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US20030004344A1 - Thrombin or factor Xa inhibitors - Google Patents

Thrombin or factor Xa inhibitors Download PDF

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US20030004344A1
US20030004344A1 US10/033,137 US3313702A US2003004344A1 US 20030004344 A1 US20030004344 A1 US 20030004344A1 US 3313702 A US3313702 A US 3313702A US 2003004344 A1 US2003004344 A1 US 2003004344A1
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phenyl
methyl
pyridyl
pyrimidyl
imidazolyl
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Patrick Lam
Charles Clark
Renhau Li
Donald Pinto
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
  • 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, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca 2+ and phospholipid).
  • factor Xa Since it is calculated that one molecule of 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 more efficient than inactivation of thrombin in interrupting the blood coagulation system.
  • one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
  • 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 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.
  • the present invention provides a novel compound selected from the group:
  • ring D is selected from —(CH 2 ) 3 —, —CH 2 CH ⁇ CH—, —CH 2 N ⁇ CH—, and a 5 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present;
  • ring D 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, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , CH 2 NH 2 , CH 2 NH(C 1-3 alkyl), CH 2 N(C 1-3 alkyl) 2 , CH 2 CH 2 NH 2 , CH 2 CH 2 NH(C 1-3 alkyl), and CH 2 CH 2 N(C 1-3 alkyl) 2 ;
  • M is selected from the group:
  • J is O or S
  • J a is NH or NR 1a ;
  • Z is selected from (CR 8 R 9 ) 1-4 , (CR 8 R 9 ) r O(CR 8 R 9 ) r , (CR 8 R 9 ) r NR 3 (CR 8 R 9 ) r , (CR 8 R 9 ) r C(O)(CR 8 R 9 ) r , (CR 8 R 9 ) r C(O)O(CR 8 R 9 ) r , (CR 8 R 9 ) r OC(O)(CR 8 R 9 ) r , (CR 8 R 9 ) r C(O)NR 3 (CR 8 R 9 ) r , (CR 8 R 9 ) r NR 3 C(O)(CR 8 R 9 ) r , (CR 8 R 9 ) r OC(O)O(CR 8 R 9 ) r , (CH 2 ) r OC(O)NR 3 (CR 8 R 9 ) r , (CR 8 R 9 ) r NR 3 C(CH 2
  • R 1a is selected from H, —(CH 2 ) r —R 1′ , —CH ⁇ CH—R 1′ , NHCH 2 R 1′′ , OCH 2 R 1′′ , SCH 2 R 1′′ , NH(CH 2 ) 2 (CH 2 ) t R 1′ , O(CH 2 ) 2 (CH 2 ) t R 1′ , and S(CH 2 ) 2 (CH 2 ) t R 1′ ;
  • R 1′ is selected from H, C 1-3 alkyl, F, Cl, Br, I, —CN, —CHO, (CF 2 ) r CF 3 , (CH 2 ) r OR 2 , NR 2 R 2a , C(O)R 2c , OC(O)R 2 , (CF 2 ) r CO 2 R 2c , S(O) p R 2b , NR 2 (CH 2 ) r OR 2 , C( ⁇ NR 2c )NR 2 R 2a , NR 2 C(O)R 2b , NR 2 C(O)NHR 2b ,NR 2 C(O) 2 R 2a , OC(O)NR 2a R 2b , C(O)NR 2 R 2a , C(O)NR 2 (CH 2 ) r OR 2 , SO 2 NR 2 R 2a , NR 2 SO 2 R 2b , C 3-6 carbocyclic residue substituted with 0-2 R 4 , and
  • R 1′′ is selected from H, CH(CH 2 OR 2 ) 2 , C(O)R 2c , C(O)NR 2 R 2a , S(O)R 2b , S(O) 2 R 2b , and SO 2 NR 2 R 2a ;
  • R 2 is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;
  • R 2a is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 cycloalkylmethyl substituted with 0-2 R 4b , C 3-6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;
  • R 2b is selected from CF 3 , C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;
  • R 2c is selected from CF 3 , OH, C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;
  • R 2 and R 2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R 4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
  • R 2 and R 2a 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 R 4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
  • R 3 at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;
  • R 3a at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;
  • R 3b at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;
  • R 3c at each occurrence, is selected from C 1-4 alkyl, and phenyl;
  • A is selected from: C 3-10 carbocyclic residue substituted with 0-2 R 4 , and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4 ;
  • B is selected from: X—Y, NR 2 R 2a , C( ⁇ NR 2 )NR 2 R 2a , NR 2 C( ⁇ NR 2 )NR 2 R 2a , C 3-10 carbocyclic residue substituted with 0-2 R 4a , and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4a ;
  • X is selected from C 1-4 alkylene, —CR 2 (CR 2 R 2b )(CH 2 ) t —, —C(O)—, —C( ⁇ NR 1′′ )—, —CR 2 (NR 1′′ R 2 )—, —CR 2 (OR 2 )—, —CR 2 (SR 2 )—, —C(O)CR 2 R 2a —, —CR 2 R 2a C(O), —S(O) p —, —S(O) p CR 2 R 2a —, —CR 2 R 2a S(O) p —, —S(O) 2 NR 2 —, —NR 2 S(O) 2 —, —NR 2 S(O) 2 —, —NR 2 S(O) 2 CR 2 R 2a —, —CR 2 R 2a S(O) 2 NR 2 —, —NR 2 S(O) 2 —, —NR 2 S(O) 2
  • Y is selected from: (CH 2 ) r NR 2 R 2a , provided that X—Y do not form a N—N, O—N, or S—N bond, C 3-10 carbocyclic residue substituted with 0-2 R 4a , and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4a ;
  • R 4 is selected from H, ⁇ O, (CH 2 ) r OR 2 , F, Cl, Br, I, C 1-4 alkyl, —CN, NO 2 , (CH 2 ) r NR 2 R 2a , (CH 2 ) r C(O)R 2c , NR 2 C(O)R 2b , C(O)NR 2 R 2a , NR 2 C(O)NR 2 R 2a , C( ⁇ NR 2 )NR 2 R 2a , C( ⁇ NS(O) 2 R 5 )NR 2 R 2a , NHC( ⁇ NR 2 )NR 2 R 2a , C(O)NHC( ⁇ NR 2 )NR 2 R 2a , SO 2 NR 2 R 2a , NR 2 SO 2 NR 2 R 2a , NR 2 SO 2 —C 1-4 alkyl, NR 2 SO 2 R 5 , S(O) p R 5 , (CF 2 ) r
  • one R 4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
  • R 4a is selected from H, ⁇ O, (CH 2 ) r OR 2 , (CH 2 ) r —F, (CH 2 ) r —Br, (CH 2 ) r Cl, Cl, Br, F, I, C 1-4 alkyl, —CN, NO 2 , (CH 2 ) r NR 2 R 2a , (CH 2 ) r C(O)R 2c , NR 2 C(O)R 2b , C(O)NR 2 R 2a , C(O)NH(CH 2 ) 2 NR 2 R 2a , NR 2 C(O)NR 2 R 2a , C( ⁇ NR 2 )NR 2 R 2a , NHC( ⁇ NR 2 )NR 2 R 2a , SO 2 NR 2 R 2a , NR 2 SO 2 NR 2 R 2a , NR 2 SO 2 —C 1-4 alkyl, C(O)NHSO 2 —C 1-4 alkyl, C(O)NHSO 2
  • one R 4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R 5 ;
  • R 4b is selected from H, ⁇ O, (CH 2 ) r OR 3 , F, Cl, Br, I, C 1-4 alkyl, —CN, NO 2 , (CH 2 ) r NR 3 R 3a , (CH 2 ) r C(O)R 3 , (CH 2 ) r C(O)OR 3c , NR 3 C(O)R 3a , C(O)NR 3 R 3a , NR 3 C(O)NR 3 R 3a , C( ⁇ NR 3 )NR 3 R 3a , NR 3 C( ⁇ NR 3 )NR 3 R 3a , SO 2 NR 3 R 3a , NR 3 SO 2 NR 3 R 3a , NR 3 SO 2 NR 3 R 3a , NR 3 SO 2 —C 1-4 alkyl, NR 3 SO 2 CF 3 , NR 3 SO 2 -phenyl, S(O) p CF 3 , S(O) p —C 1-4 al
  • R 5 is selected from CF 3 , C 1-6 alkyl, phenyl substituted with 0-2 R 6 , and benzyl substituted with 0-2 R 6 ;
  • R 6 is selected from H, OH, (CH 2 ) r OR 2 , halo, C 1-4 alkyl, CN, NO 2 , (CH 2 ) r NR 2 R 2a ,(CH 2 ) r C(O)R 2b , NR 2 C(O)R 2b , NR 2 C(O)NR 2 R 2a , C( ⁇ NH)NH 2 , NHC( ⁇ NH)NH 2 , SO 2 NR 2 R 2a , NR 2 SO 2 NR 2 R 2a , and NR 2 SO 2 C 1-4 alkyl;
  • R 7 is selected from H, OH, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-4 alkoxycarbonyl, (CH 2 ) n -phenyl, C 6-10 aryloxy, C 6-10 aryloxycarbonyl, C 6-10 arylmethylcarbonyl, C 1-4 alkylcarbonyloxy C 1-4 alkoxycarbonyl, C 6-10 arylcarbonyloxy C 1-4 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C 1-4 alkoxycarbonyl;
  • R 8 at each occurrence, is selected from H, C 1-6 alkyl and (CH 2 ) n -phenyl;
  • R 7 and R 8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
  • R 9 at each occurrence, is selected from H, C 1-6 alkyl and (CH 2 ) n -phenyl;
  • n at each occurrence, is selected from 0, 1, 2, and 3;
  • m at each occurrence, is selected from 0, 1, and 2;
  • p at each occurrence, is selected from 0, 1, 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;
  • t at each occurrence, is selected from 0, 1, 2, and 3.
  • the present invention provides a novel compound selected from the group:
  • M is selected from the group:
  • R is selected from H, Cl, F, Br, I, (CH 2 ) t OR 3 , C 1-4 alkyl, OCF 3 , CF 3 , C(O)NR 7 R 8 , and (CR 8 R 9 ) t NR 7 R 8 ;
  • Z is selected from CH 2 O, OCH 2 , CH 2 NH, NHCH 2 , C(O), CH 2 C(O), C(O)CH 2 , NHC(O), C(O)NH, CH 2 S(O) 2 , S(O) 2 (CH 2 ), SO 2 NH, and NHSO 2 , provided that Z does not form a N—N, N—O, NCH 2 N, or NCH 2 O bond with ring M or group A;
  • A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4 ;
  • B is selected from: H, Y, and X—Y;
  • X is selected from C 1-4 alkylene, —C(O)—, —C( ⁇ NR)—, —CR 2 (NR 2 R 2a )—, —C(O)CR 2 R 2a —, —CR 2 R 2a C(O), —C(O)NR 2 —, —NR 2 C(O)—, C(O)NR 2 CR 2 R 2a —, —NR 2 C(O)CR 2 R 2a —, —NR 2 C(O)CR 2 R 2a —, —CR 2 R 2a C(O)NR 2 —, —CR 2 R 2a NR 2 C(O)—, —NR 2 C(O)NR 2 —, —NR 2 —, —NR 2 CR 2 R 2a —, —CR 2 R 2a NR 2 —, O, —CR 2 R 2a O—, and —OCR 2 R 2a —;
  • Y is NR 2 R 2a or CH 2 NR 2 R 2a , provided that X—Y do not form a N—N or O—N bond;
  • Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ;
  • Y is selected from the following bicyclic heteroaryl ring systems:
  • K is selected from O, S, NH, and N.
  • the present invention provides a novel compound selected from the group:
  • M is selected from the group:
  • Z is C(O)CH 2 and CONH, provided that Z does not form a N—N bond with group A;
  • A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R 4 ;
  • B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R 4a ;
  • B is selected from: Y and X—Y;
  • X is selected from CH 2 , —C(O)—, and O;
  • Y is NR 2 R 2a or CH 2 NR 2 R 2a , provided that X—Y does not form an O—N bond;
  • Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ;
  • R 2 at each occurrence, is selected from H, CF 3 , CH 3 , benzyl, and phenyl;
  • R 2a is selected from H, CF 3 , CH 3 , CH(CH 3 ) 2 , cyclopropylmethyl, benzyl, and phenyl;
  • R 2 and R 2a combine to form a ring system substituted with 0-2 R 4b , the ring system being selected from pyrrolidinyl, piperazinyl and morpholino;
  • R 4 at each occurrence, is selected from OH, (CH 2 ) r OR 2 , Cl, F, C 1-4 alkyl, (CH 2 ) r NR 2 R 2a , and (CF 2 ) r CF 3 ;
  • R 4a is selected from Cl, F, C 1-4 alkyl, CF 3 , (CH 2 ) r NR 2 R 2a , S(O) p R 5 , SO 2 NR 2 R 2a , and 1-CF 3 -tetrazol-2-yl;
  • R 4b at each occurrence, is selected from OH, Cl, F, CH 3 , and CF 3 ;
  • R 5 at each occurrence, is selected from CF 3 , C 1-6 alkyl, phenyl, and benzyl;
  • R 7 at each occurrence, is selected from H, CH 3 , and CH 2 CH 3 ; and,
  • R 8 at each occurrence, is selected from H and CH 3 .
  • the present invention provides a novel compound wherein:
  • M is selected from the group:
  • J is N
  • R 1a is absent or is —(CH 2 ) r —R 1′ ;
  • R 1′ is selected from H, C 1-3 alkyl, F, Cl, —CN, CF 3 , (CH 2 ) r OR 2 , NR 2 R 2a , C(O)R 2c , OC(O)R 2 , S(O) p R 2b , NR 2 C(O)R 2b , C(O)NR 2 R 2a , SO 2 NR 2 R 2a , C 3-6 carbocyclic residue substituted with 0-2 R 4a , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4a ;
  • A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,
  • B is selected from the group: 2-CF 3 -phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl, 2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino, 2-(1′-CF 3 -tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-(N,N-dimethylaminomethyl)imid
  • the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of present invention or a pharmaceutically acceptable salt form thereof.
  • the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
  • the compounds herein described may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C ⁇ N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • a substituent is keto (i.e., ⁇ O) group, then 2 hydrogens on the atom are replaced.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • any variable e.g., R 6
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 6 at each occurrence is selected independently from the definition of R 6 .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1-10 alkyl (or alkylene), is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • C 1-10 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkoxy groups.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
  • C 3-7 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , and C 7 cycloalkyl groups.
  • Alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl.
  • C 2-10 alkenyl (or alkenylene) is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkenyl groups.
  • Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
  • C 2-10 alkynyl (or alkynylene) is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkynyl groups.
  • Halo or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
  • “carbocycle” or “carbocyclic group” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
  • heterocycle or “heterocyclic group” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
  • aromatic heterocyclic group or “heteroaryl” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, ind
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa or thrombin or treat diseases related to factor Xa or thrombin in a host.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of factor Xa or thrombin) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
  • the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • amino intermediates such as 3(B) and phenoxy analogs 6 and 7 can be obtained easily via the methods previously described. These intermediates can be further coupled to requisite precursors followed by conversion of the phenoxy group to an amino via standard techniques to afford the amino-pyridyl compounds of formula 1-3.
  • Scheme VI describes the preparation of indole intermediates.
  • Scheme VII describes the preparation of 3-halo-4-aminobenzothiophene intermediates.
  • Scheme VIII describes the preparation of 1-substituted-7-amino-azabenzimidazole intermediates.
  • Scheme X describes the preparation of 2-substituted-7-amino-azabenzimidazole intermediates.
  • Scheme XIII describes the preparation of 5-aminobenzisothiazole intermediates.
  • Scheme XIV describes the preparation of 6-aminobenzisoxazoleintermediates.
  • Scheme XV describes the preparation of 5-aminoindazole intermediates.
  • Scheme XVI describes the preparation of 6-aminobenzisothiazole intermediates.
  • Scheme XIX describes the preparation of 2-aminoindole derivatives a intermediates.
  • Scheme XX describes the preparation of 2-amino-1-H-pyrrolo[3,2-c]pyridine intermediates.
  • BOC-Protected aminobenzisoxazolemethylbromide can be reacted with the lithium salt of acetonitrile to give the nitrile.
  • the nitrile can be further reacted in a similar fashion as in WO96/16940 to give the desired compound.
  • the compounds of the present invention have a group “A-B” attached to ring M.
  • Preparations of some of the rings M and the “A-B” moieties can follow the same methods described in WO97/23212, WO97/30971, WO97/38984, WO98/01428, WO98/06694, WO98/28269, WO98/28282, WO98/57934, WO98/57937, and WO98/57951, the contents of which are incorporated herein by reference.
  • Preparations of the some of the rings M can also follow the same methods described in WO98/28269, WO98/5795 1, and WO98/57937, the contents of which are incorporated herein by reference.
  • Compounds of Formula I can be prepared by reacting an appropriate 6-5 system described above with an appropriate intermediate to either form the desired ring M or to be attached to desired ring M.
  • the above noted publications describe conditions for coupling ring M and a desired 6-5 system.
  • the compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals.
  • thromboembolic disorders as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms.
  • the anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa, thrombin, or both.
  • the effectiveness of compounds of the present invention as inhibitors of factor Xa can be determined using purified human factor Xa and synthetic substrate.
  • the rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) can be measured both in the absence and presence of compounds of the present invention.
  • Hydrolysis of the substrate resulted in the release of pNA, which can be monitored spectrophotometrically by measuring the increase in absorbance at 405 nM.
  • a decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition.
  • the results of this assay are expressed as inhibitory constant, K i .
  • K i The Michaelis constant, K m , for substrate hydrolysis can be determined at 25° C. using the method of Lineweaver and Burk. Values of K i were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship can be used to calculate K i values:
  • v o is the velocity of the control in the absence of inhibitor
  • v s is the velocity in the presence of inhibitor
  • I is the concentration of inhibitor
  • K i is the dissociation constant of the enzyme:inhibitor complex
  • S is the concentration of substrate
  • K m is the Michaelis constant
  • Compounds tested in the above assay are considered to be active if they exhibit a K i of ⁇ 10 ⁇ M.
  • Preferred compounds of the present invention have K i 's of ⁇ 1 ⁇ M. More preferred compounds of the present invention have K i 's of ⁇ 0.1 ⁇ M. Even more preferred compounds of the present invention have K i 's of ⁇ 0.01 ⁇ M. Still more preferred compounds of the present invention have K i 's of ⁇ 0.001 ⁇ M.
  • the antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model.
  • AV arterio-venous
  • rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used.
  • a saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae.
  • the AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein.
  • the exposure of flowing blood to a silk thread will induce the formation of a significant thrombus.
  • the shunt is disconnected and the silk thread covered with thrombus is weighed.
  • Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt.
  • the percentage inhibition of thrombus formation is determined for each treatment group.
  • the ID50 values dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
  • the compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
  • serine proteases notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes.
  • the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as rea
  • Compounds of the present invention can be shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system.
  • In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference.
  • thrombin-mediated hydrolysis of the chromogenic substrate S2238 Helena Laboratories, Beaumont, Tex.
  • Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition.
  • Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, can be incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity can be assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk.
  • Compounds tested in the above assay are considered to be active if they exhibit a K i of ⁇ 10 ⁇ M.
  • Preferred compounds of the present invention have K i 's of ⁇ 1 ⁇ M. More preferred compounds of the present invention have K i 's of ⁇ 0.1 ⁇ M. Even more preferred compounds of the present invention have K i 's of ⁇ 0.01 ⁇ M. Still more preferred compounds of the present invention have K i 's of ⁇ 0.001 ⁇ M.
  • the compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
  • the compounds are administered to a mammal in a therapeutically effective amount.
  • therapeutically effective amount it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
  • administered in combination or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order at different points in time.
  • each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • Other anticoagulant agents or coagulation inhibitory agents
  • warfarin and heparin as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.
  • anti-platelet agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • aspirin acetylsalicyclic acid or ASA
  • piroxicam are preferred.
  • Suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof
  • thrombin inhibitors denotes inhibitors of the serine protease thrombin.
  • various thrombin-mediated processes such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted.
  • thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds.
  • Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
  • Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof.
  • hirudin includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
  • Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and EP 293 881 A2, the disclosures of which are hereby incorporated herein by reference.
  • Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in WO92/07869 and EP 471,651 A2, the disclosures of which are hereby incorporated herein by reference.
  • thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi).
  • agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof.
  • anistreplase refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein.
  • urokinase as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
  • Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each.
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa.
  • Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa.
  • a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
  • compounds according to the present invention could be used to test their effectiveness.
  • the compounds of the present invention may also be used in diagnostic assays involving factor Xa.
  • the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired.
  • a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences , Mack Publishing Company, a standard reference text in this field.
  • a large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.
  • a digestable oil such as soybean oil, cottonseed oil or olive oil
  • Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • a parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.
  • An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.
  • a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
  • the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.
  • a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
  • a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
  • the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced).
  • one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
  • HPMC hydroxypropyl methylcellulose
  • the polymer coating serves to form an additional barrier to interaction with the other component.
  • each entry in each table is intended to be paired with each formulae at the start of the table.
  • example 1 of Table 1 is intended to be paired with each of the formulae shown in Table 1.
  • Example 1 of Table 2 is intended to be paired with each of the formulae shown in Table 2.

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Abstract

This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

Description

    FIELD OF THE INVENTION
  • This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders. [0001]
    • BACKGROUND OF THE 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, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca[0002] 2+ and phospholipid). Since it is calculated that one molecule of 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 more efficient than inactivation of thrombin in interrupting the blood coagulation system.
  • Therefore, efficacious and specific inhibitors of factor Xa, thrombin, or both are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa, thrombin, or both inhibitors. [0003]
    • SUMMARY OF THE INVENTION
  • Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof. [0004]
  • 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. [0005]
  • It is another object of the present invention to provide 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 invention or a pharmaceutically acceptable salt or prodrug form thereof. [0006]
  • It is another object of the present invention to provide novel compounds for use in therapy. [0007]
  • It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of thrombosis or a disease mediated by factor Xa.[0008]
    • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • [1] Thus, in an embodiment, the present invention provides a novel compound selected from the group: [0009]
    Figure US20030004344A1-20030102-C00001
  • ring D is selected from —(CH[0010] 2)3—, —CH2CH═CH—, —CH2N═CH—, and a 5 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present;
  • ring D is substituted with 0-2 R; [0011]
  • E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R; [0012]
  • R is selected from Cl, F, Br, I, OH, C[0013] 1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2;
  • M is selected from the group: [0014]
    Figure US20030004344A1-20030102-C00002
  • J is O or S; [0015]
  • J[0016] a is NH or NR1a;
  • Z is selected from (CR[0017] 8R9)1-4, (CR8R9)rO(CR8R9)r, (CR8R9)rNR3(CR8R9)r, (CR8R9)rC(O)(CR8R9)r, (CR8R9)rC(O)O(CR8R9)r, (CR8R9)rOC(O)(CR8R9)r, (CR8R9)rC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)(CR8R9)r, (CR8R9)rOC(O)O(CR8R9)r, (CH2)rOC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)O(CR8R9)r, (CH2)rNR3C(O)NR3(CR8R9)r, (CR8R9)rS(O)p(CR8R9)r, (CCR8R9)rSO2NR3(CR8R9)r, (CR8R9)rNR3SO2(CR8R9)r, and (CR8R9)rNR3SO2NR3(CR8R9)r, provided that Z does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with the groups to which Z is attached;
  • R[0018] 1a is selected from H, —(CH2)r—R1′, —CH═CH—R1′, NHCH2R1″, OCH2R1″, SCH2R1″, NH(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′;
  • R[0019] 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)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, C(═NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b,NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
  • R[0020] 1″ is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
  • R[0021] 2, 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 of N, O, and S substituted with 0-2 R4b;
  • R[0022] 2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 cycloalkylmethyl substituted with 0-2 R4b, 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 of N, O, and S substituted with 0-2 R4b;
  • R[0023] 2b, at each occurrence, is selected from CF3, C1-4 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 of N, O, and S substituted with 0-2 R4b;
  • R[0024] 2c, at each occurrence, is selected from CF3, OH, C1-4 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 of N, O, and S substituted with 0-2 R4b;
  • alternatively, R[0025] 2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
  • alternatively, R[0026] 2 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, O, and S;
  • R[0027] 3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
  • R[0028] 3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
  • R[0029] 3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
  • R[0030] 3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
  • A is selected from: C[0031] 3-10 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
  • B is selected from: X—Y, NR[0032] 2R2a, C(═NR2)NR2R2a, NR2C(═NR2)NR2R2a, 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 of N, O, and S substituted with 0-2 R4a;
  • X is selected from C[0033] 1-4 alkylene, —CR2(CR2R2b)(CH2)t—, —C(O)—, —C(═NR1″)—, —CR2(NR1″R2)—, —CR2(OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —S(O)p—, —S(O)pCR2R2a—, —CR2R2aS(O)p—, —S(O)2NR2—, —NR2S(O)2—, —NR2S(O)2CR2R2a—, —CR2R2aS(O)2NR2—, —NR2S(O)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—, O, —CR2R2aO—, and —OCR2R2a—;
  • Y is selected from: (CH[0034] 2)rNR2R2a, provided that X—Y do not form a N—N, O—N, or S—N bond, 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 of N, O, and S substituted with 0-2 R4a;
  • R[0035] 4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(═NR2)NR2R2a, C(═NS(O)2R5)NR2R2a, NHC(═NR2)NR2R2a, C(O)NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NHCH2R1″, OCH2R1″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′,
  • alternatively, one R[0036] 4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
  • R[0037] 4a, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CH2)r—F, (CH2)r—Br, (CH2)r Cl, Cl, Br, F, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
  • alternatively, one R[0038] 4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
  • R[0039] 4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (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, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
  • R[0040] 5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
  • R[0041] 6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a,(CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
  • R[0042] 7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
  • R[0043] 8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
  • alternatively, R[0044] 7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
  • R[0045] 9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
  • n, at each occurrence, is selected from 0, 1, 2, and 3; [0046]
  • m, at each occurrence, is selected from 0, 1, and 2; [0047]
  • p, at each occurrence, is selected from 0, 1, and 2; [0048]
  • r, at each occurrence, is selected from 0, 1, 2, and 3; [0049]
  • s, at each occurrence, is selected from 0, 1, and 2; and, [0050]
  • t, at each occurrence, is selected from 0, 1, 2, and 3. [0051]
  • [2] In another embodiment, the present invention provides a novel compound selected from the group: [0052]
    Figure US20030004344A1-20030102-C00003
  • wherein, M is selected from the group: [0053]
    Figure US20030004344A1-20030102-C00004
  • R is selected from H, Cl, F, Br, I, (CH[0054] 2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
  • Z is selected from CH[0055] 2O, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a N—N, N—O, NCH2N, or NCH2O bond with ring M or group A;
  • A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R[0056] 4;
  • phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, 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, 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, benzothiofiranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; [0057]
  • B is selected from: H, Y, and X—Y; [0058]
  • X is selected from C[0059] 1-4 alkylene, —C(O)—, —C(═NR)—, —CR2(NR2R2a)—, —C(O)CR2R2a—, —CR2R2aC(O), —C(O)NR2—, —NR2C(O)—, C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—;
  • Y is NR[0060] 2R2a or CH2NR2R2a, provided that X—Y do not form a N—N or O—N bond;
  • alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R[0061] 4a;
  • cylcopropyl, 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, 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; [0062]
  • alternatively, Y is selected from the following bicyclic heteroaryl ring systems: [0063]
    Figure US20030004344A1-20030102-C00005
  • K is selected from O, S, NH, and N. [0064]
  • [3] In another embodiment, the present invention provides a novel compound selected from the group: [0065]
    Figure US20030004344A1-20030102-C00006
  • M is selected from the group: [0066]
    Figure US20030004344A1-20030102-C00007
  • Z is C(O)CH[0067] 2 and CONH, provided that Z does not form a N—N bond with group A;
  • A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R[0068] 4; and,
  • B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R[0069] 4a;
  • B is selected from: Y and X—Y; [0070]
  • X is selected from CH[0071] 2, —C(O)—, and O;
  • Y is NR[0072] 2R2a or CH2NR2R2a, provided that X—Y does not form an O—N bond;
  • alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R[0073] 4a;
  • phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl; [0074]
  • R[0075] 2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
  • R[0076] 2a, at each occurrence, is selected from H, CF3, CH3, CH(CH3)2, cyclopropylmethyl, benzyl, and phenyl;
  • alternatively, R[0077] 2 and R2a combine to form a ring system substituted with 0-2 R4b, the ring system being selected from pyrrolidinyl, piperazinyl and morpholino;
  • R[0078] 4, at each occurrence, is selected from OH, (CH2)rOR2, Cl, F, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
  • R[0079] 4a is selected from Cl, F, C1-4 alkyl, CF3, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
  • R[0080] 4b, at each occurrence, is selected from OH, Cl, F, CH3, and CF3;
  • R[0081] 5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
  • R[0082] 7, at each occurrence, is selected from H, CH3, and CH2CH3; and,
  • R[0083] 8, at each occurrence, is selected from H and CH3.
  • [4] In another embodiment, the present invention provides a novel compound wherein: [0084]
  • M is selected from the group: [0085]
    Figure US20030004344A1-20030102-C00008
  • J is N; [0086]
  • R[0087] 1a is absent or is —(CH2)r—R1′;
  • R[0088] 1′ is selected from H, C1-3 alkyl, F, Cl, —CN, CF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, S(O)pR2b, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
  • A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, [0089]
  • B is selected from the group: 2-CF[0090] 3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl, 2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino, 2-(1′-CF3-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
  • In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of present invention or a pharmaceutically acceptable salt form thereof. [0091]
  • In another embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof. [0092]
    • DEFINITIONS
  • The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. [0093]
  • “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced. [0094]
  • The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. [0095]
  • When any variable (e.g., R[0096] 6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. [0097]
  • As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C[0098] 1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. “Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. “Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
  • “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate. [0099]
  • As used herein, “carbocycle” or “carbocyclic group” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. [0100]
  • As used herein, the term “heterocycle” or “heterocyclic group” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. [0101]
  • Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles. [0102]
  • The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0103]
  • As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. [0104]
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in [0105] Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • “Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. [0106]
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [0107]
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa or thrombin or treat diseases related to factor Xa or thrombin in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of factor Xa or thrombin) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components. [0108]
    • SYNTHESIS
  • The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts ([0109] Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
  • Compounds wherein rings D-E are A or B, shown below: [0110]
    Figure US20030004344A1-20030102-C00009
  • can be prepared via the methodology outlined in Scheme I below. [0111]
    Figure US20030004344A1-20030102-C00010
  • Removal of the amino protecting group followed by further manipulation can afford key starting materials wherein the amino is a benzylamine or alpha-amino acid or all analogs stated earlier. The starting material can also be obtained from intermediate 4 via an SN2 type displacement of the o-tosylate. Decarboxylation of intermediate 3 affords the ketone analog that also can be further manipulated to afford additional starting materials D-E. Coupling of analogs such as intermediate 7 via standard techniques followed by displacement of the phenoxy pyridine via standard techniques known to those in the art should afford the compounds of formula A. Chiral compounds can be separated via chiral HPLC techniques or by co-crystallization methods with a known chiral precursor. [0112]
  • Compounds wherein D-E is of formula B as shown above can be prepared as shown in Scheme II. [0113]
    Figure US20030004344A1-20030102-C00011
  • Via this scheme amino intermediates such as 3(B) and phenoxy analogs 6 and 7 can be obtained easily via the methods previously described. These intermediates can be further coupled to requisite precursors followed by conversion of the phenoxy group to an amino via standard techniques to afford the amino-pyridyl compounds of formula 1-3. [0114]
  • The unsaturated analogs can be prepared according to Scheme III. [0115]
    Figure US20030004344A1-20030102-C00012
  • Intermediate 3 can be further manipulated to afford other D-E intermediates via methods described previously. In a similar fashion the other unsaturated analog can be prepared via Scheme IV shown below. [0116]
    Figure US20030004344A1-20030102-C00013
  • Scheme V describes the preparation of 3-aminobenzofuran intermediates. [0117]
    Figure US20030004344A1-20030102-C00014
  • 4-benzyloxy-2(1H)-pyridone (available from Aldrich) can be converted to the aminopyridine derivative using standard procedures known to the practitioners of the art. Debenzylation, coupling with bromoethylacetate, followed by basic hydrolysis affords an intermediate that undergoes the Friedel-Crafts acylation. [0118]
  • Scheme VI describes the preparation of indole intermediates. [0119]
    Figure US20030004344A1-20030102-C00015
  • Scheme VII describes the preparation of 3-halo-4-aminobenzothiophene intermediates. [0120]
    Figure US20030004344A1-20030102-C00016
  • Scheme VIII describes the preparation of 1-substituted-7-amino-azabenzimidazole intermediates. [0121]
    Figure US20030004344A1-20030102-C00017
  • Scheme X describes the preparation of 2-substituted-7-amino-azabenzimidazole intermediates. [0122]
    Figure US20030004344A1-20030102-C00018
  • Scheme XI describes the preparation of 5-aminobenzisoxazole intermediates. [0123]
    Figure US20030004344A1-20030102-C00019
  • Synthesis of 5-aminobenzisoxazoles in which the 3-position may be a protected amine could be accomplished starting from the commercially available 3-cyano-4-fluoronitrobenzene. Displacement of flourine with acetohydroxamic acid under basic conditions followed by ring closure by subsequent addition to the nitrile would yield the benzisoxazole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0124]
  • Scheme XII describes the preparation of 5-aminoindazole intermediates. [0125]
    Figure US20030004344A1-20030102-C00020
  • Synthesis of 5-aminoindazoles in which the 3-position may be a protected amine could be accomplished starting from the commercially available 3-cyano-4-fluoronitrobenzene. Displacement of flourine with hydrazine followed by ring closure by subsequent addition to the nitrile would yield the indazole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0126]
  • Scheme XIII describes the preparation of 5-aminobenzisothiazole intermediates. [0127]
    Figure US20030004344A1-20030102-C00021
  • Synthesis of 5-aminobenzisothiazoles in which the 3-position may be a protected amine could be accomplished starting from the commercially available 2-benzylthio-5-nitrobenzonitrile. Conversion of the aryl nitrile to benzamidine, sulfoxide formation and ring closure/debenzylation would yield the benzisothiazole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0128]
  • Scheme XIV describes the preparation of 6-aminobenzisoxazoleintermediates. [0129]
    Figure US20030004344A1-20030102-C00022
  • Synthesis of 6-aminobenzisoxazoles in which the 3-position may be a protected amine could be accomplished starting from commercially available 2-fluoro-4-nitrobenzoic acid. Conversion of carboxylic acid to nitrile via standard manipulations would give 2-fluoro-4-nitrobenzonitrile. Displacement of flourine with acetohydroxamic acid under basic conditions followed by ring closure by subsequent addition to the nitrile would yield the benzisoxazole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0130]
  • Scheme XV describes the preparation of 5-aminoindazole intermediates. [0131]
    Figure US20030004344A1-20030102-C00023
  • Synthesis of 5-aminoindazoles in which the 3-position may be a protected amine could be accomplished starting from from 2-fluoro-4-nitrobenzonitrile whose synthesis is described elsewhere in this patent. Displacement of flourine with hydrazine followed by ring closure by subsequent addition to the nitrile would yield the indazole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0132]
  • Scheme XVI describes the preparation of 6-aminobenzisothiazole intermediates. [0133]
    Figure US20030004344A1-20030102-C00024
  • Synthesis of 6-aminobenzisothiazoles in which the 3-position may be a protected amine could be accomplished starting from 2-fluoro-4-nitrobenzonitrile whose synthesis is described elsewhere in this patent. Displacement of flourine with benzylthio anion yields 2-benzylthio-4-nitrobenzonitrile. Conversion of the aryl nitrile to benzamidine, sulfoxide formation and ring closure/debenzylation would yield the benzisothiazole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0134]
  • Scheme XVII describes the preparation of 6-aminoisoindole intermediates. [0135]
    Figure US20030004344A1-20030102-C00025
  • Synthesis of 6-aminoisoindoles in which the 1-position may be a protected amine could be accomplished starting from commercially available 2-cyano-4-nitrotoluene. Bromination of tolyl methyl to give a benzyl bromide followed by displacement with azide and reduction to benzylamine would cyclize to the isoindole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0136]
  • Scheme XVIII describes the preparation of 5-aminoisoindole intermediates. [0137]
    Figure US20030004344A1-20030102-C00026
  • Synthesis of 5-aminoisoindoles in which the 1-position may be a protected amine could be accomplished starting from commercially available 2-cyano-5-nitrotoluene. Bromination of tolyl methyl to give a benzyl bromide followed by displacement with azide and reduction to benzylamine would cyclize to the isoindole core. Suitable protection and reduction of the aryl nitro group would provide the desired compound. [0138]
  • Scheme XIX describes the preparation of 2-aminoindole derivatives a intermediates. [0139]
    Figure US20030004344A1-20030102-C00027
  • Synthesis of the desired compounds in which the 4-position may be a protected amine could be accomplished starting from the commercially available furan or thiophene. Using literature methods ([0140] J. Med. Chem. 1989, 32, 1147) one could obtain the 2-nitro-4-chloro-furo or thieno<3,2-c>pyridine. Displacement of the 4-chloro with phenoxide then conversion to 4-amino followed by suitable protection and reduction of the aryl nitro group would provide the desired compound.
  • Scheme XX describes the preparation of 2-amino-1-H-pyrrolo[3,2-c]pyridine intermediates. [0141]
    Figure US20030004344A1-20030102-C00028
  • Synthesis of 2-amino-1-H-pyrrolo[3,2-c]pyridine in which the 4-position may be a protected amine could be accomplished starting from the commercially available pyrrole-2-carboxaldehyde. Nitration and protection of pyrrole nitrogen with P1 would afford the nitro/aldehyde intermediate. Using literature methods ([0142] J. Med. Chem. 1989, 32, 1147) one could obtain the 2-nitro-4-chloro-pyrrolo[3,2-c]pyridine. Displacement of the 4-chloro with phenoxide then conversion to 4-amino followed by suitable protection and reduction of the aryl nitro group would provide the desired compound.
  • BOC-Protected aminobenzisoxazolemethylbromide can be reacted with the lithium salt of acetonitrile to give the nitrile. The nitrile can be further reacted in a similar fashion as in WO96/16940 to give the desired compound. [0143]
  • The compounds of the present invention have a group “A-B” attached to ring M. Preparations of some of the rings M and the “A-B” moieties can follow the same methods described in WO97/23212, WO97/30971, WO97/38984, WO98/01428, WO98/06694, WO98/28269, WO98/28282, WO98/57934, WO98/57937, and WO98/57951, the contents of which are incorporated herein by reference. Preparations of the some of the rings M can also follow the same methods described in WO98/28269, WO98/5795 1, and WO98/57937, the contents of which are incorporated herein by reference. Compounds of Formula I can be prepared by reacting an appropriate 6-5 system described above with an appropriate intermediate to either form the desired ring M or to be attached to desired ring M. The above noted publications describe conditions for coupling ring M and a desired 6-5 system. [0144]
  • Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof. [0145]
    • Utility
  • The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term “thromboembolic disorders” as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa, thrombin, or both. [0146]
  • The effectiveness of compounds of the present invention as inhibitors of factor Xa can be determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) can be measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which can be monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K[0147] i.
  • Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K[0148] m, for substrate hydrolysis can be determined at 25° C. using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship can be used to calculate Ki values:
  • (v o −v s)/v s =I/(K i(1+S/K m))
  • where: [0149]
  • v[0150] o is the velocity of the control in the absence of inhibitor;
  • v[0151] s is the velocity in the presence of inhibitor;
  • I is the concentration of inhibitor; [0152]
  • K[0153] i is the dissociation constant of the enzyme:inhibitor complex;
  • S is the concentration of substrate; [0154]
  • K[0155] m is the Michaelis constant.
  • Compounds tested in the above assay are considered to be active if they exhibit a K[0156] i of ≦10 μM. Preferred compounds of the present invention have Ki's of ≦1 μM. More preferred compounds of the present invention have Ki's of ≦0.1 μM. Even more preferred compounds of the present invention have Ki's of ≦0.01 μM. Still more preferred compounds of the present invention have Ki's of ≦0.001 μM.
  • The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression. [0157]
  • The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes. [0158]
  • Compounds of the present invention can be shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in [0159] J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) can be monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, can be incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity can be assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk.
  • Compounds tested in the above assay are considered to be active if they exhibit a K[0160] i of ≦10 μM. Preferred compounds of the present invention have Ki's of ≦1 μM. More preferred compounds of the present invention have Ki's of ≦0.1 μM. Even more preferred compounds of the present invention have Ki's of ≦0.01 μM. Still more preferred compounds of the present invention have Ki's of ≦0.001 μM.
  • The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents. [0161]
  • The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease. [0162]
  • By “administered in combination” or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention. [0163]
  • The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof [0164]
  • The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and EP 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in WO92/07869 and EP 471,651 A2, the disclosures of which are hereby incorporated herein by reference. [0165]
  • The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase. [0166]
  • Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. [0167]
  • The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. [0168]
  • The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present. [0169]
    • Dosage and Formulation
  • The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. [0170]
  • The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder. [0171]
  • By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. [0172]
  • Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. [0173]
  • The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. [0174]
  • For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. [0175]
  • The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. [0176]
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. [0177]
  • Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. [0178]
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. [0179]
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. [0180]
  • In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. [0181]
  • Suitable pharmaceutical carriers are described in [0182] Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: [0183]
  • Capsules [0184]
  • A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate. [0185]
  • Soft Gelatin Capsules [0186]
  • A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried. [0187]
  • Tablets [0188]
  • Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. [0189]
  • Injectable [0190]
  • A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized. [0191]
  • Suspension [0192]
  • An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin. [0193]
  • Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit. [0194]
  • Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight. [0195]
  • Where the compounds of Formula I are administered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I. [0196]
  • Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination. [0197]
  • Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. [0198]
  • These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure. [0199]
  • The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, example 1 of Table 1 is intended to be paired with each of the formulae shown in Table 1. Example 1 of Table 2 is intended to be paired with each of the formulae shown in Table 2. [0200]
  • The following nomenclature is intended for group A in the following tables. [0201]
    Figure US20030004344A1-20030102-C00029
    TABLE 1
    Figure US20030004344A1-20030102-C00030
    Figure US20030004344A1-20030102-C00031
    Figure US20030004344A1-20030102-C00032
    Figure US20030004344A1-20030102-C00033
    Figure US20030004344A1-20030102-C00034
    Figure US20030004344A1-20030102-C00035
    Figure US20030004344A1-20030102-C00036
    Figure US20030004344A1-20030102-C00037
    Figure US20030004344A1-20030102-C00038
    Figure US20030004344A1-20030102-C00039
    Figure US20030004344A1-20030102-C00040
    Figure US20030004344A1-20030102-C00041
    Figure US20030004344A1-20030102-C00042
    Figure US20030004344A1-20030102-C00043
    Figure US20030004344A1-20030102-C00044
    Figure US20030004344A1-20030102-C00045
    Figure US20030004344A1-20030102-C00046
    Figure US20030004344A1-20030102-C00047
    Figure US20030004344A1-20030102-C00048
    Figure US20030004344A1-20030102-C00049
    Figure US20030004344A1-20030102-C00050
    Figure US20030004344A1-20030102-C00051
    Figure US20030004344A1-20030102-C00052
    Figure US20030004344A1-20030102-C00053
    Figure US20030004344A1-20030102-C00054
    Figure US20030004344A1-20030102-C00055
    Figure US20030004344A1-20030102-C00056
    Figure US20030004344A1-20030102-C00057
    Figure US20030004344A1-20030102-C00058
    Figure US20030004344A1-20030102-C00059
    Figure US20030004344A1-20030102-C00060
    Figure US20030004344A1-20030102-C00061
    Figure US20030004344A1-20030102-C00062
    Figure US20030004344A1-20030102-C00063
    Figure US20030004344A1-20030102-C00064
    Figure US20030004344A1-20030102-C00065
    Figure US20030004344A1-20030102-C00066
    Figure US20030004344A1-20030102-C00067
    Figure US20030004344A1-20030102-C00068
    Figure US20030004344A1-20030102-C00069
    Figure US20030004344A1-20030102-C00070
    Figure US20030004344A1-20030102-C00071
    Figure US20030004344A1-20030102-C00072
    Figure US20030004344A1-20030102-C00073
    Figure US20030004344A1-20030102-C00074
    Figure US20030004344A1-20030102-C00075
    Figure US20030004344A1-20030102-C00076
    Figure US20030004344A1-20030102-C00077
    Figure US20030004344A1-20030102-C00078
    Figure US20030004344A1-20030102-C00079
    Figure US20030004344A1-20030102-C00080
    Figure US20030004344A1-20030102-C00081
    Figure US20030004344A1-20030102-C00082
    Figure US20030004344A1-20030102-C00083
    Figure US20030004344A1-20030102-C00084
    Figure US20030004344A1-20030102-C00085
    Figure US20030004344A1-20030102-C00086
    Figure US20030004344A1-20030102-C00087
    Figure US20030004344A1-20030102-C00088
    Figure US20030004344A1-20030102-C00089
    Figure US20030004344A1-20030102-C00090
    Figure US20030004344A1-20030102-C00091
    Figure US20030004344A1-20030102-C00092
    Figure US20030004344A1-20030102-C00093
    Figure US20030004344A1-20030102-C00094
    Figure US20030004344A1-20030102-C00095
    Figure US20030004344A1-20030102-C00096
    Figure US20030004344A1-20030102-C00097
    Figure US20030004344A1-20030102-C00098
    Figure US20030004344A1-20030102-C00099
    Figure US20030004344A1-20030102-C00100
    Figure US20030004344A1-20030102-C00101
    Figure US20030004344A1-20030102-C00102
    Figure US20030004344A1-20030102-C00103
    Figure US20030004344A1-20030102-C00104
    Figure US20030004344A1-20030102-C00105
    Figure US20030004344A1-20030102-C00106
    Figure US20030004344A1-20030102-C00107
    Figure US20030004344A1-20030102-C00108
    Figure US20030004344A1-20030102-C00109
    Figure US20030004344A1-20030102-C00110
    Figure US20030004344A1-20030102-C00111
    Figure US20030004344A1-20030102-C00112
    Figure US20030004344A1-20030102-C00113
    Figure US20030004344A1-20030102-C00114
    Figure US20030004344A1-20030102-C00115
    Figure US20030004344A1-20030102-C00116
    Figure US20030004344A1-20030102-C00117
    Figure US20030004344A1-20030102-C00118
    Figure US20030004344A1-20030102-C00119
    Figure US20030004344A1-20030102-C00120
    Figure US20030004344A1-20030102-C00121
    Figure US20030004344A1-20030102-C00122
    Figure US20030004344A1-20030102-C00123
    Figure US20030004344A1-20030102-C00124
    Figure US20030004344A1-20030102-C00125
    Figure US20030004344A1-20030102-C00126
    Figure US20030004344A1-20030102-C00127
    Figure US20030004344A1-20030102-C00128
    Figure US20030004344A1-20030102-C00129
    Figure US20030004344A1-20030102-C00130
    Figure US20030004344A1-20030102-C00131
    Figure US20030004344A1-20030102-C00132
    Figure US20030004344A1-20030102-C00133
    Figure US20030004344A1-20030102-C00134
    Figure US20030004344A1-20030102-C00135
    Figure US20030004344A1-20030102-C00136
    Figure US20030004344A1-20030102-C00137
    Z is C(O)NH or C(O)CH2
    Ex# R1a A B
    1 CH3 phenyl 2-(aminosulfonyl)phenyl
    2 CH3 phenyl 2-(methylaminosulfonyl)phenyl
    3 CH3 phenyl 1-pyrrolidinocarbonyl
    4 CH3 phenyl 2-(methylsulfonyl)phenyl
    5 CH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    6 CH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    7 CH3 phenyl 1-methyl-2-imidazolyl
    8 CH3 phenyl 2-methyl-1-imidazolyl
    9 CH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    10 CH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    11 CH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    12 CH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    13 CH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    14 CH3 2-pyridyl 2-(aminosulfonyl)phenyl
    15 CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    16 CH3 2-pyridyl 1-pyrrolidinocarbonyl
    17 CH3 2-pyridyl 2-(methylsulfonyl)phenyl
    18 CH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    19 CH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    20 CH3 2-pyridyl 1-methyl-2-imidazolyl
    21 CH3 2-pyridyl 2-methyl-1-imidazolyl
    22 CH3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    23 CH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    24 CH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    25 CH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    26 CH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    27 CH3 3-pyridyl 2-(aminosulfonyl)phenyl
    28 CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    29 CH3 3-pyridyl 1-pyrrolidinocarbonyl
    30 CH3 3-pyridyl 2-(methylsulfonyl)phenyl
    31 CH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    32 CH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    33 CH3 3-pyridyl 1-methyl-2-imidazolyl
    34 CH3 3-pyridyl 2-methyl-1-imidazolyl
    35 CH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    36 CH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    37 CH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    38 CH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    39 CH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    40 CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    41 CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    42 CH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    43 CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    44 CH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    45 CH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    46 CH3 2-pyrimidyl 1-methyl-2-imidazolyl
    47 CH3 2-pyrimidyl 2-methyl-1-imidazolyl
    48 CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    49 CH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    50 CH3 2-pyrimidyl 2-(N-(cyclobutyb-
    aminomethyl)phenyl
    51 CH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    52 CH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    53 CH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    54 CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    55 CH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    56 CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    57 CH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    58 CH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    59 CH3 5-pyrimidyl 1-methyl-2-imidazolyl
    60 CH3 5-pyrimidyl 2-methyl-1-imidazolyl
    61 CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    62 CH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    63 CH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    64 CH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    65 CH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    66 CH3 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    67 CH3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    68 CH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
    69 CH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    70 CH3 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    71 CH3 2-Cl-phenyl 2-(N-pyrrolidinylmethylphenyl
    72 CH3 2-Cl-phenyl 1-methyl-2-imidazolyl
    73 CH3 2-Cl-phenyl 2-methyl-1-imidazolyl
    74 CH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    75 CH3 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    76 CH3 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    77 CH3 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    78 CH3 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    79 CH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    80 CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    81 CH3 2-F-phenyl 1-pyrrolidinocarbonyl
    82 CH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    83 CH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    84 CH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    85 CH3 2-F-phenyl 1-methyl-2-imidazolyl
    86 CH3 2-F-phenyl 2-methyl-1-imidazolyl
    87 CH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    88 CH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    89 CH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    90 CH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    91 CH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    92 CH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    93 CH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    94 CH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    95 CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    96 CH3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    97 CH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    98 CH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    99 CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    100 CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    101 CH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    102 CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    103 CH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    104 CH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    105 CH2CH3 phenyl 2-(aminosulfonyl)phenyl
    106 CH2CH3 phenyl 2-(methylaminosulfonyl)phenyl
    107 CH2CH3 phenyl 1-pyrrolidinocarbonyl
    108 CH2CH3 phenyl 2-(methylsulfonyl)phenyl
    109 CH2CH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    110 CH2CH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    111 CH2CH3 phenyl 1-methyl-2-imidazolyl
    112 CH2CH3 phenyl 2-methyl-1-imidazolyl
    113 CH2CH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    114 CH2CH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    115 CH2CH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    116 CH2CH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    117 CH2CH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    118 CH2CH3 2-pyridyl 2-(aminosulfonyl)phenyl
    119 CH2CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    120 CH2CH3 2-pyridyl 1-pyrrolidinocarbonyl
    121 CH2CH3 2-pyridyl 2-(methylsulfonyl)phenyl
    122 CH2CH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    123 CH2CH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    124 CH2CH3 2-pyridyl 1-methyl-2-imidazolyl
    125 CH2CH3 2-pyridyl 2-methyl-1-imidazolyl
    126 CH2CH3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    127 CH2CH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    128 CH2CH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    129 CH2CH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    130 CH2CH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    131 CH2CH3 3-pyridyl 2-(aminosulfonyl)phenyl
    132 CH2CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    133 CH2CH3 3-pyridyl 1-pyrrolidinocarbonyl
    134 CH2CH3 3-pyridyl 2-(methylsulfonyl)phenyl
    135 CH2CH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    136 CH2CH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    137 CH2CH3 3-pyridyl 1-methyl-2-imidazolyl
    138 CH2CH3 3-pyridyl 2-methyl-1-imidazolyl
    139 CH2CH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    140 CH2CH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    141 CH2CH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    142 CH2CH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    143 CH2CH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    144 CH2CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    145 CH2CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    146 CH2CH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    147 CH2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    148 CH2CH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    149 CH2CH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    150 CH2CH3 2-pyrimidyl 1-methyl-2-imidazolyl
    151 CH2CH3 2-pyrimidyl 2-methyl-1-imidazolyl
    152 CH2CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    153 CH2CH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    154 CH2CH3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    155 CH2CH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    156 CH2CH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    157 CH2CH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    158 CH2CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    159 CH2CH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    160 CH2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    161 CH2CH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    162 CH2CH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    163 CH2CH3 5-pyrimidyl 1-methyl-2-imidazolyl
    164 CH2CH3 5-pyrimidyl 2-methyl-1-imidazolyl
    165 CH2CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    166 CH2CH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    167 CH2CH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    168 CH2CH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    169 CH2CH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    170 CH2CH3 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    171 CH2CH3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    172 CH2CH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
    173 CH2CH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    174 CH2CH3 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    175 CH2CH3 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    176 CH2CH3 2-Cl-phenyl 1-methyl-2-imidazolyl
    177 CH2CH3 2-Cl-phenyl 2-methyl-1-imidazolyl
    178 CH2CH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    179 CH2CH3 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    180 CH2CH3 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    181 CH2CH3 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    182 CH2CH3 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    183 CH2CH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    184 CH2CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    185 CH2CH3 2-F-phenyl 1-pyrrolidinocarbonyl
    186 CH2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    187 CH2CH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    188 CH2CH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    189 CH2CH3 2-F-phenyl 1-methyl-2-imidazolyl
    190 CH2CH3 2-F-phenyl 2-methyl-1-imidazolyl
    191 CH2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    192 CH2CH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    193 CH2CH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    194 CH2CH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    195 CH2CH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    196 CH2CH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    197 CH2CH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    198 CH2CH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    199 CH2CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    200 CH2CH3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    201 CH2CH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    202 CH2CH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    203 CH2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    204 CH2CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    205 CH2CH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    206 CH2CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    207 CH2CH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    208 CH2CH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    209 CF3 phenyl 2-(aminosulfonyl)phenyl
    210 CF3 phenyl 2-(methylaminosulfonyl)phenyl
    211 CF3 phenyl 1-pyrrolidinocarbonyl
    212 CF3 phenyl 2-(methylsulfonyl)phenyl
    213 CF3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    214 CF3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    215 CF3 phenyl 1-methyl-2-imidazolyl
    216 CF3 phenyl 2-methyl-i-imidazolyl
    217 CF3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    218 CF3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    219 CF3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    220 CF3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    221 CF3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    222 CF3 2-pyridyl 2-(aminosulfonyl)phenyl
    223 CF3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    224 CF3 2-pyridyl 1-pyrrolidinocarbonyl
    225 CF3 2-pyridyl 2-(methylsulfonyl)phenyl
    226 CF3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    227 CF3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    228 CF3 2-pyridyl 1-methyl-2-imidazolyl
    229 CF3 2-pyridyl 2-methyl-1-imidazolyl
    230 CF3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    231 CF3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    232 CF3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    233 CF3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    234 CF3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    235 CF3 3-pyridyl 2-(aminosulfonyl)phenyl
    236 CF3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    237 CF3 3-pyridyl 1-pyrrolidinocarbonyl
    238 CF3 3-pyridyl 2-(methylsulfonyl)phenyl
    239 CF3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    240 CF3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    241 CF3 3-pyridyl 1-methyl-2-imidazolyl
    242 CF3 3-pyridyl 2-methyl-1-imidazolyl
    243 CF3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    244 CF3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    245 CF3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    246 CF3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    247 CF3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    248 CF3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    249 CF3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    250 CF3 2-pyrimidyl 1-pyrrolidinocarbonyl
    251 CF3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    252 CF3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    253 CF3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    254 CF3 2-pyrimidyl 1-methyl-2-imidazolyl
    255 CF3 2-pyrimidyl 2-methyl-1-imidazolyl
    256 CF3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    257 CF3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    258 CF3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    259 CF3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    260 CF3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    261 CF3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    262 CF3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    263 CF3 5-pyrimidyl 1-pyrrolidinocarbonyl
    264 CF3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    265 CF3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    266 CF3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    267 CF3 5-pyrimidyl 1-methyl-2-imidazolyl
    268 CF3 5-pyrimidyl 2-methyl-1-imidazolyl
    269 CF3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    270 CF3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    271 CF3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    272 CF3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    273 CF3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    274 CF3 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    275 CF3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    276 CF3 2-Cl-phenyl 1-pyrrolidinocarbonyl
    277 CF3 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    278 CF3 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    279 CF3 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    280 CF3 2-Cl-phenyl 1-methyl-2-imidazolyl
    281 CF3 2-Cl-phenyl 2-methyl-1-imidazolyl
    282 CF3 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    283 CF3 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    284 CF3 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    285 CF3 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    286 CF3 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    287 CF3 2-F-phenyl 2-(aminosulfonyl)phenyl
    288 CF3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    289 CF3 2-F-phenyl 1-pyrrolidinocarbonyl
    290 CF3 2-F-phenyl 2-(methylsulfonyl)phenyl
    291 CF3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    292 CF3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    293 CF3 2-F-phenyl 1-methyl-2-imidazolyl
    294 CF3 2-F-phenyl 2-methyl-1-imidazolyl
    295 CF3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    296 CF3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    297 CF3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    298 CF3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    299 CF3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    300 CF3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    301 CF3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    302 CF3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    303 CF3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    304 CF3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    305 CF3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    306 CF3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    307 CF3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    308 CF3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    309 CF3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    310 CF3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    311 CF3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    312 CF3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    313 SCH3 phenyl 2-(aminosulfonyl)phenyl
    314 SCH3 phenyl 2-(methylaminosulfonyl)phenyl
    315 SCH3 phenyl 1-pyrrolidinocarbonyl
    316 SCH3 phenyl 2-(methylsulfonyl)phenyl
    317 SCH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    318 SCH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    319 SCH3 phenyl 1-methyl-2-imidazolyl
    320 SCH3 phenyl 2-methyl-1-imidazolyl
    321 SCH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    322 SCH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    323 SCH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    324 SCH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    325 SCH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    326 SCH3 2-pyridyl 2-(aminosulfonyl)phenyl
    327 SCH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    328 SCH3 2-pyridyl 1-pyrrolidinocarbonyl
    329 SCH3 2-pyridyl 2-(methylsulfonyl)phenyl
    330 SCH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    331 SCH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    332 SCH3 2-pyridyl 1-methyl-2-imidazolyl
    333 SCH3 2-pyridyl 2-methyl-1-imidazolyl
    334 SCH3 2-pyridyl 2-(dimethylaminomethyl)-l-
    imidazolyl
    335 SCH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    336 SCH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    337 SCH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    338 SCH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    339 SCH3 3-pyridyl 2-(aminosulfonyl)phenyl
    340 SCH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    341 SCH3 3-pyridyl 1-pyrrolidinocarbonyl
    342 SCH3 3-pyridyl 2-(methylsulfonyl)phenyl
    343 SCH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    344 SCH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    345 SCH3 3-pyridyl 1-methyl-2-imidazolyl
    346 SCH3 3-pyridyl 2-methyl-1-imidazolyl
    347 SCH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    348 SCH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    349 SCH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    350 SCH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    351 SCH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    352 SCH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    353 SCH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    354 SCH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    355 SCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    356 SCH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    357 SCH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    358 SCH3 2-pyrimidyl 1-methyl-2-imidazolyl
    359 SCH3 2-pyrimidyl 2-methyl-1-imidazolyl
    360 SCH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    361 SCH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    362 SCH3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    363 SCH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    364 SCH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    365 SCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    366 SCH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    367 SCH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    368 SCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    369 SCH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    370 SCH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    371 SCH3 5-pyrimidyl 1-methyl-2-imidazolyl
    372 SCH3 5-pyrimidyl 2-methyl-1-imidazolyl
    373 SCH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    374 SCH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    375 SCH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    376 SCH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    377 SCH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    378 SCH3 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    379 SCH3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    380 SCH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
    381 SCH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    382 SCH3 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    383 SCH3 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    384 SCH3 2-Cl-phenyl 1-methyl-2-imidazolyl
    385 SCH3 2-Cl-phenyl 2-methyl-1-imidazolyl
    386 SCH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    387 SCH3 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    388 SCH3 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    389 SCH3 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    390 SCH3 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    391 SCH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    392 SCH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    393 SCH3 2-F-phenyl 1-pyrrolidinocarbonyl
    394 SCH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    395 SCH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    396 SCH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    397 SCH3 2-F-phenyl 1-methyl-2-imidazolyl
    398 SCH3 2-F-phenyl 2-methyl-1-imidazolyl
    399 SCH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    400 SCH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    401 SCH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    402 SCH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    403 SCH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    404 SCH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    405 SCH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    406 SCH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    407 SCH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    408 SCH3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    409 SCH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    410 SCH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    411 SCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    412 SCH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    413 SCH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    414 SCH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    415 SCH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    416 SCH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    417 SOCH3 phenyl 2-(aminosulfonyl)phenyl
    418 SOCH3 phenyl 2-(methylaminosulfonyl)phenyl
    419 SOCH3 phenyl 1-pyrrolidinocarbonyl
    420 SOCH3 phenyl 2-(methylsulfonyl)phenyl
    421 SOCH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    422 SOCH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    423 SOCH3 phenyl 1-methyl-2-imidazolyl
    424 SOCH3 phenyl 2-methyl-1-imidazolyl
    425 SOCH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    426 SOCH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    427 SOCH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    428 SOCH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    429 SOCH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    430 SOCH3 2-pyridyl 2-(aminosulfonyl)phenyl
    431 SOCH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    432 SOCH3 2-pyridyl 1-pyrrolidinocarbonyl
    433 SOCH3 2-pyridyl 2-(methylsulfonyl)phenyl
    434 SOCH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    435 SOCH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    436 SOCH3 2-pyridyl 1-methyl-2-imidazolyl
    437 SOCH3 2-pyridyl 2-methyl-1-imidazolyl
    438 SOCH3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    439 SOCH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    440 SOCH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    441 SOCH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    442 SOCH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    443 SOCH3 3-pyridyl 2-(aminosulfonyl)phenyl
    444 SOCH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    445 SOCH3 3-pyridyl 1-pyrrolidinocarbonyl
    446 SOCH3 3-pyridyl 2-(methylsulfonyl)phenyl
    447 SOCH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    448 SOCH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    449 SOCH3 3-pyridyl 1-methyl-2-imidazolyl
    450 SOCH3 3-pyridyl 2-methyl-1-imidazolyl
    451 SOCH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    452 SOCH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    453 SOCH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    454 SOCH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    455 SOCH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    456 SOCH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    457 SOCH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    458 SOCH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    459 SOCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    460 SOCH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    461 SOCH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    462 SOCH3 2-pyrimidyl 1-methyl-2-imidazolyl
    463 SOCH3 2-pyrimidyl 2-methyl-1-imidazolyl
    464 SOCH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    465 SOCH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    466 SOCH3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    467 SOCH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    468 SOCH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    469 SOCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    470 SOCH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    471 SOCH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    472 SOCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    473 SOCH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    474 SOCH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    475 SOCH3 5-pyrimidyl 1-methyl-2-imidazolyl
    476 SOCH3 5-pyrimidyl 2-methyl-1-imidazolyl
    477 SOCH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    478 SOCH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    479 SOCH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    480 SOCH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    481 SOCH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    482 SOCH3 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    483 SOCH3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    484 SOCH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
    485 SOCH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    486 SOCH3 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    487 SOCH3 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    488 SOCH3 2-Cl-phenyl 1-methyl-2-imidazolyl
    489 SOCH3 2-Cl-phenyl 2-methyl-1-imidazolyl
    490 SOCH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    491 SOCH3 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    492 SOCH3 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    493 SOCH3 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    494 SOCH3 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    495 SOCH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    496 SOCH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    497 SOCH3 2-F-phenyl 1-pyrrolidinocarbonyl
    498 SOCH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    499 SOCH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    500 SOCH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    501 SOCH3 2-F-phenyl 1-methyl-2-imidazolyl
    502 SOCH3 2-F-phenyl 2-methyl-1-imidazolyl
    503 SOCH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    504 SOCH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    505 SOCH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    506 SOCH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    507 SOCH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    508 SOCH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    509 SOCH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    510 SOCH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    511 SOCH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    512 SOCH3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    513 SOCH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    514 SOCH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    515 SOCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    516 SOCH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    517 SOCH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    518 SOCH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    519 SOCH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    520 SOCH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    521 SO2CH3 phenyl 2-(aminosulfonyl)phenyl
    522 SO2CH3 phenyl 2-(methylaminosulfonyl)phenyl
    523 SO2CH3 phenyl 1-pyrrolidinocarbonyl
    524 SO2CH3 phenyl 2-(methylsulfonyl)phenyl
    525 SO2CH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    526 SO2CH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    527 SO2CH3 phenyl 1-methyl-2-imidazolyl
    528 SO2CH3 phenyl 2-methyl-1-imidazolyl
    529 SO2CH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    530 SO2CH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    531 SO2CH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    532 SO2CH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    533 SO2CH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    534 SO2CH3 2-pyridyl 2-(aminosulfonyl)phenyl
    535 SO2CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    536 SO2CH3 2-pyridyl 1-pyrrolidinocarbonyl
    537 SO2CH3 2-pyridyl 2-(methylsulfonyl)phenyl
    538 SO2CH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    539 SO2CH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    540 SO2CH3 2-pyridyl 1-methyl-2-imidazolyl
    541 SO2CH3 2-pyridyl 2-methyl-1-imidazolyl
    542 SO2CH3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    543 SO2CH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    544 SO2CH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    545 SO2CH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    546 SO2CH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    547 SO2CH3 3-pyridyl 2-(aminosulfonyl)phenyl
    548 SO2CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    549 SO2CH3 3-pyridyl 1-pyrrolidinocarbonyl
    550 SO2CH3 3-pyridyl 2-(methylsulfonyl)phenyl
    551 SO2CH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    552 SO2CH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    553 SO2CH3 3-pyridyl 1-methyl-2-imidazolyl
    554 SO2CH3 3-pyridyl 2-methyl-1-imidazolyl
    555 SO2CH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    556 SO2CH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    557 SO2CH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    558 SO2CH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    559 SO2CH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    560 SO2CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    561 SO2CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    562 SO2CH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    563 SO2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    564 SO2CH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    565 SO2CH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    566 SO2CH3 2-pyrimidyl 1-methyl-2-imidazolyl
    567 SO2CH3 2-pyrimidyl 2-methyl-1-imidazolyl
    568 SO2CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    569 SO2CH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    570 SO2CH3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    571 SO2CH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    572 SO2CH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    573 SO2CH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    574 SO2CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    575 SO2CH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    576 SO2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    577 SO2CH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    578 SO2CH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    579 SO2CH3 5-pyrimidyl 1-methyl-2-imidazolyl
    580 SO2CH3 5-pyrimidyl 2-methyl-1-imidazolyl
    581 SO2CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    582 SO2CH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    583 SO2CH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    584 SO2CH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    585 SO2CH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    586 SO2CH3 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    587 SO2CH3 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    588 SO2CH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
    589 SO2CH3 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    590 SO2CH3 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    591 SO2CH3 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    592 SO2CH3 2-Cl-phenyl 1-methyl-2-imidazolyl
    593 SO2CH3 2-Cl-phenyl 2-methyl-1-imidazolyl
    594 SO2CH3 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    595 SO2CH3 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    596 SO2CH3 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    597 SO2CH3 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    598 SO2CH3 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    599 SO2CH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    600 SO2CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    601 SO2CH3 2-F-phenyl 1-pyrrolidinocarbonyl
    602 SO2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    603 SO2CH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    604 SO2CH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    605 SO2CH3 2-F-phenyl 1-methyl-2-imidazolyl
    606 SO2CH3 2-F-phenyl 2-methyl-1-imidazolyl
    607 SO2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    608 SO2CH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    609 SO2CH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    610 SO2CH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    611 SO2CH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    612 SO2CH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    613 SO2CH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    614 SO2CH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    615 SO2CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    616 SO2CH3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    617 SO2CH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    618 SO2CH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    619 SO2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    620 SO2CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    621 SO2CH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    622 SO2CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    623 SO2CH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    624 SO2CH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    625 Cl phenyl 2-(aminosulfonyl)phenyl
    626 Cl phenyl 2-(methylaminosulfonyl)phenyl
    627 Cl phenyl 1-pyrrolidinocarbonyl
    628 Cl phenyl 2-(methylsulfonyl)phenyl
    629 Cl phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    630 Cl phenyl 2-(N-pyrrolidinylmethyl)phenyl
    631 Cl phenyl 1-methyl-2-imidazolyl
    632 Cl phenyl 2-methyl-1-imidazolyl
    633 Cl phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    634 Cl phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    635 Cl phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    636 Cl phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    637 Cl phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    638 Cl 2-pyridyl 2-(aminosulfonyl)phenyl
    639 Cl 2-pyridyl 2-(methylaminosulfonyl)phenyl
    640 Cl 2-pyridyl 1-pyrrolidinocarbonyl
    641 Cl 2-pyridyl 2-(methylsulfonyl)phenyl
    642 Cl 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    643 Cl 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    644 Cl 2-pyridyl 1-methyl-2-imidazolyl
    645 Cl 2-pyridyl 2-methyl-1-imidazolyl
    646 Cl 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    647 Cl 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    648 Cl 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    649 Cl 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    650 Cl 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    651 Cl 3-pyridyl 2-(aminosulfonyl)phenyl
    652 Cl 3-pyridyl 2-(methylaminosulfonyl)phenyl
    653 Cl 3-pyridyl 1-pyrrolidinocarbonyl
    654 Cl 3-pyridyl 2-(methylsulfonyl)phenyl
    655 Cl 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    656 Cl 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    657 Cl 3-pyridyl 1-methyl-2-imidazolyl
    658 Cl 3-pyridyl 2-methyl-1-imidazolyl
    659 Cl 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    660 Cl 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    661 Cl 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    662 Cl 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    663 Cl 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    664 Cl 2-pyrimidyl 2-(aminosulfonyl)phenyl
    665 Cl 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    666 Cl 2-pyrimidyl 1-pyrrolidinocarbonyl
    667 Cl 2-pyrimidyl 2-(methylsulfonyl)phenyl
    668 Cl 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    669 Cl 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    670 Cl 2-pyrimidyl 1-methyl-2-imidazolyl
    671 Cl 2-pyrimidyl 2-methyl-1-imidazolyl
    672 Cl 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    673 Cl 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    674 Cl 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    675 Cl 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    676 Cl 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    677 Cl 5-pyrimidyl 2-(aminosulfonyl)phenyl
    678 Cl 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    679 Cl 5-pyrimidyl 1-pyrrolidinocarbonyl
    680 Cl 5-pyrimidyl 2-(methylsulfonyl)phenyl
    681 Cl 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    682 Cl 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    683 Cl 5-pyrimidyl 1-methyl-2-imidazolyl
    684 Cl 5-pyrimidyl 2-methyl-1-imidazolyl
    685 Cl 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    686 Cl 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    687 Cl 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    688 Cl 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    689 Cl 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    690 Cl 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    691 Cl 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    692 Cl 2-Cl-phenyl 1-pyrrolidinocarbonyl
    693 Cl 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    694 Cl 2-Cl-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    695 Cl 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    696 Cl 2-Cl-phenyl 1-methyl-2-imidazolyl
    697 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl
    698 Cl 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    699 Cl 2-Cl-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    700 Cl 2-Cl-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    701 Cl 2-Cl-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    702 Cl 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    703 Cl 2-F-phenyl 2-(aminosulfonyl)phenyl
    704 Cl 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    705 Cl 2-F-phenyl 1-pyrrolidinocarbonyl
    706 Cl 2-F-phenyl 2-(methylsulfonyl)phenyl
    707 Cl 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    708 Cl 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    709 Cl 2-F-phenyl 1-methyl-2-imidazolyl
    710 Cl 2-F-phenyl 2-methyl-1-imidazolyl
    711 Cl 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    712 Cl 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    713 Cl 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    714 Cl 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    715 Cl 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    716 Cl 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    717 Cl 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    718 Cl 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    719 Cl 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    720 Cl 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    721 Cl 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    722 Cl 2,6-diF-phenyl 1-methyl-2-imidazolyl
    723 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl
    724 Cl 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    725 Cl 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    726 Cl 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    727 Cl 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    728 Cl 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    729 F phenyl 2-(aminosulfonyl)phenyl
    730 F phenyl 2-(methylaminosulfonyl)phenyl
    731 F phenyl 1-pyrrolidinocarbonyl
    732 F phenyl 2-(methylsulfonyl)phenyl
    733 F phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    734 F phenyl 2-(N-pyrrolidinylmethyl)phenyl
    735 F phenyl 1-methyl-2-imidazolyl
    736 F phenyl 2-methyl-1-imidazolyl
    737 F phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    738 F phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    739 F phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    740 F phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    741 F phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    742 F 2-pyridyl 2-(aminosulfonyl)phenyl
    743 F 2-pyridyl 2-(methylaminosulfonyl)phenyl
    744 F 2-pyridyl 1-pyrrolidinocarbonyl
    745 F 2-pyridyl 2-(methylsulfonyl)phenyl
    746 F 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    747 F 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    748 F 2-pyridyl 1-methyl-2-imidazolyl
    749 F 2-pyridyl 2-methyl-1-imidazolyl
    750 F 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    751 F 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    752 F 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    753 F 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    754 F 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    755 F 3-pyridyl 2-(aminosulfonyl)phenyl
    756 F 3-pyridyl 2-(methylaminosulfonyl)phenyl
    757 F 3-pyridyl 1-pyrrolidinocarbonyl
    758 F 3-pyridyl 2-(methylsulfonyDphenyl
    759 F 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    760 F 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    761 F 3-pyridyl 1-methyl-2-imidazolyl
    762 F 3-pyridyl 2-methyl-1-imidazolyl
    763 F 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    764 F 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    765 F 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    766 F 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    767 F 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    768 F 2-pyrimidyl 2-(aminosulfonyl)phenyl
    769 F 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    770 F 2-pyrimidyl 1-pyrrolidinocarbonyl
    771 F 2-pyrimidyl 2-(methylsulfonyl)phenyl
    772 F 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    773 F 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    774 F 2-pyrimidyl 1-methyl-2-imidazolyl
    775 F 2-pyrimidyl 2-methyl-1-imidazolyl
    776 F 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    777 F 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    778 F 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    779 F 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    780 F 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    781 F 5-pyrimidyl 2-(aminosulfonyl)phenyl
    782 F 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    783 F 5-pyrimidyl 1-pyrrolidinocarbonyl
    784 F 5-pyrimidyl 2-(methylsulfonyl)phenyl
    785 F 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    786 F 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    787 F 5-pyrimidyl 1-methyl-2-imidazolyl
    788 F 5-pyrimidyl 2-methyl-1-imidazolyl
    789 F 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    790 F 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    791 F 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    792 F 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    793 F 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    794 F 2-F-phenyl 2-(aminosulfonyl)phenyl
    795 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    796 F 2-F-phenyl 1-pyrrolidinocarbonyl
    797 F 2-F-phenyl 2-(methylsulfonyl)phenyl
    798 F 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    799 F 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    800 F 2-F-phenyl 1-methyl-2-imidazolyl
    801 F 2-F-phenyl 2-methyl-1-imidazolyl
    802 F 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    803 F 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    804 F 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    805 F 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    806 F 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    807 F 2-F-phenyl 2-(aminosulfonyl)phenyl
    808 F 2-F-phenyl 2-(methylaminosuLfonyl)phenyl
    809 F 2-F-phenyl 1-pyrrolidinocarbonyl
    810 F 2-F-phenyl 2-(methylsulfonyl)phenyl
    811 F 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    812 F 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    813 F 2-F-phenyl 1-methyl-2-imidazolyl
    814 F 2-F-phenyl 2-methyl-1-imidazolyl
    815 F 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    816 F 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    817 F 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    818 F 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    819 F 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    820 F 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    821 F 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    822 F 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    823 F 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    824 F 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    825 F 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    826 F 2,6-diF-phenyl 1-methyl-2-imidazolyl
    827 F 2,6-diF-phenyl 2-methyl-1-imidazolyl
    828 F 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    829 F 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    830 F 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    831 F 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    832 F 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    833 CO2CH3 phenyl 2-(aminosulfonyl)phenyl
    834 CO2CH3 phenyl 2-(methylaminosulfonyl)phenyl
    835 CO2CH3 phenyl 1-pyrrolidinocarbonyl
    836 CO2CH3 phenyl 2-(methylsulfonyl)phenyl
    837 CO2CH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    838 CO2CH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    839 CO2CH3 phenyl 1-methyl-2-imidazolyl
    840 CO2CH3 phenyl 2-methyl-1-imidazolyl
    841 CO2CH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    842 CO2CH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    843 CO2CH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    844 CO2CH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    845 CO2CH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    846 CO2CH3 2-pyridyl 2-(aminosulfonyl)phenyl
    847 CO2CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    848 CO2CH3 2-pyridyl 1-pyrrolidinocarbonyl
    849 CO2CH3 2-pyridyl 2-(methylsulfonyl)phenyl
    850 CO2CH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    851 CO2CH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    852 CO2CH3 2-pyridyl 1-methyl-2-imidazolyl
    853 CO2CH3 2-pyridyl 2-methyl-1-imidazolyl
    854 CO2CH3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    855 CO2CH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    856 CO2CH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    857 CO2CH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    858 CO2CH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    859 CO2CH3 3-pyridyl 2-(aminosulfonyl)phenyl
    860 CO2CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    861 CO2CH3 3-pyridyl 1-pyrrolidinocarbonyl
    862 CO2CH3 3-pyridyl 2-(methylsulfonyl)phenyl
    863 CO2CH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    864 CO2CH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    865 CO2CH3 3-pyridyl 1-methyl-2-imidazolyl
    866 CO2CH3 3-pyridyl 2-methyl-1-imidazolyl
    867 CO2CH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    868 CO2CH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    869 CO2CH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    870 CO2CH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    871 CO2CH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    872 CO2CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    873 CO2CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    874 CO2CH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    875 CO2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    876 CO2CH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    877 CO2CH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    878 CO2CH3 2-pyrimidyl 1-methyl-2-imidazolyl
    879 CO2CH3 2-pyrimidyl 2-methyl-1-imidazolyl
    880 CO2CH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    881 CO2CH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    882 CO2CH3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    883 CO2CH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    884 CO2CH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    885 CO2CH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    886 CO2CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    887 CO2CH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    888 CO2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    889 CO2CH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    890 CO2CH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    891 CO2CH3 5-pyrimidyl 1-methyl-2-imidazolyl
    892 CO2CH3 5-pyrimidyl 2-methyl-1-imidazolyl
    893 CO2CH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    894 CO2CH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    895 CO2CH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    896 CO2CH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    897 CO2CH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    898 CO2CH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    899 CO2CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    900 CO2CH3 2-F-phenyl 1-pyrrolidinocarbonyl
    901 CO2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    902 CO2CH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    903 CO2CH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    904 CO2CH3 2-F-phenyl 1-methyl-2-imidazolyl
    905 CO2CH3 2-F-phenyl 2-methyl-1-imidazolyl
    906 CO2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    907 CO2CH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    908 CO2CH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    909 CO2CH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    910 CO2CH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    911 CO2CH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    912 CO2CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    913 CO2CH3 2-F-phenyl 1-pyrrolidinocarbonyl
    914 CO2CH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    915 CO2CH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)pheny
    916 CO2CH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    917 CO2CH3 2-F-phenyl 1-methyl-2-imidazolyl
    918 CO2CH3 2-F-phenyl 2-methyl-1-imidazolyl
    919 CO2CH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    920 CO2CH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    921 CO2CH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    922 CO2CH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    923 CO2CH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    924 CO2CH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    925 CO2CH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    926 CO2CH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    927 CO2CH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    928 CO2CH3 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phen)
    929 CO2CH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    930 CO2CH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    931 CO2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    932 CO2CH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    933 CO2CH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    934 CO2CH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    935 CO2CH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    936 CO2CH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    937 CH2OCH3 phenyl 2-(aminosulfonyl)phenyl
    938 CH2OCH3 phenyl 2-(methylaminosulfonyl)phenyl
    939 CH2OCH3 phenyl 1-pyrrolidinocarbonyl
    940 CH2OCH3 phenyl 2-(methylsulfonyl)phenyl
    941 CH2OCH3 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    942 CH2OCH3 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    943 CH2OCH3 phenyl 1-methyl-2-imidazolyl
    944 CH2OCH3 phenyl 2-methyl-1-imidazolyl
    945 CH2OCH3 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    946 CH2OCH3 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    947 CH2OCH3 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    948 CH2OCH3 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    949 CH2OCH3 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    950 CH2OCH3 2-pyridyl 2-(aminosulfonyl)phenyl
    951 CH2OCH3 2-pyridyl 2-(methylaminosulfonyl)phenyl
    952 CH2OCH3 2-pyridyl 1-pyrrolidinocarbonyl
    953 CH2OCH3 2-pyridyl 2-(methylsulfonyl)phenyl
    954 CH2OCH3 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    955 CH2OCH3 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    956 CH2OCH3 2-pyridyl 1-methyl-2-imidazolyl
    957 CH2OCH3 2-pyridyl 2-methyl-1-imidazolyl
    958 CH2OCH3 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    959 CH2OCH3 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    960 CH2OCH3 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    961 CH2OCH3 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    962 CH2OCH3 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    963 CH2OCH3 3-pyridyl 2-(aminosulfonyl)phenyl
    964 CH2OCH3 3-pyridyl 2-(methylaminosulfonyl)phenyl
    965 CH2OCH3 3-pyridyl 1-pyrrolidinocarbonyl
    966 CH2OCH3 3-pyridyl 2-(methylsulfonyl)phenyl
    967 CH2OCH3 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    968 CH2OCH3 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    969 CH2OCH3 3-pyridyl 1-methyl-2-imidazolyl
    970 CH2OCH3 3-pyridyl 2-methyl-1-imidazolyl
    971 CH2OCH3 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    972 CH2OCH3 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    973 CH2OCH3 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    974 CH2OCH3 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    975 CH2OCH3 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    976 CH2OCH3 2-pyrimidyl 2-(aminosulfonyl)phenyl
    977 CH2OCH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    978 CH2OCH3 2-pyrimidyl 1-pyrrolidinocarbonyl
    979 CH2OCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl
    980 CH2OCH3 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    981 CH2OCH3 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    982 CH2OCH3 2-pyrimidyl 1-methyl-2-imidazolyl
    983 CH2OCH3 2-pyrimidyl 2-methyl-1-imidazolyl
    984 CH2OCH3 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    985 CH2OCH3 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    986 CH2OCH3 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    987 CH2OCH3 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    988 CH2OCH3 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    989 CH2OCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl
    990 CH2OCH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    991 CH2OCH3 5-pyrimidyl 1-pyrrolidinocarbonyl
    992 CH2OCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl
    993 CH2OCH3 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    994 CH2OCH3 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    995 CH2OCH3 5-pyrimidyl 1-methyl-2-imidazolyl
    996 CH2OCH3 5-pyrimidyl 2-methyl-1-imidazolyl
    997 CH2OCH3 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    998 CH2OCH3 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    999 CH2OCH3 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1000 CH2OCH3 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1001 CH2OCH3 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1002 CH2OCH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    1003 CH2OCH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1004 CH2OCH3 2-F-phenyl 1-pyrrolidinocarbonyl
    1005 CH2OCH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    1006 CH2OCH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1007 CH2OCH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1008 CH2OCH3 2-F-phenyl 1-methyl-2-imidazolyl
    1009 CH2OCH3 2-F-phenyl 2-methyl-1-imidazolyl
    1010 CH2OCH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1011 CH2OCH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1012 CH2OCH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1013 CH2OCH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1014 CH2OCH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1015 CH2OCH3 2-F-phenyl 2-(aminosulfonyl)phenyl
    1016 CH2OCH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1017 CH2OCH3 2-F-phenyl 1-pyrrolidinocarbonyl
    1018 CH2OCH3 2-F-phenyl 2-(methylsulfonyl)phenyl
    1019 CH2OCH3 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1020 CH2OCH3 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1021 CH2OCH3 2-F-phenyl 1-methyl-2-imidazolyl
    1022 CH2OCH3 2-F-phenyl 2-methyl-1-imidazolyl
    1023 CH2OCH3 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1024 CH2OCH3 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1025 CH2OCH3 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1026 CH2OCH3 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1027 CH2OCH3 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1028 CH2OCH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    1029 CH2OCH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    1030 CH2OCH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    1031 CH2OCH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    1032 CH2OCH3 2,6-diF-phenyl 2-(N,N-
    dimethylaininomethyl)phenyl
    1033 CH2OCH3 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1034 CH2OCH3 2,6-diF-phenyl 1-methyl-2-imidazolyl
    1035 CH2OCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl
    1036 CH2OCH3 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1037 CH2OCH3 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1038 CH2OCH3 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1039 CH2OCH3 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1040 CH2OCH3 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1041 CONH2 phenyl 2-(aminosulfonyl)phenyl
    1042 CONH2 phenyl 2-(methylaminosulfonyl)phenyl
    1043 CONH2 phenyl 1-pyrrolidinocarbonyl
    1044 CONH2 phenyl 2-(methylsulfonyl)phenyl
    1045 CONH2 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1046 CONH2 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1047 CONH2 phenyl 1-methyl-2-imidazolyl
    1048 CONH2 phenyl 2-methyl-1-imidazolyl
    1049 CONH2 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1050 CONH2 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1051 CONH2 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1052 CONH2 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1053 CONH2 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1054 CONH2 2-pyridyl 2-(aminosulfonyl)phenyl
    1055 CONH2 2-pyridyl 2-(methylaminosulfonyl)phenyl
    1056 CONH2 2-pyridyl 1-pyrrolidinocarbonyl
    1057 CONH2 2-pyridyl 2-(methylsulfonyl)phenyl
    1058 CONH2 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1059 CONH2 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    1060 CONH2 2-pyridyl 1-methyl-2-imidazolyl
    1061 CONH2 2-pyridyl 2-methyl-1-imidazolyl
    1062 CONH2 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1063 CONH2 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1064 CONH2 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1065 CONH2 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1066 CONH2 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1067 CONH2 3-pyridyl 2-(aminosulfonyl)phenyl
    1068 CONH2 3-pyridyl 2-(methylaminosulfonyl)phenyl
    1069 CONH2 3-pyridyl 1-pyrrolidinocarbonyl
    1070 CONH2 3-pyridyl 2-(methylsulfonyl)phenyl
    1071 CONH2 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1072 CONH2 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    1073 CONH2 3-pyridyl 1-methyl-2-imidazolyl
    1074 CONH2 3-pyridyl 2-methyl-1-imidazolyl
    1075 CONH2 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1076 CONH2 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1077 CONH2 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1078 CONH2 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1079 CONH2 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1080 CONH2 2-pyrimidyl 2-(aminosulfonyl)phenyl
    1081 CONH2 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    1082 CONH2 2-pyrimidyl 1-pyrrolidinocarbonyl
    1083 CONH2 2-pyrimidyl 2-(methylsulfonyl)phenyl
    1084 CONH2 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1085 CONH2 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    1086 CONH2 2-pyrimidyl 1-methyl-2-imidazolyl
    1087 CONH2 2-pyrimidyl 2-methyl-1-imidazolyl
    1088 CONH2 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1089 CONH2 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1090 CONH2 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1091 CONH2 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1092 CONH2 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1093 CONH2 5-pyrimidyl 2-(aminosulfonyl)phenyl
    1094 CONH2 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    1095 CONH2 5-pyrimidyl 1-pyrrolidinocarbonyl
    1096 CONH2 5-pyrimidyl 2-(methylsulfonyl)phenyl
    1097 CONH2 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1098 CONH2 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    1099 CONH2 5-pyrimidyl 1-methyl-2-imidazolyl
    1100 CONH2 5-pyrimidyl 2-methyl-1-imidazolyl
    1101 CONH2 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1102 CONH2 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1103 CONH2 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1104 CONH2 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1105 CONH2 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1106 CONH2 2-F-phenyl 2-(aminosulfonyl)phenyl
    1107 CONH2 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1108 CONH2 2-F-phenyl 1-pyrrolidinocarbonyl
    1109 CONH2 2-F-phenyl 2-(methylsulfonyl)phenyl
    1110 CONH2 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1111 CONH2 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1112 CONH2 2-F-phenyl 1-methyl-2-imidazolyl
    1113 CONH2 2-F-phenyl 2-methyl-1-imidazolyl
    1114 CONH2 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1115 CONH2 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1116 CONH2 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1117 CONH2 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1118 CONH2 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1119 CONH2 2-F-phenyl 2-(aminosulfonyl)phenyl
    1120 CONH2 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1121 CONH2 2-F-phenyl 1-pyrrolidinocarbonyl
    1122 CONH2 2-F-phenyl 2-(methylsulfonyl)phenyl
    1123 CONH2 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1124 CONH2 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1125 CONH2 2-F-phenyl 1-methyl-2-imidazolyl
    1126 CONH2 2-F-phenyl 2-methyl-1-imidazolyl
    1127 CONH2 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1128 CONH2 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1129 CONH2 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1130 CONH2 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1131 CONH2 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1132 CONH2 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    1133 CONH2 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    1134 CONH2 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    1135 CONH2 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    1136 CONH2 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1137 CONH2 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1138 CONH2 2,6-diF-phenyl 1-methyl-2-imidazolyl
    1139 CONH2 2,6-diF-phenyl 2-methyl-1-imidazolyl
    1140 CONH2 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1141 CONH2 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1142 CONH2 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1143 CONH2 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1144 CONH2 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1145 CN phenyl 2-(aminosulfonyl)phenyl
    1146 CN phenyl 2-(methylaminosulfonyl)phenyl
    1147 CN phenyl 1-pyrrolidinocarbonyl
    1148 CN phenyl 2-(methylsulfonyl)phenyl
    1149 CN phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1150 CN phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1151 CN phenyl 1-methyl-2-imidazolyl
    1152 CN phenyl 2-methyl-1-imidazolyl
    1153 CN phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1154 CN phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1155 CN phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1156 CN phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1157 CN phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1158 CN 2-pyridyl 2-(aminosulfonyl)phenyl
    1159 CN 2-pyridyl 2-(methylaminosulfonyl)phenyl
    1160 CN 2-pyridyl 1-pyrrolidinocarbonyl
    1161 CN 2-pyridyl 2-(methylsulfonyl)phenyl
    1162 CN 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1163 CN 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    1164 CN 2-pyridyl 1-methyl-2-imidazolyl
    1165 CN 2-pyridyl 2-methyl-1-imidazolyl
    1166 CN 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1167 CN 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1168 CN 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1169 CN 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1170 CN 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1171 CN 3-pyridyl 2-(aminosulfonyl)phenyl
    1172 CN 3-pyridyl 2-(methylaminosulfonyl)phenyl
    1173 CN 3-pyridyl 1-pyrrolidinocarbonyl
    1174 CN 3-pyridyl 2-(methylsulfonyl)phenyl
    1175 CN 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1176 CN 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    1177 CN 3-pyridyl 1-methyl-2-imidazolyl
    1178 CN 3-pyridyl 2-methyl-1-imidazolyl
    1179 CN 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1180 CN 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1181 CN 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1182 CN 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1183 CN 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1184 CN 2-pyrimidyl 2-(aminosulfonyl)phenyl
    1185 CN 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    1186 CN 2-pyrimidyl 1-pyrrolidinocarbonyl
    1187 CN 2-pyrimidyl 2-(methylsulfonyl)phenyl
    1188 CN 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1189 CN 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    1190 CN 2-pyrimidyl 1-methyl-2-imidazolyl
    1191 CN 2-pyrimidyl 2-methyl-1-imidazolyl
    1192 CN 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1193 CN 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1194 CN 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1195 CN 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1196 CN 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1197 CN 5-pyrimidyl 2-(aminosulfonyl)phenyl
    1198 CN 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    1199 CN 5-pyrimidyl 1-pyrrolidinocarbonyl
    1200 CN 5-pyrimidyl 2-(methylsulfonyl)phenyl
    1201 CN 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1202 CN 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    1203 CN 5-pyrimidyl 1-methyl-2-imidazolyl
    1204 CN 5-pyrimidyl 2-methyl-1-imidazolyl
    1205 CN 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1206 CN 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1207 CN 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1208 CN 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1209 CN 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1210 CN 2-F-phenyl 2-(aminosulfonyl)phenyl
    1211 CN 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1212 CN 2-F-phenyl 1-pyrrolidinocarbonyl
    1213 CN 2-F-phenyl 2-(methylsulfonyl)phenyl
    1214 CN 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1215 CN 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1216 CN 2-F-phenyl 1-methyl-2-imidazolyl
    1217 CN 2-F-phenyl 2-methyl-1-imidazolyl
    1218 CN 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1219 CN 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1220 CN 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1221 CN 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1222 CN 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1223 CN 2-F-phenyl 2-(aminosulfonyl)phenyl
    1224 CN 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1225 CN 2-F-phenyl 1-pyrrolidinocarbonyl
    1226 CN 2-F-phenyl 2-(methylsulfonyl)phenyl
    1227 CN 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1228 CN 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1229 CN 2-F-phenyl 1-methyl-2-imidazolyl
    1230 CN 2-F-phenyl 2-methyl-1-imidazolyl
    1231 CN 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1232 CN 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1233 CN 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1234 CN 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1235 CN 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1236 CN 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    1237 CN 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    1238 CN 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    1239 CN 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    1240 CN 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1241 CN 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1242 CN 2,6-diF-phenyl 1-methyl-2-imidazolyl
    1243 CN 2,6-diF-phenyl 2-methyl-1-imidazolyl
    1244 CN 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1245 CN 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1246 CN 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1247 CN 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1248 CN 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1249 CH2NH2 phenyl 2-(aminosulfonyl)phenyl
    1250 CH2NH2 phenyl 2-(methylaminosulfonyl)phenyl
    1251 CH2NH2 phenyl 1-pyrrolidinocarbonyl
    1252 CH2NH2 phenyl 2-(methylsulfonyl)phenyl
    1253 CH2NH2 phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1254 CH2NH2 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1255 CH2NH2 phenyl 1-methyl-2-imidazolyl
    1256 CH2NH2 phenyl 2-methyl-1-imidazolyl
    1257 CH2NH2 phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1258 CH2NH2 phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1259 CH2NH2 phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1260 CH2NH2 phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1261 CH2NH2 phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1262 CH2NH2 2-pyridyl 2-(aminosulfonyl)phenyl
    1263 CH2NH2 2-pyridyl 2-(methylaminosulfonyl)phenyl
    1264 CH2NH2 2-pyridyl 1-pyrrolidinocarbonyl
    1265 CH2NH2 2-pyridyl 2-(methylsulfonyl)phenyl
    1266 CH2NH2 2-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1267 CH2NH2 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    1268 CH2NH2 2-pyridyl 1-methyl-2-imidazolyl
    1269 CH2NH2 2-pyridyl 2-methyl-1-imidazolyl
    1270 CH2NH2 2-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1271 CH2NH2 2-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1272 CH2NH2 2-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1273 CH2NH2 2-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1274 CH2NH2 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1275 CH2NH2 3-pyridyl 2-(aminosulfonyl)phenyl
    1276 CH2NH2 3-pyridyl 2-(methylaminosulfonyl)phenyl
    1277 CH2NH2 3-pyridyl 1-pyrrolidinocarbonyl
    1278 CH2NH2 3-pyridyl 2-(methylsulfonyl)phenyl
    1279 CH2NH2 3-pyridyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1280 CH2NH2 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    1281 CH2NH2 3-pyridyl 1-methyl-2-imidazolyl
    1282 CH2NH2 3-pyridyl 2-methyl-1-imidazolyl
    1283 CH2NH2 3-pyridyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1284 CH2NH2 3-pyridyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1285 CH2NH2 3-pyridyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1286 CH2NH2 3-pyridyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1287 CH2NH2 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1288 CH2NH2 2-pyrimidyl 2-(aminosulfonyl)phenyl
    1289 CH2NH2 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    1290 CH2NH2 2-pyrimidyl 1-pyrrolidinocarbonyl
    1291 CH2NH2 2-pyrimidyl 2-(methylsulfonyl)phenyl
    1292 CH2NH2 2-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1293 CH2NH2 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    1294 CH2NH2 2-pyrimidyl 1-methyl-2-imidazolyl
    1295 CH2NH2 2-pyrimidyl 2-methyl-1-imidazolyl
    1296 CH2NH2 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1297 CH2NH2 2-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1298 CH2NH2 2-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1299 CH2NH2 2-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1300 CH2NH2 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1301 CH2NH2 5-pyrimidyl 2-(aminosulfonyl)phenyl
    1302 CH2NH2 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    1303 CH2NH2 5-pyrimidyl 1-pyrrolidinocarbonyl
    1304 CH2NH2 5-pyrimidyl 2-(methylsulfonyl)phenyl
    1305 CH2NH2 5-pyrimidyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1306 CH2NH2 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    1307 CH2NH2 5-pyrimidyl 1-methyl-2-imidazolyl
    1308 CH2NH2 5-pyrimidyl 2-methyl-1-imidazolyl
    1309 CH2NH2 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1310 CH2NH2 5-pyrimidyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1311 CH2NH2 5-pyrimidyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1312 CH2NH2 5-pyrimidyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1313 CH2NH2 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1314 CH2NH2 2-F-phenyl 2-(aminosulfonyl)phenyl
    1315 CH2NH2 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1316 CH2NH2 2-F-phenyl 1-pyrrolidinocarbonyl
    1317 CH2NH2 2-F-phenyl 2-(methylsulfonyl)phenyl
    1318 CH2NH2 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1319 CH2NH2 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1320 CH2NH2 2-F-phenyl 1-methyl-2-imidazolyl
    1321 CH2NH2 2-F-phenyl 2-methyl-1-imidazolyl
    1322 CH2NH2 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1323 CH2NH2 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1324 CH2NH2 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1325 CH2NH2 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1326 CH2NH2 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1327 CH2NH2 2-F-phenyl 2-(aminosulfonyl)phenyl
    1328 CH2NH2 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    1329 CH2NH2 2-F-phenyl 1-pyrrolidinocarbonyl
    1330 CH2NH2 2-F-phenyl 2-(methylsulfonyl)phenyl
    1331 CH2NH2 2-F-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1332 CH2NH2 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1333 CH2NH2 2-F-phenyl 1-methyl-2-imidazolyl
    1334 CH2NH2 2-F-phenyl 2-methyl-1-imidazolyl
    1335 CH2NH2 2-F-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1336 CH2NH2 2-F-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1337 CH2NH2 2-F-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1338 CH2NH2 2-F-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1339 CH2NH2 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1340 CH2NH2 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    1341 CH2NH2 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    1342 CH2NH2 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    1343 CH2NH2 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    1344 CH2NH2 2,6-diF-phenyl 2-(N,N-
    dimethylaminomethyl)phenyl
    1345 CH2NH2 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    1346 CH2NH2 2,6-diF-phenyl 1-methyl-2-imidazolyl
    1347 CH2NH2 2,6-diF-phenyl 2-methyl-1-imidazolyl
    1348 CH2NH2 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    imidazolyl
    1349 CH2NH2 2,6-diF-phenyl 2-(N-(cyclopropyl-
    methyl)aminomethyl)phenyl
    1350 CH2NH2 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    aminomethyl)phenyl
    1351 CH2NH2 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    aminomethyl)phenyl
    1352 CH2NH2 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    methyl)phenyl
    1353 CH2NH- phenyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1354 CH2NH- phenyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1355 CH2NH- phenyl 1-pyrrolidinocarbonyl
    SO2CH3
    1356 CH2NH- phenyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1357 CH2NH- phenyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1358 CH2NH- phenyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1359 CH2NH- phenyl 1-methyl-2-imidazolyl
    SO2CH3
    1360 CH2NH- phenyl 2-methyl-1-imidazolyl
    SO2CH3
    1361 CH2NH- phenyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1362 CH2NH- phenyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1363 CH2NH- phenyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1364 CH2NH- phenyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1365 CH2NH- phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1366 CH2NH- 2-pyridyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1367 CH2NH- 2-pyridyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1368 CH2NH- 2-pyridyl 1-pyrrolidinocarbonyl
    SO2CH3
    1369 CH2NH- 2-pyridyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1370 CH2NH- 2-pyridyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    SO2CH3
    1371 CH2NH- 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1372 CH2NH- 2-pyridyl 1-methyl-2-imidazolyl
    SO2CH3
    1373 CH2NH- 2-pyridyl 2-methyl-1-imidazolyl
    SO2CH3
    1374 CH2NH- 2-pyridyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1375 CH2NH- 2-pyridyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1376 CH2NH- 2-pyridyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1377 CH2NH- 2-pyridyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1378 CH2NH- 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1379 CH2NH- 3-pyridyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1380 CH2NH- 3-pyridyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1381 CH2NH- 3-pyridyl 1-pyrrolidinocarbonyl
    SO2CH3
    1382 CH2NH- 3-pyridyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1383 CH2NH- 3-pyridyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1384 CH2NH- 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1385 CH2NH- 3-pyridyl 1-methyl-2-imidazolyl
    SO2CH3
    1386 CH2NH- 3-pyridyl 2-methyl-1-imidazolyl
    SO2CH3
    1387 CH2NH- 3-pyridyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1388 CH2NH- 3-pyridyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1389 CH2NH- 3-pyridyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1390 CH2NH- 3-pyridyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1391 CH2NH- 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1392 CH2NH- 2-pyrimidyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1393 CH2NH- 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1394 CH2NH- 2-pyrimidyl 1-pyrrolidinocarbonyl
    SO2CH3
    1395 CH2NH- 2-pyrimidyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1396 CH2NH- 2-pyrimidyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1397 CH2NH- 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1398 CH2NH- 2-pyrimidyl 1-methyl-2-imidazolyl
    SO2CH3
    1399 CH2NH- 2-pyrimidyl 2-methyl-1-imidazolyl
    SO2CH3
    1400 CH2NH- 2-pyrimidyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1401 CH2NH- 2-pyrimidyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1402 CH2NH- 2-pyrimidyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1403 CH2NH- 2-pyrimidyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1404 CH2NH- 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1405 CH2NH- 5-pyrimidyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1406 CH2NH- 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1407 CH2NH- 5-pyrimidyl 1-pyrrolidinocarbonyl
    SO2CH3
    1408 CH2NH- 5-pyrimidyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1409 CH2NH- 5-pyrimidyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1410 CH2NH- 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1411 CH2NH- 5-pyrimidyl 1-methyl-2-imidazolyl
    SO2CH3
    1412 CH2NH- 5-pyrimidyl 2-methyl-1-imidazolyl
    SO2CH3
    1413 CH2NH- 5-pyrimidyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1414 CH2NH- 5-pyrimidyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1415 CH2NH- 5-pyrimidyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1416 CH2NH- 5-pyrimidyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1417 CH2NH- 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1418 CH2NH- 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1419 CH2NH- 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1420 CH2NH- 2-Cl-phenyl 1-pyrrolidinocarbonyl
    SO2CH3
    1421 CH2NH- 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1422 CH2NH- 2-Cl-phenyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1423 CH2NH- 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1424 CH2NH- 2-Cl-phenyl 1-methyl-2-imidazolyl
    SO2CH3
    1425 CH2NH- 2-Cl-phenyl 2-methyl-1-imidazolyl
    SO2CH3
    1426 CH2NH- 2-Cl-phenyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1427 CH2NH- 2-Cl-phenyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1428 CH2NH- 2-Cl-phenyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1429 CH2NH- 2-Cl-phenyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1430 CH2NH- 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1431 CH2NH- 2-F-phenyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1432 CH2NH- 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1433 CH2NH- 2-F-phenyl 1-pyrrolidinocarbonyl
    SO2CH3
    1434 CH2NH- 2-F-phenyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1435 CH2NH- 2-F-phenyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1436 CH2NH- 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1437 CH2NH- 2-F-phenyl 1-methyl-2-imidazolyl
    SO2CH3
    1438 CH2NH- 2-F-phenyl 2-methyl-1-imidazolyl
    SO2CH3
    1439 CH2NH- 2-F-phenyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1440 CH2NH- 2-F-phenyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1441 CH2NH- 2-F-phenyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1442 CH2NH- 2-F-phenyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1443 CH2NH- 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
    1444 CH2NH- 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    SO2CH3
    1445 CH2NH- 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    SO2CH3
    1446 CH2NH- 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    SO2CH3
    1447 CH2NH- 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    SO2CH3
    1448 CH2NH- 2,6-diF-phenyl 2-(N,N-
    SO2CH3 dimethylaminomethyl)phenyl
    1449 CH2NH- 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    SO2CH3
    1450 CH2NH- 2,6-diF-phenyl 1-methyl-2-imidazolyl
    SO2CH3
    1451 CH2NH- 2,6-diF-phenyl 2-methyl-1-imidazolyl
    SO2CH3
    1452 CH2NH- 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-
    SO2CH3 imidazolyl
    1453 CH2NH- 2,6-diF-phenyl 2-(N-(cyclopropyl-
    SO2CH3 methyl)aminomethyl)phenyl
    1454 CH2NH- 2,6-diF-phenyl 2-(N-(cyclobutyl)-
    SO2CH3 aminomethyl)phenyl
    1455 CH2NH- 2,6-diF-phenyl 2-(N-(cyclopentyl)-
    SO2CH3 aminomethyl)phenyl
    1456 CH2NH- 2,6-diF-phenyl 2-(N-(3-hydroxypyrrolidinyl)-
    SO2CH3 methyl)phenyl
  • [0202]
    TABLE 2
    Figure US20030004344A1-20030102-C00138
    Figure US20030004344A1-20030102-C00139
    Figure US20030004344A1-20030102-C00140
    Figure US20030004344A1-20030102-C00141
    Figure US20030004344A1-20030102-C00142
    Figure US20030004344A1-20030102-C00143
    Figure US20030004344A1-20030102-C00144
    Figure US20030004344A1-20030102-C00145
    Figure US20030004344A1-20030102-C00146
    Figure US20030004344A1-20030102-C00147
    Figure US20030004344A1-20030102-C00148
    Figure US20030004344A1-20030102-C00149
    Figure US20030004344A1-20030102-C00150
    Figure US20030004344A1-20030102-C00151
    Figure US20030004344A1-20030102-C00152
    Figure US20030004344A1-20030102-C00153
    Figure US20030004344A1-20030102-C00154
    Figure US20030004344A1-20030102-C00155
    Z is C(O)NH or C(O)CH2
    Ex# A B
    1 phenyl 2-(aminosulfonyl)phenyl
    2 phenyl 2-(methylaminosulfonyl)phenyl
    3 phenyl 1-pyrrolidinocarbonyl
    4 phenyl 2-(methylsulfonyl)phenyl
    5 phenyl 2-(N,N-dimethylaminomethyl)phenyl
    6 phenyl 2-(N-pyrrolidinylmethyl)phenyl
    7 phenyl 1-methyl-2-imidazolyl
    8 phenyl 2-methyl-1-imidazolyl
    9 phenyl 2-(dimethylaminomethyl)-1-imidazolyl
    10 phenyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    11 phenyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    12 phenyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    13 phenyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    14 2-pyridyl 2-(aminosulfonyl)phenyl
    15 2-pyridyl 2-(methylaminosulfonyl)phenyl
    16 2-pyridyl 1-pyrrolidinocarbonyl
    17 2-pyridyl 2-(methylsulfonyl)phenyl
    18 2-pyridyl 2-(N,N-dimethylaminomethyl)phenyl
    19 2-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    20 2-pyridyl 1-methyl-2-imidazolyl
    21 2-pyridyl 2-methyl-1-imidazolyl
    22 2-pyridyl 2-(dimethylaminomethyl)-1-imidazolyl
    23 2-pyridyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    24 2-pyridyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    25 2-pyridyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    26 2-pyridyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    27 3-pyridyl 2-(aminosulfonyl)phenyl
    28 3-pyridyl 2-(methylaminosulfonyl)phenyl
    29 3-pyridyl 1-pyrrolidinocarbonyl
    30 3-pyridyl 2-(methylsulfonyl)phenyl
    31 3-pyridyl 2-(N,N-dimethylaminomethyl)phenyl
    32 3-pyridyl 2-(N-pyrrolidinylmethyl)phenyl
    33 3-pyridyl 1-methyl-2-imidazolyl
    34 3-pyridyl 2-methyl-1-imidazolyl
    35 3-pyridyl 2-(dimethylaminomethyl)-1-imidazolyl
    36 3-pyridyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    37 3-pyridyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    38 3-pyridyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    39 3-pyridyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    40 2-pyrimidyl 2-(aminosulfonyl)phenyl
    41 2-pyrimidyl 2-(methylaminosulfonyl)phenyl
    42 2-pyrimidyl 1-pyrrolidinocarbonyl
    43 2-pyrimidyl 2-(methylsulfonyl)phenyl
    44 2-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl
    45 2-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    46 2-pyrimidyl 1-methyl-2-imidazolyl
    47 2-pyrimidyl 2-methyl-1-imidazolyl
    48 2-pyrimidyl 2-(dimethylaminomethyl)-1-imidazolyl
    49 2-pyrimidyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    50 2-pyrimidyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    51 2-pyrimidyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    52 2-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    53 5-pyrimidyl 2-(aminosulfonyl)phenyl
    54 5-pyrimidyl 2-(methylaminosulfonyl)phenyl
    55 5-pyrimidyl 1-pyrrolidinocarbonyl
    56 5-pyrimidyl 2-(methylsulfonyl)phenyl
    57 5-pyrimidyl 2-(N,N-dimethylaminomethyl)phenyl
    58 5-pyrimidyl 2-(N-pyrrolidinylmethyl)phenyl
    59 5-pyrimidyl 1-methyl-2-imidazolyl
    60 5-pyrimidyl 2-methyl-1-imidazolyl
    61 5-pyrimidyl 2-(dimethylaminomethyl)-1-imidazolyl
    62 5-pyrimidyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    63 5-pyrimidyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    64 5-pyrimidyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    65 5-pyrimidyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    66 2-Cl-phenyl 2-(aminosulfonyl)phenyl
    67 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl
    68 2-Cl-phenyl 1-pyrrolidinocarbonyl
    69 2-Cl-phenyl 2-(methylsulfonyl)phenyl
    70 2-Cl-phenyl 2-(N,N-dimethylaminomethyl)phenyl
    71 2-Cl-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    72 2-Cl-phenyl 1-methyl-2-imidazolyl
    73 2-Cl-phenyl 2-methyl-1-imidazolyl
    74 2-Cl-phenyl 2-(dimethylaminomethyl)-1-imidazolyl
    75 2-Cl-phenyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    76 2-Cl-phenyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    77 2-Cl-phenyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    78 2-Cl-phenyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    79 2-F-phenyl 2-(aminosulfonyl)phenyl
    80 2-F-phenyl 2-(methylaminosulfonyl)phenyl
    81 2-F-phenyl 1-pyrrolidinocarbonyl
    82 2-F-phenyl 2-(methylsulfonyl)phenyl
    83 2-F-phenyl 2-(N,N-dimethylaminomethyl)phenyl
    84 2-F-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    85 2-F-phenyl 1-methyl-2-imidazolyl
    86 2-F-phenyl 2-methyl-1-imidazolyl
    87 2-F-phenyl 2-(dimethylaminomethyl)-1-imidazolyl
    88 2-F-phenyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    89 2-F-phenyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    90 2-F-phenyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    91 2-F-phenyl 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl
    92 2,6-diF-phenyl 2-(aminosulfonyl)phenyl
    93 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl
    94 2,6-diF-phenyl 1-pyrrolidinocarbonyl
    95 2,6-diF-phenyl 2-(methylsulfonyl)phenyl
    96 2,6-diF-phenyl 2-(N,N-dimethylaminomethyl)phenyl
    97 2,6-diF-phenyl 2-(N-pyrrolidinylmethyl)phenyl
    98 2,6-diF-phenyl 1-methyl-2-imidazolyl
    99 2,6-diF-phenyl 2-methyl-1-imidazolyl
    100 2,6-diF-phenyl 2-(dimethylaminomethyl)-1-imidazolyl
    101 2,6-diF-phenyl 2-(N-(cyclopropylmethyl)aminomethyl)phenyl
    102 2,6-diF-phenyl 2-(N-(cyclobutyl)aminomethyl)phenyl
    103 2,6-diF-phenyl 2-(N-(cyclopentyl)aminomethyl)phenyl
    104 2,6-diF-phenyl 2-(N-(3 -hydroxypyrrolidinyl)methyl)phenyl
  • Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. [0203]

Claims (13)

What is claimed is:
1. A compound of formula I:
Figure US20030004344A1-20030102-C00156
ring D is selected from —(CH2)3—, —CH2CH═CH—, —CH2N═CH—, and a 5 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present;
ring D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
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(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2;
M is selected from the group:
Figure US20030004344A1-20030102-C00157
J is O or S;
Ja is NH or NR1a;
Z is selected from (CR8R9)1-4, (CR8R9)rO(CR8R9)r, (CR8R9)rNR3(CR8R9)r, (CR8R9)rC(O)(CR8R9)r, (CR8R9)rC(O)O(CR8R9)r, (CR8R9)rOC(O)(CR8R9)r, (CR8R9)rC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)(CR8R9)r, (CR8R9)rOC(O)O(CR8R9)r, (CH2)rOC(O)NR3(CR8R9)r, (CR8R9)rNR3 C(O)O(CR8R9)r, (CH2)rNR3C(O)NR3(CR8R9)r, (CR8R9)rS(O)p(CR8R9)r, (CCR8R9)rSO2NR3(CR8R9)r, (CR8R9)rNR3SO2(CR8R9)r, and (CR8R9)rNR3SO2NR3(CR8R9)r, provided that Z does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with the groups to which Z is attached;
R1a is selected from H, —(CH2)r—R1′, —CH═CH—R1′, NHCH2R1″, OCH2R1″, SCH2R1″, NH(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′;
R1′ 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)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, C(═NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1″ is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, 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 of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 cycloalkylmethyl substituted with 0-2 R4b, 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 of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 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 of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 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 of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
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, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
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 of N, O, and S substituted with 0-2 R4;
B is selected from:
X—Y, NR2R2a, C(═NR2)NR2R2a, NR2C(═NR2)NR2R2a,
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 of N, O, and S substituted with 0-2 R4a;
X is selected from C1-4 alkylene, —CR2(CR2R2b)(CH2)t—, —C(O)—, —C(═NR1″)—, —CR2(NR1 1″R2)—, —CR2(OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —S(O)p—, —S(O)pCR2R2a—, —CR2R2aS(O)p—, —S(O)2NR2—, —NR2S(O)2—, —NR2S(O)2CR2R2a—, —CR2R2aS(O)2NR2—, —NR2S(O)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—, O, —CR2R2aO—, and —OCR2R2a—;
Y is selected from:
(CH2)rNR2R2a, provided that X—Y do not form a N—N, O—N, or S—N bond,
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 of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(═NR2)NR2R2a, C(═NS(O)2R5)NR2R2a, NHC(═NR2)NR2R2a, C(O)NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NHCH2R1″, OCH2R1″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′,
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4a, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CH2)r—F, (CH2)r—Br, (CH2)r—Cl, Cl, Br, F, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (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, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
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, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a,(CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
alternatively, 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 of N, O, and S;
R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, 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,
t, at each occurrence, is selected from 0, 1, 2, and 3.
2. A compound according to claim 1, wherein the compound is selected from the group:
Figure US20030004344A1-20030102-C00158
wherein, M is selected from the group:
Figure US20030004344A1-20030102-C00159
R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
Z is selected from CH2O, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a N—N, N—O, NCH2N, or NCH2O bond with ring M or group A;
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, 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, 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;
B is selected from: H, Y, and X—Y;
X is 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—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—;
Y is NR2R2a or CH2NR2R2a, provided that X—Y do not form a N—N or O—N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
cylcopropyl, 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, 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;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems:
Figure US20030004344A1-20030102-C00160
K is selected from O, S, NH, and N.
3. A compound according to claim 2, wherein the compound is selected from the group:
Figure US20030004344A1-20030102-C00161
M is selected from the group:
Figure US20030004344A1-20030102-C00162
Z is C(O)CH2 and CONH, provided that Z does not form a N—N bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,
B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
B is selected from: Y and X—Y;
X is selected from CH2, —C(O)—, and O;
Y is NR2R2a or CH2NR2R2a, provided that X—Y does not form an O—N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, CH(CH3)2, cyclopropylmethyl, benzyl, and phenyl;
alternatively, R2 and R2a combine to form a ring system substituted with 0-2 R4b, the ring system being selected from pyrrolidinyl, piperazinyl and morpholino;
R4, at each occurrence, is selected from OH, (CH2)rOR2, Cl, F, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
R4a is selected from Cl, F, C1-4 alkyl, CF3, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R4b, at each occurrence, is selected from OH, Cl, F, CH3, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
R7, at each occurrence, is selected from H, CH3, and CH2CH3; and,
R8, at each occurrence, is selected from H and CH3.
4. A compound according to claim 3, wherein:
M is selected from the group:
Figure US20030004344A1-20030102-C00163
J is N,
R1a is absent or is —(CH2)r—R1′;
R1′ is selected from H, C1-3 alkyl, F, Cl, —CN, CF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, S(O)pR2b, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,
B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl, 2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino, 2-(1′-CF3-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
5. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
9. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
10. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
11. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
12. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
13. A compound according to Table 1 or 2.
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