) 3 , benzyl,
`and phenyl;
`alternatively, R3 and R3 a, together with the nitrogen atom
`to which they are attached, combine to form a 5 or 6
`membered saturated, partially unsaturated, or unsatur(cid:173)
`ated ring consisting of: carbon atoms, the nitrogen atom
`to which R3 and R3
`a are attached, and 0-1 additional
`heteroatoms selected from the group consisting of N,
`0, and S(O)P;
`b, at each occurrence, is selected from H, C1_6 alkyl
`substituted with 0-2 R 1a, C2_6 alkenyl substituted with
`0---2 R1a, C2_6 alkynyl substituted with 0-2 R 1a, -(C0 _4
`alkyl)-5-10 membered carbocycle substituted with 0-3
`R 1a, and -(C0 _4 alkyl)-5-10 membered heterocycle
`substituted with 0-3 R 1
`a and consisting of: carbon
`atoms and 1-4 heteroatoms selected from the group
`consisting of N, 0, and S(O)P;
`R3C, at each occurrence, is selected from CH3, CH2CH3,
`CH2CH2 CH3 , CH(CH3) 2 , CH2 CH2CH2 CH3 , CH2 CH
`(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phe(cid:173)
`nyl;
`R 3 a, at each occurrence, is selected from H, CH3,
`CH2CH3 , CH2CH2 CH3 , CH(CH3) 2 , CH2CH2 CH2CH3 ,
`CH2CH(CH3)2, CH(CH3)CH2CH3, C1_4 alkyl-phenyl,
`and C(=O)R3°;
`R3e, at each occurrence, is selected from H, S02NHR3,
`S02NR3R3, C(O)R3, C(O)NHR3, C(O)OR3t, S(O)R3t,
`S(0)2R31, C1_6 alkyl substituted with 0-2 R 1a, C2_6
`alkenyl substituted with 0-2 R 1a, C2_6 alkynyl substi(cid:173)
`tuted with 0-2 R 1a, -(C0 _4 alkyl)-5-10 membered
`carbocycle substituted with 0-3 R 1a, and -(C0 _4
`alkyl)-5-10 membered heterocycle substituted with
`0---3 R 1
`a and consisting of: carbon atoms and 1-4
`heteroatoms selected from the group consisting of N,
`0, and S(O)P;
`R3f, at each occurrence, is selected from: C1_6 alkyl
`substituted with 0-2 R 1a, C2_6 alkenyl substituted with
`0---2 R 1a, C2_6 alkynyl substituted with 0-2 R 1a, -(C0 _4
`alkyl)-5-10 membered carbocycle substituted with 0-3
`R 1a, and -(C0 _4 alkyl)-5-10 membered heterocycle
`
`R3
`
`

`

`US 6,967,208 B2
`
`20
`
`11
`substituted with 0-3 R 1
`a and consisting of: carbon
`atoms and 1-4 heteroatoms selected from the group
`consisting of N, 0, and S(O)P;
`R4, at each occurrence, is selected from H, =0,
`(CR3R3a)r OR2, F, Cl, Br, I, C1_4 alkyl, (CR3R3atCN, 5
`(CR3R3a)rN02, (CR3R3a)rNR2R2a, (CR3R3a)rC(O)
`R2C, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a,
`(CR3R 3 a)rNR 2C(O)NR 2R2a, (CR3R 3a)rC(=NR2)
`NR2R2a, (CR 3 R3 a)rC(=NS(0)2Rs)NR2R2a, (CR 3
`R3 atNHC(=NR2)NR2R2a, (CR 3 R3 atC(O)NHC 10
`(=NR2)NR2R2a, (CR3R3a)rS02NR2R2a, (CR3R3a)r
`NR2S0 2NR2R2a, (CR 3 R3 atNR2S0 2-C1_4 alkyl,
`(CR3R3a)rNR2S02Rs, (CR3R3a)rS(O)pRsa, (CR3R3a)r
`(CF2)rCF 3 , NHCH 2R1C, OCH 2R1C, SCH2R1C,
`NH(CH2)iCH2),R1b, O(CH2)iCH2),R1b, S(CH2)2 15
`(CH2),R1b, (CR3R3a)r-5-6 membered carbocycle sub(cid:173)
`stituted with 0-1 Rs, and a (CR3R3at-5-6 membered
`heterocycle consisting of: carbon atoms and 1-4 het(cid:173)
`eroatoms selected from the group consisting of N, 0,
`and S(O)P and substituted with 0-1 Rs;
`R4a, at each occurrence, is selected from H, =0,
`(CR3R3a)rOR2, (CR3R3a)~, (CR3R3a)rBr, (CR3R3a)r
`Cl, C14 alkyl, (CR3R3a)rCN, (CR3R3a)~02, (CR3
`R3a)rNR2R2a, (CR3 R3a)rC(O)R2C, (CR3 R3a)~R2C(O)
`b, (CR3R3atC(O)NR2R2a, (CR3R3a)~=CHOR3, 25
`R2
`( CR 3R 3 a)rC( 0 )NH( CH2)2NR 2R 2 a, ( CR 3R 3 a)rNR 2C
`(O)NR2R2a, (CR 3 R3 atC(=NR2)NR2R2a, (CR 3
`R3a)rNHC(=NR2)NR2R2a, (CR 3 R3 a)rS02NR2R2a,
`(CR3R3a)~R2S02NR2R2a, (CR3R3a)~R2S02-C1_4
`alkyl, (CR3R3a)rC(O)NHS02-C1_4 alkyl, (CR3R3a) 30
`NR2S02Rs, (CR3R3a)rS(O)pRsa, (CR3R3a)r{CF2)rCF3,
`(CR3R3a)r-5-6 membered carbocycle substituted with
`0-1 Rs, and a (CR3R3a)r-5-6 membered heterocycle
`consisting of: carbon atoms and 1-4 heteroatoms
`selected from the group consisting of N, 0, and S(O)p, 35
`and substituted with 0-1 Rs;
`R4b, a; each occurrence, is selected from H, =0, (CH2t
`OR , (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)), C1_4 alkyl,
`(CH2)rCN, (CH2)~02, (CH2)rNR3R3a, (CH2)rC(O) 40
`R3, (CH2)rC(O)OR3C, (CH2)~R3C(O)R3a, (CH2)r-C
`(O)NR3R3a, (CH2)rNR3C(O)NR3R3a, (CH2)r-C
`(=NR 3 )NR 3 R3 a, (CH2tNR 3 C(=NR 3 )NR 3 R 3 a,
`(CH2)r S02NR3R3a, (CH2)~R3S02NR3R3a, (CH2)r
`NR3S02-C1_4 alkyl, (CH2tNR3S02CF3, (CH2t
`NR3S02-phenyl, (CH2)rS(O)PCF3 , (CH2)rS(O)P-C1_4
`alkyl, (CH2)rS(O)P-phenyl, and (CH2)r{CF2)rCF3;
`R4C, at each occurrence, is selected from H, C1_4 alkyl
`(CR3R3a)r10R2, (CR3R3a)r1F, (CR3R3a)r1Br, (CR3
`R 3 a)r1 Cl, (CR 3 R 3 a)r1 CN, (CR3R 3 a)r1 N02, (CR 3 50
`R3at1NR2R2a, (CR3R3atC(O)R2C, (CR3R3a)r1NR2C
`(O)R2b, (CR3R3a)rC(O)NR2R2\ (CR3R3a)r1
`N=CHOR 3, (CR3R3atC(O)NH(CH2)2NR2R 2 a,
`(CR3R3a)r1 NR2C(O)NR2R2a, (CR3R3a)r1 C(=NR2)
`NR2R2a, (CR3R3a)r1NHC(=NR2)NR2R2a, (CR3R3a)r 55
`S02NR2R2a, (CR 3 R 3 a)r1NR2S02NR2R2a, (CR 3
`R3a)r1NR2S02-C1_4 alkyl, (CR3R3a)rC(O)NHS02-
`c1-4 alkyl, (CR3R3at1NR2S02Rs, (CR3R3a)rS(O)PRsa,
`(CR3R3a)r{CF2)rCF3, (CR3R3a)r-5-