Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
  • C07D231/24—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms having sulfone or sulfonic acid radicals in the molecule
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• • 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
  • 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
  • C07D401/14—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 three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention relates generally to nitrogen containing heteroaromatics, with ortho-substituted PI groups, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders .
• R 1 represents the basic termini
• U is an alkylene or heteroatom linker
• V may be a heterocycle
• the right hand portion of the molecule represents the acidic termini .
• the presently claimed compounds do not contain the acidic termini of WO 95/18111.
• Hi melsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula:
• heterocycle may be aromatic and groups A-B-C- and F-E-D- are attached to the ring system.
• A-B-C- can be a wide variety of substituents including a basic group attached to an aromatic ring.
• the F-E-D- group would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
• R 1 may be pyrrolidine or piperidine and A may be a basic group including amino and amidino .
• Baker et al do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics .
• R 1 represents a nitrogen containing ring system or a nitrogen substituted cyclobutane
• A may be a basic group including amino and amidino.
• Baker et al do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics .
• R 1 can be a substituted aryl group
• Z is a two carbon linker containing at least one heteroatome
• X is a heterocycle
• Y is an optional linker
• W is an amidino or guanidino containing group.
• cytokine inhibitors useful for inhibiting angiogenesis .
• These inhibitors include imidazoles of the formula:
• Ri is a variety of heteroaryl groups
• R 4 is phenyl, naphthyl, or a heteroaryl group
• R 2 can be a wide variety of groups .
• Jackson et al do not teach inhibition of factor Xa. Furthermore, the imidazoles of Jackson et al are not considered part of the present invention.
• Activated factor Xa whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation.
• the generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca 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.
• 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 PI groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof .
• 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.
• ring M contains, in addition to J, 0-3 N atoms, provided that if M contains 2 N atoms then R lb is not present and if M contains 3 N atoms then R la and R lb are not present;
• J is N or NH
• E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R;
• R is selected from H, Cl, F, Br, I, (CH 2 ) t OR 3 , C 1 - 4 alkyl, OCF 3 , CF 3 , C(0)NR 7 R 8 , and (CR 8 R 9 ) t NR 7 R 8 ;
• G is absent or is selected from NHCH 2 , OCH 2 , and SCH2, provided that when s is 0, then G is attached to a carbon atom on ring M;
• Z is selected from a C ⁇ _ 4 alkylene, (CH 2 ) r O (CH 2 ) r >
• R la and R lb are independently absent or selected from -(CH 2 ) r -R 1' -CH ⁇ H-R 1 ', NCH2R 1 ", OCH2R 1" , SCH2R 1" , NH(CH 2 ) 2 (CH 2 ) t R 1 ', 0(CH 2 ) 2 (CH 2 ) t R 1 ', and S (CH 2 ) 2 ( CH 2 ) tR 1 ' ;
• R la and R lb when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R 4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
• R 1 " is selected from H, CH(CH 2 OR 2 ) 2 , C(0)R 2c , C(0)NR 2 R 2a , S(0)R 2b , S(0) 2 R 2b , and S0 2 NR 2 R 2a ;
• R 2 is selected from H, CF 3 , C 1 - 5 alkyl, benzyl, C 3 - 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4b ;
• R 2a is selected from H, CF 3 , -e alkyl, benzyl, C 3 - 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4b ;
• R 2b at each occurrence, is selected from CF 3 , C ⁇ _ 4 alkoxy, C 1 - 6 alkyl, benzyl, C 3 .-6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4b ;
• R 2c is selected from CF 3 , OH, C 1 - 4 alkoxy, C ⁇ _6 alkyl, benzyl, C 3 _ 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, 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, 0, 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 ⁇ _ 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, 0, and S substituted with 0-2 R ;
• B is selected from:
• Y is selected from:
• one R 4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S;
• one R 4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-1 R 5 ;
• R 5 at each occurrence, is selected from CF 3 , C ⁇ _ 6 alkyl, phenyl substituted with 0-2 R 6 , and benzyl substituted with 0-2 R 6 ;
• R 7 is selected from H, OH, C ⁇ _ 6 alkyl, C 1 - 6 alkylcarbonyl , C - ⁇ alkoxy, C ⁇ _ 4 alkoxycarbonyl , (CH 2 ) n -phenyl, C 6 _ ⁇ o aryloxy, C 6 - ⁇ o aryloxycarbonyl , C 6 - ⁇ o arylmethylcarbonyl , C 1 - 4 alkylcarbonyloxy C 1 - 4 alkoxycarbonyl, C ⁇ -io arylcarbonyloxy C 1 - 4 alkoxycarbonyl, C ⁇ _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, 0, and S;
• R 9 at each occurrence, is selected from H, C ⁇ _ 6 alkyl and (CH 2 )n-phenyl;
• n at each occurrence, is selected from 0, 1, 2, and 3 ;
• n 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;
• D-E-G- (CH 2 ) s - and -Z-A-B are not both benzamidines .
• groups D-E- and -Z-A-B are attached to adjacent atoms on the ring;
• R is selected from H, Cl, F, Br, I, (CH 2 ) t OR 3 , C 1 - 4 alkyl, OCF 3 , CF 3 , C(0)NR 7 R 8 , and (CR 8 R 9 ) t NR 7 R 8 ;
• Z is selected from a CH 2 0, 0CH 2 , CH 2 NH, NHCH 2 , C(0), CH 2 C(0), C(0)CH 2 , NHC(O), C(0)NH, CH 2 S(0) 2 , S(0) 2 (CH 2 ), S0 2 NH, and NHS0 2 , provided that Z does not form a N-N, N-0, 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 ; 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,
• Y is NR 2 R 2a , 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 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
• Y is selected from the following bicyclic heteroaryl ring systems:
• K is selected from O, S, NH, and N.
• Z is selected from a C(0), CH 2 C(0), C(0)CH 2 , NHC(O), C(0)NH, C(0)N(CH 3 ), CH 2 S(0) 2 , S(0) 2 (CH 2 ), S0 2 NH, and NHS0 2 , provided that Z does not form a N-N or NCH 2 N bond with ring M or group A.
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• E is phenyl substituted with R or 2-pyridyl substituted with R;
• D is selected from NH 2 , NHCH 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH(CH 3 )NH 2 , and C(CH 3 ) 2 H 2 , provided that D is substituted ortho to ring M on E; and,
• R is selected from H, OCH 3 , Cl, and F.
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• D-E is selected from 2-aminophenyl, 2-methylaminophenyl, 2- aminomethylphenyl , 4-methoxy-2-aminophenyl, 4-methoxy-2- (methylamino) phenyl, 4-methoxy-2-aminomethylphenyl , 4- methoxy-2- (methylaminomethyl ) phenyl , 4-methoxy-2- (1- aminoethyl) phenyl, 4-methoxy-2- (2-amino-2-propyl) phenyl, 4-Cl-2-aminophenyl, 4-Cl-2- (methylamino) phenyl, 4-C1-2- aminomethylphenyl, 4-C1-2- (methylaminomethyl) phenyl, 4- Cl-2- (1-aminoethyl) phenyl, 4-C1-2- (2-amino-2- propyl) phenyl , 4-F-2-aminophenyl, 4-F-2- (methylamino) phen
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• Z is C(0)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 X-Y, phenyl, pyrrolidino, morpholino,
• R 4 at each occurrence, is selected from OH, (CH 2 ) r OR 2 , halo, C ⁇ - 4 alkyl, (CH 2 ) r NR 2 R 2a , and (CF 2 ) r CF 3 ;
• R 4a is selected from C ⁇ _ alkyl, CF 3 , S(0) p R 5 , S0 2 NR 2 R 2a , and l-CF 3 -tetrazol-2-yl;
• R 5 at each occurrence, is selected from CF 3 , -e alkyl, phenyl, and benzyl;
• X is CH 2 or C(O);
• Y is selected from pyrrolidino and morpholino, [7]
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• 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-
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• E is phenyl substituted with R or 2-pyridyl substituted with R;
• D is selected from NH 2 , NHCH 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH(CH 3 )NH 2 , and C(CH 3 ) 2 NH 2 , provided that D is substituted ortho to ring M on E; and,
• R is selected from H, OCH 3 , Cl, and F;
• Z is C(0)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 ; and, B is selected from X-Y, phenyl, pyrrolidino, morpholino,
• R 4 at each occurrence, is selected from OH, (CH 2 ) r OR 2 , halo, C ⁇ - 4 alkyl, (CH 2 ) r NR 2 R 2a , and (CF 2 )rCF 3 ;
• R 4 a i s selected from C ⁇ _ 4 alkyl, CF 3 , S(0) P R 5 , S0 2 NR 2 R 2a , and l-CF 3 -tetrazol-2-yl;
• R 5 at each occurrence, is selected from CF 3 , C ⁇ _ 6 alkyl, phenyl, and benzyl;
• X is CH 2 or C(O);
• Y is selected from pyrrolidino and morpholino.
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• D-E is selected from 2-aminophenyl, 2-methylaminophenyl, 2- aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2- (methylamino) phenyl, 4-methoxy-2-aminomethylphenyl, 4- methoxy-2- (methylaminomethyl) phenyl, 4-methoxy-2- (1- aminoethyl) phenyl , 4-methoxy-2- (2-amino-2-propyl) phenyl, 4-Cl-2-aminophenyl, 4-C1-2- (methylamino) phenyl, 4-C1-2- aminomethylphenyl , 4-Cl-2- (methylaminomethyl) phenyl , 4- Cl-2- (1-aminoethyl) phenyl, 4-C1-2- (2-amino-2- propyl) phenyl , 4-F-2-aminophenyl, 4-F-2- (methylamino)phenyl
• 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- ethoxyphenyl ; and,
• B is selected from the group: 2-CF3 -phenyl, 2- (aminosulfonyl) phenyl, 2- (methylaminosulfonyl) phenyl, 2- (dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholino, 2- (1' -CF3 ⁇ tetrazol- 2-yl)phenyl, 4-morpholinocarbonyl , 2-methyl-l-imidazolyl, 5-methyl-l-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-l, 2 , 3 -triazolyl .
• the present invention provides a novel compound of formula Ha.
• the present invention provides a novel compound of formula lib.
• the present invention provides a novel compound of formula lie
• the present invention provides a novel compound of formula lid.
• the present invention provides a novel compound of formula lie
• the present invention provides a novel compound of formula Ilf [16] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ila-IIf, wherein;
• E is phenyl substituted with R or pyridyl substituted with R;
• R is selected from H, Cl, F, OR 3 , CH 3 , CH 2 CH 3 , OCF 3 , CF 3 , NR 7 R 8 , and CH 2 NR 7 R 8 ;
• Z is selected from C(O), CH 2 C(0), C(0)CH 2 , NHC(O), and C(0)NH, provided that Z does not form a N-N bond with ring M or group A;
• R la and R lb are independently absent or selected from
• R 1 ' is selected from H, C 1 - 3 alkyl, halo, (CF 2 ) r CF 3 , OR 2 , NR 2 R a , C(0)R 2c , (CF 2 ) r C0 2 R 2c , S(0) p R 2b , NR 2 (CH 2 ) r OR 2 , NR 2 C(0)R 2b , NR 2 C(0) 2 R 2b , C(0)NR 2 R 2a , S0 2 NR 2 R 2 , and NR 2 S0 2 R 2b ;
• A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4 ,- phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;
• Y is NR 2 R 2a , provided that X-Y do not form a N-N or 0-N bond;
• Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ; 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-trifluor
• R 5 at each occurrence, 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 7 is selected from H, OH, C s alkyl, C ⁇ _ 6 alkylcarbonyl , C ⁇ _ 6 alkoxy, C 1 - 4 alkoxycarbonyl, benzyl, C6-10 aryloxy, C ⁇ -io aryloxycarbonyl, Ce-io arylmethylcarbonyl , C 1 - 4 alkylcarbonyloxy C 1 - 4 alkoxycarbonyl, C ⁇ -io arylcarbonyloxy C _ 4 alkoxycarbonyl, C 1 - 6 alkylaminocarbonyl , phenylaminocarbonyl , and phenyl C 1 - 4 alkoxycarbonyl;
• R 8 at each occurrence, is selected from H, C_ . - alkyl and benzyl ;
• R 7 and R 8 combine to form a morpholino group
• R 9 at each occurrence, is selected from H, Cis alkyl and benzyl .
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• E is phenyl substituted with R or 2-pyridyl substituted with R;
• R is selected from H, Cl, F, OCH 3 , CH 3 , OCF 3 , CF 3 , NH , and CH 2 NH 2 ;
• Z is selected from a C(0)CH 2 and C(0)NH, provided that Z does not form a N-N bond with group A;
• R la is selected from H, CH 3 , CH 2 CH 3 , Cl , F, CF3 , OCH3 , NR 2 R 2a , S(0) p R b , CH 2 S(0) p R 2b , CH 2 NR 2 S(0) p R 2b , C(0)R 2c , CH 2 C(0)R 2c , C(0)NR 2 R 2a , and S0 2 NR 2 R 2a ;
• R lb ig selected from H, CH , CH 2 CH 3 , Cl, F, CF 3 , OCH 3 , NR 2 R 2 , S(0) p R 2b , CH 2 S(0) p R 2b , CH 2 NR 2 S(0) p R 2b , C(0)R 2c , CH 2 C(0)R 2 , C(0)NR 2 R 2a , and S0 2 NR 2 R 2a ;
• A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4 ; phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;
• B is selected from: Y and X-Y;
• Y is NR 2 R 2 , 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 ; 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,
• R 2 at each occurrence, is selected from H, CF 3 , CH 3 , benzyl, and phenyl;
• R 2a at each occurrence, is selected from H, CF 3 , CH 3 , benzyl, and phenyl
• R 2b at each occurrence, is selected from CF 3 , OCH3 , CH3 , benzyl, and phenyl
• R 2c at each occurrence, is selected from CF 3 , OH, OCH3 , CH 3 , benzyl, and phenyl;
• R 2 and R 2a combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
• R 3 at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , and phenyl ;
• R 3a at each occurrence, is selected from H, CH 3 , CH 2 CH3 , and phenyl ;
• R 4 at each occurrence, is selected from OH, Cl, F, CH3 ,
• R 4a at each occurrence, is selected from OH, Cl, F, CH3,
• R 5 at each occurrence, is selected from CF 3 , Cis alkyl, phenyl substituted with 0-2 R 6 , and benzyl substituted with 1 R 6 ;
• R 6 at each occurrence, is selected from H, OH, OCH 3 , Cl, F, CH 3 CN, N0 2 , NR 2 R 2a , CH 2 NR 2 R 2a , and S0 2 NR 2 R 2a ;
• R 7 at each occurrence, is selected from H and C 1 - 3 alkyl
• R 8 at each occurrence, is selected from H, CH 3 , and benzyl;
• R 9 at each occurrence, is selected from H, CH 3 , and benzyl; and, t, at each occurrence, is selected from 0 and 1.
• the present invention provides novel compounds of formulae Ila-IIf, wherein;
• D is selected from NR 7 R 8 , and CHNR 7 R 8 , provided that D is substituted ortho to ring M on E;
• R la is absent or is selected from H, CH 3 , CH 2 CH 3 , Cl, F, CF 3 , OCH 3 , NR 2 R 2a , S(0) p R 2b , C(0)NR 2 R 2a , CH 2 S(0) p R 2b , CH 2 NR 2 S(0) p R 2b , C(0)R 2c , CH 2 C(0)R 2c , and S0 2 NR 2 R 2a ;
• R lb is absent or is selected from H, CH 3 , CH 2 CH 3 , Cl , F, CF 3 , OCH 3 , NR 2 R 2a , S(0) p R 2b , C(0)NR 2 R 2a , CH 2 S(0) p R 2b , CH 2 NR 2 S(0) p R 2b , C(0)R 2b , CH 2 C(0)R 2b , and S0NR 2 R 2a ;
• A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4 ; phenyl, pyridyl, and pyrimidyl;
• B is selected from: Y and X-Y;
• X is selected from -C(O)- and 0;
• Y is NR 2 R 2a , provided that X-Y do not form a O-N bond;
• Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R a ; phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3- triazolyl;
• R 2 at each occurrence, is selected from H, CF 3 , CH 3 , benzyl, and phenyl
• R 2a at each occurrence, is selected from H, CF 3 , CH 3 , benzyl, and phenyl
• R 2b at each occurrence, is selected from CF 3 , OCH 3 , CH 3 , benzyl, and phenyl;
• R 2c at each occurrence, is selected from CF 3 , OH, OCH 3 , CH 3 , benzyl, and phenyl;
• R 2 and R 2a combine to form a ring system selected from pyrrolidinyl , piperazinyl and morpholino;
• R 4 at each occurrence, is selected from Cl, F, CH 3 , NR 2 R 2a , and CF 3 ;
• R 4a at each occurrence, is selected from Cl, F, CH 3 , S0 2 NR 2 R 2a , S(0) p R 5 , and CF 3 ;
• R 5 at each occurrence, is selected from CF 3 and CH 3 ;
• R 7 at each occurrence, is selected from H, CH 3 , and CH 2 CH 3 ;
• R 8 at each occurrence, is selected from H and CH 3 .
• Specifically preferred compounds of the present invention are selected from the group:
• the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) 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 formula (I) 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 welJ 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.
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• 2 hydrogens on the atom are replaced.
• Keto substituents are not present on aromatic moieties .
• 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 "
• 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 is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• 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.
• alkoxy examples 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.
• Alkenyl 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 .
• Alkynyl 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 .
• 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 residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 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. O]bicyclodecane,
• heterocycle or “heterocyclic system” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 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 0 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 0 atoms in the heterocycle is not more than 1.
• aromatic heterocyclic system or “heteroaryl” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 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, lff-indazolyl, indolen
• Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
• 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.
• 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 .
• 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.
• 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.
• More preferred prodrugs are where R 7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl
• Solid 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 .
• “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.
• “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 HIV infection or treat the symptoms of HIV infection 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 HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
• 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.
• the compounds of Formula I in which ring M is pyrrole can be prepared by the procedures described in Schemes 1-9.
• Scheme 1 is shown how to prepare pyrroles in which the group Q-E is attached to the pyrrole nitrogen, wherein Q is a functionality that can be converted into D of Formula I, R e is functionality that can be converted into Z-A-B of Formula I and R f is or can be converted into R la of Formula I .
• Oxidation of a furan with bromine in acetic acid can afford a 2,5- diacetoxydihydrofuran which can react with amine Q-E-NH2 to afford a pyrrole.
• Derivatives which contain a sulfur atom attached to the pyrrole ring can be obtained by direct sulfonation with pyridine sulfur trioxide complex to give the sulfonic acids or treatment with copper (II) thiocyanate (J. Het . Chem . 1988, 25, 431) followed by the reduction of the intermediate thiocyanate with sodium borohydride to give a mercaptan.
• Pyrroles which contain a 3-amino substituent can be prepared from the acids by treatment with phosphoryl azide and triethylamine to effect a Curtius rearrangement to afford the isocyanates (J. Med. Chem. 1981, 24 , 33) which upon hydrolysis can yield 3- aminopyrroles .
• Pyrroles which contain a sulfur atom at C-3 can be prepared from the acids by employing the Hunsdiecker procedure to give the 3-bromo derivatives.
• Halogen-metal exchange at low temperature with an alkyllithium reagent can afford the 3-lithio derivative which can be quenched with a variety of electrophiles, such as Ss to afford thiols directly or Cu(SCN) 2 to afford a thiocyanate which can be reduced with sodium borohydride.
• the thiols can further be oxidized to the sulfonic acid derivatives by an oxidant such as KMn ⁇ 4 •
• R e Z-A-B precursor
• acidic hydrolysis can selectively hydrolyze the C-3 ester. Heating should then effect decarboxylation.
• Hydrolysis of the 2-carboxylic acid can be achieved under basic conditions. Curtius rearrangement of the acid as described previously can afford the amino derivatives.
• basic hydrolysis and decarboxylation can afford the C-2 unsubstituted pyrroles. These pyrroles can undergo electrophilic substitution to afford thiols (Cu(SCN) 2 , then NaBH 4 ) and sulfonic acids (pyridine SO 3 complex or chlorosulfonic acid) .
• R la group contained in Formula I can be derived either from the remaining ester or from R f .
• the thiol and sulfonic acid derivatives can also be derived form the C-2 acids by manipulation of the carboxylic acid group as described previously.
• the Hunsdiecker procedure can be used to prepare the 3-bromopyrroles.
• Halogen metal exchange with t-BuLi at low temperature followed by quenching with copper isocyanate should introduce -an isocyanate group at C-3.
• This intermediate can be reduced with sodium borohydride to afford the 3-mercaptopyrroles .
• the carboxylic acids can be decarboxylated to afford pyrroles which can be N- protected with a bulky protecting group such as triisopropylsilyl (TIPS) . This bulky group directs electrophilic substitution to C-3 of the pyrrole ring.
• TIPS triisopropylsilyl
• reaction with copper isocyanate followed by sodium borohydride reduction and then fluoride induced TIPS deprotection can afford 3-mercaptopyrroles.
• Sulfonation of N-protected pyrrole with pyridine sulfur trioxide complex can again be directed to C-3 of the pyrrole to afford, after TIPS deprotection, the 3- sulfonic acids .
• aldehydes and ketones can be allowed to react with the enolates of additional ketones to afford intermediate aldol addition products which under acidic conditions cyclize to form pyrroles.
• the reacting partners in this approach can be of wide scope and can be chosen so -that one skilled in the art will be able to prepare varied pyrroles .
• Another very general method of pyrrole synthesis useful for preparing compounds of the present invention is the Paal- Knorr reaction shown in Scheme 6.
• This reaction involves the reacting 1, 4-diketones or 1, 4-ketoaldehydes with primary amines to afford pyrroles.
• the starting 1, 4-diketones and 1, 4-ketoaldehydes can be prepared using standard enolate chemistry or by other procedures which are familiar to those skilled in the art of organic synthesis.
• the reaction is of wide scope and the starting materials can be chosen so that a variety of pyrroles can be prepared.
• the acid can be combined with amine H 2 N-A-B in the presence of a suitable peptide coupling agent, such as BOP-C1, HBTU or DCC.
• a suitable peptide coupling agent such as BOP-C1, HBTU or DCC.
• the ester can be directly coupled with an aluminum reagent, prepared by the addition of trimethylalu inum to the amine H 2 N-A-B.
• the acid can be reduced to the alcohol.
• the alcohol can be oxidized to the aldehyde by a number of procedures, two preferred methods of which are the Swern oxidation and oxidation with pyridinium chlorochromate (PCC) .
• the aldehyde may be directly prepared by direct formylation of the pyrrole ring by the Vilsmeier-Haack procedure in certain cases , as described in previous schemes. Reductive amination of the aldehyde with an appropriate amine H 2 N-A-B and sodium cyanoborohydride can then afford the amine linked compounds.
• Additional compounds of Formula I in which the linking group m/z contains a nitrogen atom attached to ring M can be prepared by the procedures described in Scheme 8.
• the amines can be converted to sulfonamides (Formula I, m/z-NHS02-) by treatment with an appropriate sulfonyl chloride B-A-SO2CI in the presence of a base such as triethylamine.
• Additional compounds of Formula I in which the linking group Z contains a sulfur atom attached to ring M can be prepared by the procedures described in Scheme 9.
• N- Substituted imidazole derivatives can be made by the general procedure shown in Scheme 10, wherein V is either V or a precusor of (CH 2 ) n V, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide, n is 0 and 1, and PG is either a hydrogen or a protecting group.
• Substitution can be achieved by coupling an imidazole with a halogen containing fragment Q-E-G-Hal in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base, followed by conversion of V to (CH 2 ) n V. Then, Q can be converted to D, and finally V can be converted to -Z-A-B following the procedures outlined in Schemes 7-9. Alternatively, V can be converted to Z-A-B followed by deprotection of N. This product can then be coupled as before to obtain the desired imidazole.
• a catalyst such as base, Cu/CuBr/base, or Pd/base
• Step a involves coupling in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base.
• a catalyst such as base, Cu/CuBr/base, or Pd/base.
• R lb When R lb is a hydrogen, it can be deprotonated with a lithium base and trapped by formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine) , or isocyanate to give 1, 2-disubstituted imidazoles (Route bl) . Also, in Route bl when R lb is CH 3 , it can be oxidized with Se ⁇ 2 , Mn ⁇ 2 , NaI0 4 /cat. RI1CI 3 , or NBS to form U.
• R lb When R lb is hydrogen, sequential deprotonation and quenching with a lithium base and trimethysilyl chloride, followed by a second deprotonation with a lithium base and quenching with formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate can afford 1, 5-disubstituted imidazoles (Route b2 ) .
• R lb When R lb is not hydrogen, the procedure of Route b2 can again be used to form 1, 5-disubstituted imidazoles (Route b3 ) .
• the tetrazole compounds of the present invention where Z is -CONH- can be prepared as exemplified in Scheme 18.
• An appropiately substituted amine can be acylated with ethyl oxalyl chloride.
• the resulting amide can be converted to the tetrazole either by the methods described by Duncia ⁇ J. Org. Chem . 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768).
• the amide can be converted to the iminoyl chloride first and the reacted with NaN 3 to form the 5-carboethoxytetrazole (J " . Org. Chem. 1993, 58, 32-35 and Bioorg. & Med. Chem . Lett . 1996, 6, 1015-1020) .
• the 5-carboethoxytetrazole can then be further modified as described in Scheme 7.
• the tetrazole compounds of the present invention where Z is -CO- can also be prepared via iminoyl chloride ( Chem. Ber. 1961, 94 , 1116 and J. Org. Chem . 1976, 41 , 1073) using an appropriately substituted acyl chloride as starting material .
• the ketone-linker can be reduced to compounds wherein Z is alkyl .
• tetrazole compounds of the present invention wherein Z is -SO 2 NH-, -S-, -S(O)-, SO 2 - can be prepared from the thiol prepared as shown in Scheme 20. Appropiately substituted thioisocyanate can be reacted with sodium azide to give the 5- thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592) .
• the thio- compound can be modified as described in Scheme 9.
• tetrazole compounds of the present invention wherein Z is -O- can be prepared via the same method described in Scheme 20 by using appropiately substituted isocyanate as the starting material.
• the hydroxy compound can be modified similarily to the thiols described in Scheme 9.
• the tetrazole compounds of the present invention wherein Z is -NH-, -NHCO-, -NHS0 2 - can be prepared from 5- aminotetrazole, which can be prepared by Smiles Rearrangement as shown in Scheme 21.
• the thio-compound prepared as described in Scheme 20 can be alkylated with 2- chloroacetamide .
• the resulting compound can then be refluxed in ethanolic sodium hydroxide to give the corresponding 5- amino-tetrazole ⁇ Chem . Pharm . Bull . 1991, 39, 3331-3334).
• the resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products.
• Pyrazoles of Formula I can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo esters. Condensations of this type typically afford a mixture of pyrazole regioisomers which can be effectively separated via silica gel column chromatography. The esters can be converted to Z-A-B as previously described.
• pyrazoles wherein the 4-position is substituted can be prepared by bromination (bromine or NBS in either dichloromethane or acetic acid) of the initial pyrazole.
• Conversion of 4-bromo-pyrazojLe to 4-carboxylic acid pyrazole can be accomplished by a number of methods commonly known to those in the art of organic synthesis . Further manipulations as previously described can afford pyrazoles of the present invention.
• Pyrazoles can also be prepared according to method described in Scheme 25.
• the bromo-pyrazoles are formed as in Scheme 24.
• QE can then be coupled using palladium catalysed Suzuki cross-coupling methodology. Further modification is achieved as previously described.
• 5-substituted phenylpyrazoles can be prepared by the method shown in Scheme 26. Conversion of the 5-hydroxy pyrazole to its triflate (triflic anhydride, lutidine in dichloromethane) or bromide (POBr3) followed by palladium Suzuki cross-coupling with an apppropriately substituted phenylboronic acid should then afford 5-substituted pyrazoles Conversion of this intermediate to the 4-bromo derivative followed by its carbonylation as described in Scheme 24 should then afford the appropriate ester which can be further afford the compounds of formula I .
• 1-Substituted-l, 2 , 3-triazoles of the present invention can be prepared by the treatment of an appropriately substituted azide with a variety of dipolarophiles ⁇ Tetrahedron 1971, 27, 845 and J. Amer. Chem. Soc. 1951, 73, 1207) as shown in Scheme 27.
• a mixture of regioisomers are obtained which can be easily separated and elaborated to the triazole carboxylic acids . Further transformations as previously described can then afford the compounds of the present invention.
• 1, 2, 4-Triazoles of the present invention can be obtained by the methodology of Huisgen et al (Liebigs Ann . Chem . 1962, 653 , 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chloro 5 hydrazone) and an appropriate nitriJe dipolarophile (Scheme 28) .
• This methodology provides a wide variety of 1,2,4 triazoles with a varied substitution pattern at the 1, 3, and 5 positions .
• 1,2,4 Triazoles can also be prepared by the methodology 5 of Zecchi et al ⁇ Synthesis 1986, 9, 772) by an aza Wittig condensation (Scheme 29) .
• the thiono-urea intermediate can be oxidized directly to the 2-H triazole which can then be converted to the ester and modified as previously described.
• the thiono-urea intermediate can also be oxidized to the sulfonyl chloride by methods shown previously.
• the imidazole core shown in Scheme 32 can be prepared by the condensation of 3-cyanoaniline with n-butylglyoxylate to afford the imine which can then be treated with TosylMIC in basic methanol to afford the desired imidazole compound. Coupling of the ester under standard conitions then affords a variety of analogs which then can be further manipulated to afford e.g. the benzylamine or the benzamidines .
• Halo X NH, 0, S
• the chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20 * C to the reflux point of the solvent and with or without a trialkylamine base.
• aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene
• the coupling chemistry of Table B can be carried out by a variety of methods .
• the Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0 C to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (- 20 C or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide'dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof .
• the ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
• a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide
• a base such as potassium carbonate, sodium hydride or potassium t-butoxide
• the thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D.
• a combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.
• Rxn D is to be then a transformation that may be used is
• Table E several methods of transforming a functional group Q into group D of Formula 1 are shown. While not all possible functional groups for Q and D are listed and the synthetic methods suggested are not comprehensive, Table E is meant to illustrate strategies and transformations available to a practitioner skilled in the art of organic synthesis for preparing compounds of Formula 1.
• reaction 1 of Table E the transformation of a nitrile into an amidine by the Pinner methodology is shown; in reaction 2 the " direct reduction of a nitrile by a hydride reducing agent to a methylene amine is illustrated.
• reaction 3 the utility of a carboxylic acid, which may be readily derived from its ester or a nitrile if necessary, in the preparation of a methylene amine is shown.
• This synthetic route is exceptionally flexible because of the several stable intermediates prepared en route to the final product.
• formation of an activated analog such as the mixed anhydride, allows for the mild reduction of the acid to the methylene alcohol, this may in turn be transformed into a leaving group by sulfonylation or halogenation or protected with a suitable protecting group to be transformed later in the synthesis as the chemistry demands.
• displacement by an efficient nitrogen nucleophile, such as azide anion can again provide another suitably stable analog, -the methylene azide- which may be used as a protected form of the methylene amine or transformed directly into the methylene amine group by reduction.
• Reaction 4 addresses the problem of appending the amine functionality directly through a bond to group E of Formula 1.
• the carboxylic acid provides a convenient entre into this selection for group D.
• the well- know Curtius rearrangement is illustrated here; an activated acid analog can be used to form an acyl azide which upon thermal decomposition is rearranged to the corresponding isocyanate.
• the isocyanate intermediate may then be captured as a stable carbamate by the addition of a suitable alcohol and further heating. This carbamate can be used as a stable protecting group for the amine or cleaved directly to the desired D. Alternatively, it may be convenient to quench the isocyanate intermediate with water to give the amine directly.
• 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.
• Part B Ethyl 2-N- (methoxy) imino-4-oxopentanoate: A mixture of ethyl pentanoate-2 , 4-dione (24.5 g, 154.9 mmol) and methoxyamine hydrogen chloride (13.58 g, 162.6 mmol) in ethanol (100 mL) was allowed to stand over activated 3 A molecular sieves (75 g) at ambient temperature for 18h. Following removal of the molecular sieves by filtration, dichloromethane (100 mL) was added and the reaction filtered. The resulting solution was evaporated and the residue applied to a silica gel column. The title compound was isolated in a homogenous form by elution with 5:1 hexane: ethyl acetate to give 9.09 g of product.
• Ethyl 3-methyl-1- (2-carboxy-4-methoxyphenyl) -IH- pyrazole-5-carboxylate and ethyl 5-methyl-l- (2-carboxy-4- methoxyphenyl)-lH-pyrazole-3-carboxylate Ethyl 2-N- (methoxy) imino-4-oxopentanoate (1.0 g, 5.35 mmol) and crude 2- carboxy-4-methoxyphenylhydrazine (5.83 g) in acetonitrile (40 mL) and acetic acid (5 mL) was stirred at ambient temperature for 3 h then heated at reflux for an additional 3 h.
• Part D Ethyl 3-methyl-1- (2-hydroxymethyl-4-me hoxyphenyl) -1H- pyrazole-5-carboxylate and ethyl 5-methyl-l- (2-hydroxymethyl- 4-methoxyphenyl ) -lH-pyrazole-3-carboxylate:
• the mixture of regioisomers prepared in part C (1.28 g, 4.2 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to 0°C.
• N-methylmorpholine (0.42 g, 4.2 mmol
• isobutylchloroformate (0.57 g, 4.2 mmol).
• reaction was stirred for 30 min at 0°C, the precipitate removed by filtration and the cold solution poured immediately into a cold (5°C) solution of sodium borohydride (0.48 g, 12.6 mmol) in water (20 mL) and tetrahydrofuran (20 mL) .
• the reaction was allowed to thaw to room temperature over 18 h.
• the reaction mixture was evaporated, partitioned between ethyl acetate (100 mL) and IN hydrochloric acid (50 mL) , then washed with 5% sodium bicarbonate (50 mL) and brine (50 mL) .
• the organic layer was dried and evaporated; three products were isolated by elution of the crude mixture from a silica gel column with 2:1 hexane: ethyl acetate.
• the first product to elute was a ring closed lactone (0.14 g) ; ESI mass spectrum analysis m/z (relative intensity) 245 (M+H, 100) .
• the second product isolated was ethyl 3-methyl-1- (2-hydroxymethyl-4- methoxyphenyl) -lH-pyrazole-5-carboxylate (0.18 g) as determined by proton NMR nOe experiments; ESI mass spectrum analysis m/z (relative intensity) 291 (M+H, 100).
• the third product to elute was the regioisomer ethyl 5-methyl-l- (2- hydroxymethyl-4-methoxyphenyl) -lH-pyrazole-3-carboxylate ( 0.14 g) ; ESI mass spectrum analysis m/z (relative intensity) 291 (M+H, 100) .
• Ethyl 3-methyl-1- (2-azidomethy1-4-methoxyphenyl ) -1H- pyrazole-5-carboxylate Ethyl 3-methyl-l- (2-hydroxymethyl-4- methoxyphenyl) -lH-pyrazole-5-carboxylate (0.18 g, 0.62 mmol) was dissolved in chloroform (20 mL) then methanesulfonyl chloride (0.3 g, 2.6 mmol) and triethylamine (0.26 g, 2.6 mmol) added.
• the final product was purified further by hplc utilizing gradient elution with a mixture of water : acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; HRMS (M+H) + calc . m/z: 492.170551, obs m/z: 492.169327.
• Part B 3-Trifluoromethyl-1- (2-hydroxymethyl-4-methoxyphenyl) - 5- (furan-2-yl) -IH-pyrazole: 3-Trifluoromethyl-l- (2-carboxy-4- methoxyphenyl) -5- (furan-2-yl) -IH-pyrazole (3.55 g, 10.1 mmol) in tetrahydrofuran (100 mL) was cooled to 0°C then N- methylmorpholine (1.02 g, 10.1 mmol) and isobutyl chloroformate (1.38 g, 10.1 mmol) were added.
• reaction mixture was stirred for 30 min at 0°C, filtered and added immediately to a cold solution of sodium borohydride (1.15 g, 30.2 mmol) in water (50 mL) and tetrahydrofuran (50 mL) .
• the reaction mixture was evaporated, partitioned between ethyl acetate (100 mL) and IN hydrochloric acid (50 mL) , then washed with 5% sodium bicarbonate (50 mL) and brine (50 mL) .
• the organic layer was dried and evaporated then purified further by flash chromatography using 4:1 hexane: ethyl acetate as the eluent.
• Part D 3-Trifluoromethyl-l- (2-azidomethyl-4-methoxyphenyl) - IH-pyrazole-5-carboxylic acid: To 1.43 g of 3- trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -5- (furan-2- yl) -IH-pyrazole (3.9 mmol) in acetone (60 mL) was added potassium permaganate (5.0 g, 27.5 m mol) in water (60 mL) . The reaction was heated at 60°C for 3 h, then cooled to ambient temperature and isopropyl alcohol (60 mL) added.
• Part B 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) - lH-pyrazole-5- (N- (3-fluoro-2 ' -methylsulfonyl- [1,1] -biphen-4- yl) ) carboxyamide*TFA: 3-Trifluoromethyl-1- (2-azidomethyl-4- methoxyphenyl) -lH-pyrazole-5- (N- (3-fluoro-2 ' -methy1sulfonyl-
• Example 8 3 -Trif luorome thy 1 - 1 - ( 2 - aminome hyl - 4 -methoxyphenyl ) - 1H- pyrazole-5- (N- (4-N- pyrrolidinocarbonyl) phenyl) carboxyamide* TFA
• the product was purified further by a column of flash Si ⁇ 2 (50 g) eluting with 5-10 % MeOH in CHCI 3 to give 0.24 g of 3-trifluoromethyl-l- (2-azidomethyl-4- methoxyphenyl ) -lH-pyrazole-5- (N- (4-N- carboxylpyrrolidino) phenyl) carboxyamide; LRMS ES+ (M+H)+: 514 m/z.
• Example 12 N-Benzyl-4- (3-trif luoromethyl-l- (2-aminomethyl-4- methoxyphenyl) -lH-pyrazole-5- carboxyamido ) piper idine • TFA 3 -Trifluoromethyl-l- (2-azidomethyl-4-methoxyphenyl) -1H- pyrazole-5-carboxylic acid prepared in Part B of Example 8 was coupled with N-Benzyl-4-aminopiperidine according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 116.1 °C; HRMS (M+H) + : 488.2266 m/z.
• the azidomethyl group was reduced to the aminomethyl group with SnCl 2 »2H 2 ⁇ by the method outlined in Part D of Example 8.
• the crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group.
• the title compound was isolated by HPLC utilizing gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; mp 128 °C; HRMS (M+H) + : 568.0832 m/z.
• the azidomethyl group was reduced to the aminomethyl group with SnCl 2 *2H 2 ⁇ by the method outlined in Part D of Example 8.
• the crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group.
• the title compound was isolated by HPLC utilizing gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; mp 127.4 °C; HRMS (M+H) + : 568.0837 m/z.
• the azidomethyl group was reduced to the aminomethyl group with SnCl 2 »2H 2 ⁇ by the method outlined in Part D of Example 8.
• the crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group.
• the title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; mp 113.1 °C; HRMS (M+H) + : 552.1112 m/z.
• the azidomethyl group was reduced to the aminomethyl group with SnCl 2 »2H 2 ⁇ by the method outlined in Part D of Example 8.
• the crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group.
• the title compound was isolated by HPLC utilizing gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; mp 101 °C; HRMS (M+H) + : 552.1120 m/z.
• the azidomethyl group was reduced to the aminomethyl group with SnCl 2 *2H 2 ⁇ by the method outlined in Part D of Example 8.
• the crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group.
• the title compound was isolated by HPLC utilizing gradient elution with a mixture of water : acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; mp 118.7 °C; HRMS (M+H) + : 570.1038 m/z.
• the azidomethyl group was reduced to the aminomethyl group with SnCl 2 *2H 2 ⁇ by the method outlined in Part D of Example 8.
• the crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group.
• the title compound was isolated by HPLC utilizing gradient elution with a mixture of water : acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 A) column; mp 115.8 °C; HRMS (M+H) + : 552.1111 m/z.
• Part A 4-Amino-N- ( (N 1 -methylsulfonyl) iminoyl)pyrrolidine : 4-Nitrobenzonitrile (5.4 g, 36.5 mmol) in anhydrous methyl acetate (200 mL) and MeOH (20 mL) was cooled to 0 °C and treated with a stream of dry HCI gas for 1 h. The reaction was securely stoppered and left to stand at 5 °C in a refrigerator for 24 h. The solvent was removed and the reaction was evaporated repeatedly (5 x) with Et2 ⁇ to remove the last traces of free HCI. There was obtained 28.6 g of the imidate as an HCI salt.
• the free base of the amidine prepared above was formed by suspending the product in IN NaOH (250 mL) and extracting this suspension with CHCI 3 (3 x) . The material was dried and evaporated to give 4.49 g of product.
• the aqueous layer was cooled in ice, acidified with 1M HCI (6 mL) and extracted with EtOAc (containing a small amount of EtOH) . Before separating, both layers were filtered through celite and treated with sat NaHC0 3 (1.5 mL) . The aqueous layer was removed and extracted twice with EtOAc/EtOH. Solid NaCl was added both times to aid separation of the emulsion. The aqueous layer was extracted with CHCI 3 , adjusted to pH 5 with 1M HCI, and extracted twice with CHCl 3 /EtOH. The final 6 organic layers were combined, dried over Na 2 S0 4 , filtered, and evaporated to yield a second batch of product (2.43 g, 68%).
• Triethylamine 150 ⁇ l, 1.1 mmol
• 4-dimethylaminopyridine 20 mg, 0.16 mmol
• the reaction was extracted with dilute brine solution, ice- cooled 1M HCI, and sat. NaHC0 3 .
• the organic layer was dried over MgS ⁇ 4 , filtered, and evaporated to yield crude product (371 mg) .
• the title compound was prepared from l-[2- ( (aminomethyl) phenyl) -5- (3-fluoro-2 ' -methylsulfonyl- [1,1']- biphen-4-yl) ) aminocarbonyl] -3- (trif luoromethyl) pyrazole trifluoroacetic acid salt (prepared in Example 34) and N-Boc glycine according to the procedure in Example 29; HRMS (M+H) + : 590.1495 m/z.
• Ethyl 1- (2-cyanophenyl) -5-tetrazole carboxylate To a solution of anthranilonitrile (10.00 g) and Et3N (13.21 mL) in CH2CI2 (250 mL) was added ethyloxalyl chloride (9.92 mL) in a dropwise fashion over 30 minutes. The reaction was stirred at RT under N2 for 3 h. The reaction mixture was filtered. The filtrate was washed with water (2 x 150 mL) and brine (1 x 150 mL) , filtered through phase separatory paper and evaporated. The residue was dissolved in 60 mL of CH2CI2 and 300 mL of hexane was added.
• Cobalt chloride (0.098 g ) was added to 1- (2 ' -cyanophenyl) -5- [ [ (2 '-methylsulfonyl) -3-fluoro- [1,1'] -biphen-4- yl] aminocarbonyl] -tetrazole (0.35 g) and sodium borohydride (0.072 g) in DMF (5 mL) .
• the reaction was stirred at room temperature for 16 h.
• the resulting mixture was stirred at room temperature for 16 h.
• 6M HCI (5 mL) was added over 5 min.
• the quenched reaction was stirred at room temperature for 3.5 h, diluted with EtOAc and water.
• Methyl 3- ( thiomethoxy) pyrazole-5-carboxylate A mixture of methyl 4, 4-bis (thiomethoxy) -2-oxo-3-butenoate (9.9 g, 48 mmol) and hydrazine monohydrate (2.6 mL, 53 mmol) in 200 mL of glacial acetic acid was stirred at 100 °C for 18 h. The reaction was cooled and concentrated. The residue was taken up in ethyl acetate, washed with sat'd aq NaHC0 3 and brine, dried (MgS0 4 ) and concentrated.
• Methyl 1- [2-formylphenyl] -3- (thiomethoxy) pyrazole-5- carboxylate To a solution of methyl 3- (thiomethoxy)pyrazole- 5-carboxylate (0.87 g, 5.05 mmol) in 20 mL of 1,4-dioxane was added 2-formylphenyl boronic acid (1.13 g, 7.58 mmol), pyridine (0.82 mL, 10.1 mmol), crushed 4 A molecular sieves and cupric acetate (1.38 g, 7.58 mmol). The flask was equipped with a drying tube and the mixture was allowed to stir at ambient temperature under an air atmosphere for 18 h.
• Triazololactone A solution of (2-azidophenyl)methyl propiolate (10.7 g, 53.2 mmol) in 100 mL of toluene was stirred at 100°C for 18 h. The reaction was cooled and concentrated and the residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 1.4 g (13%) of the title compound.
• Methyl 1- [2-methylphenyl] pyrazole-5-carboxylate A neat mixture of methyl pyruvate (11.37 mL, 125.9 mmol) and dimethylformamide dimethylacetal (16.72 mL, 125.9 mmol) was stirred at 80°C for 24 h. The mixture was cooled and concentrated. A portion of the residue (4.00 g, 25.45 mmol) was dissolved in 50 mL of glacial acetic acid and then there was added o-tolylhydrazine hydrochloride (4.44 g, 27.99 mmol). This mixture was stirred at 100°C for 18 h and then was cooled and concentrated.
• the silica gel was washed with THF.
• the resulting mixture was stirred at room temperature for 1 hour, quenched with IN HCI (10 mL) , and washed with IN HCI (100 mL x 3) .
• the combined HCI layers were neutralized with 50% NaOH to pH 12 and extracted with EtOAc (100 mL x 3) .
• Part B 1- (2-cyanophenyl) -5-furyl-3-trifluoromethylpyrazole: To a solution of 4, 4, 4-trifluoro-1- (2-furyl) -1, 3 -butanedione (2.06 g, 10 mmol) in ethanol (mL) was added hydrazine monohydrate (0.46 g, 10 mmol). The resulting mixture was refluxed for 16 hours and dried under vacuum to give 5-furyl- 3-trifluoromethyl-3-hydroxypyrazoline in almost quantitative yield.
• Part D l-(2- (N-Boc-aminomethyl) phenyl) -3-trifluoromethy1-5- [ ( (2-fluoro) - (2 ' -hydroxymethylsilyloxymethyl) -[1,1'] -biphen-4- yl) aminocarbonyl] pyrazole: To a solution of l- (2- (N-Boc- aminomethyl)phenyl) -3-trifluoromethylpyrazol-5-yl-carboxylic acid (0.768 g, 2 mmol) in CH2CI2 (50 mL) was added DMF (1 drop) and oxalyl chloride (0.381 g, 3 mmol), and the resulting mixture was stirred at room temperature for 1.5 hours .
• Part E l-(2- (aminomethyl) phenyl) -3-trifluoromethyl-5- [ ( (2- fluoro) - (2 ' -pyrrolidinomethyl) -[1,1'] -biphen-4- yl) aminocarbonyl] pyrazole, TFA salt: To a solution of l-(2- (N-Boc-aminomethyl)phenyl) -3-trifluoromethyl-5- [ ( (2-fluoro) - (2 ' -hydroxymethyl) -[1,1'] -biphen-4-yl) aminocarbonyl]pyrazole (150 mg, 0.26 mmol) in THF (5 mL) was added CS2CO3 (167 mg, 0.51 mmol) and MsCl (4 mg, 0.39 mmol).
• D is at the 2-position and is
• each entry in each table is intended to be paired with each formulae at the start of the table.
• example 1 is intended to be paired with each of formulae a-bbbb
• example 3 is intended to be paired with each of formulae a-bbbb.

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