WO2003047520A2 - SUBSTITUTED AMINO METHYL FACTOR Xa INHIBITORS - Google Patents

SUBSTITUTED AMINO METHYL FACTOR Xa INHIBITORS Download PDF

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Publication number
WO2003047520A2
WO2003047520A2 PCT/US2002/038331 US0238331W WO03047520A2 WO 2003047520 A2 WO2003047520 A2 WO 2003047520A2 US 0238331 W US0238331 W US 0238331W WO 03047520 A2 WO03047520 A2 WO 03047520A2
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substituted
phenyl
group
occurrence
alkyl
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PCT/US2002/038331
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French (fr)
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WO2003047520A3 (en
Inventor
Mimi L. Quan
Ruth R. Wexler
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Bristol-Myers Squibb Company
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Priority to AU2002365896A priority Critical patent/AU2002365896A1/en
Priority to EP02791349A priority patent/EP1450800A4/en
Publication of WO2003047520A2 publication Critical patent/WO2003047520A2/en
Publication of WO2003047520A3 publication Critical patent/WO2003047520A3/en

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    • 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
    • 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
    • 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
    • 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
    • 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

Definitions

  • This invention relates generally to substituted- aminomethyl substituted compounds, 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.
  • A is 2-3 carbon atoms
  • X can be 0, and R 1 and R 3 can be substituted or unsubstituted aromatic groups. None of these patents, however, exemplify or suggest compounds of the present invention.
  • A is a linker
  • B can be a linker or a ring
  • Q is a ring or an amino group
  • R, R lf and R 3 are a variety of groups.
  • WO00/39131 describes heterobicyclic Factor Xa inhibitors of which the following is an example formula:
  • Z is C or N
  • G is a mono- or bicyclic group
  • A is a cyclic moiety
  • B is a basic group or a cyclic moiety.
  • ring M can be a variety of heterocycles and rings
  • D-E represent a heterobicyclic group.
  • W098/57951 are not considered to be part of the present invention.
  • W098/57934 and US 6,060,491 describe Factor Xa inhibitors of the following formula: wherein ring M is a 6-membered heteroaryl, Z is a linker, A is a ring, B is a basic or cylic group, D is a basic moiety, and E is a ring.
  • Compounds specifically described in W098/57934 and US 6,060,491 are not considered to be part of the present invention.
  • ring M is a variety of rings
  • ring D is an aromatic ring
  • R and E are non-basic groups.
  • Compounds specifically described in W098/57937 and US 5,998,424 are not considered to be part of the present invention.
  • WO99/50255 and US 6,191,159 describe pyrazoline and triazoline Factor Xa inhibitors of the following formulas :
  • ring M can be a variety of rings all of which are substituted with Z-A-B, Z is a linker, A is a ring, B is a sulfonyl-containing heterobicycle, and rings D-E represent a heterobicyclic group or a 6-membered ring.
  • Z is a linker
  • A is a ring
  • B is a sulfonyl-containing heterobicycle
  • rings D-E represent a heterobicyclic group or a 6-membered ring.
  • WO01/32628 describes cyano-pyrroles, cyano-imidazoles, cyano-pyrazoles, and cyano-triazoles that are Factor Xa inhibitors. Compounds specifically described in WO01/32628 are not considered to be part of the present invention.
  • O01/05784 describes Factor Xa inhibitors of the following formulas:
  • ring M can be a variety of heterocycles and rings D-E represent a heterobicyclic group.
  • Compounds specifically described in WOOO/39108 are not considered to be 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 5 formation of prothro binase complex (factor Xa, factor V,
  • factor Xa factor Xa 15 Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors. In addition, it is also desirable to find new compounds with
  • compositions with advantageous and improved characteristics in one or more of the following categories: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages)
  • pharmaceutical properties e.g., solubility, permeability, and amenability to sustained release formulations
  • dosage requirements e.g., lower dosages
  • the present invention provides novel substituted-aminomethyl substituted compounds that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
  • the present invention provides 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.
  • the present invention provides a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder
  • the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
  • the present invention provides novel compounds for use in therapy.
  • the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
  • the present invention provides a novel compound of formula I: P 4 -P-M-M 4
  • M is a 3-10 membered carbocycle or a 4-10 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0) p , N, and NZ 2 ;
  • ring M is substituted with 0-3 R la and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
  • P is fused onto ring M and is a 5, 6, or 7 membered carbocycle or a 5, 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0) p , and N;
  • ring P is substituted with 0-3 R la and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
  • ring P is absent and P is directly attached to ring M;
  • one of P 4 and M 4 is -Z-A-B and the other -G ⁇ G, provided that P 4 and M 4 are attached to different rings when ring P is present;
  • G is a group of formula Ila or lib:
  • ring D including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
  • E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
  • ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1-2 R;
  • ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , wherein the 5-6 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and has 0-3 ring double bonds;
  • A is selected from:
  • C 3 - 10 carbocycle substituted with 0-2 R 4 and 5-12 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4 ;
  • B is Y or X-Y, provided that Z and B are attached to different atoms on A;
  • Y is selected from: C 3 _ ⁇ o carbocycle substituted with 1 R 4a and 0-2 R 4 , and,
  • G 1 is absent or is selected from (CR 3 R 3a ) 1 - 5 ,
  • Z is selected from a bond, - (CR 3 R 3e ) 1 _ 4 - ,
  • Z 2 is selected from H, S(0) 2 NHR 3b , C(0)R 3b , C(0)NHR 3b ,
  • R l at each occurrence, is selected from H, - (CR 3 R 3a ) r -R lb ,
  • R la forms other than an N-halo, N-S, 0- 0, or N-CN bond; alternatively, when two R la groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N,
  • R lb forms other than an 0-0, N-halo, N-S, or N-CN bond and provided that S(0) P R 2 forms other than S(0) 2 H or S(0)H;
  • R 2 at each occurrence, is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, - (CH 2 ) r -C 3 _ ⁇ o carbocycle substituted with 0-2 R 4b , and -(CH 2 ) r -5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2a at each occurrence, is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, - (CH 2 ) r -C 3 _ ⁇ o carbocycle substituted with 0-2 R 4b , and -(CH 2 ) r -5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • 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 b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from CF 3 , C 1 - 4 alkoxy, C 1 - 6 alkyl substituted with 0-2 R 4b , - (CH 2 ) r -C 3 _ ⁇ o carbocycle substituted with 0-2 R 4b , and -(CH 2 ) r -5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2c is selected from CF 3 , OH, C ⁇ _ 4 alkoxy, C ⁇ _6 alkyl, - (CH 2 ) r -C 3 _ ⁇ o carbocycle substituted with 0-2 R 4b , and -(CH ) r -5-10 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2d is selected from H, R c , C ⁇ _ 6 alkyl substituted with 0-2 R 4c , - (CR 3 R 3a ) r -C 3 _ ⁇ o carbocycle substituted with 0-2 R 4c , and - (CR 3 R 3a ) r -5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2d forms other than a N-halo, N-C-halo, S(0) p - halo, 0-halo, N-S, S-N, S(0) p -S(0) p , S-O, O-N, O-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, R 4c , C ⁇ _ 6 alkyl substituted with 0-2 R c , - (CR 3 R 3 ) r -C 3 - ⁇ o carbocycle substituted with 0-2 R 4c , and - (CR 3 R 3a ) r -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 3 at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, and phenyl;
  • R 3a at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, and phenyl;
  • R 3 and R 3a together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R 3 and R a are attached, and 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 3b at each occurrence, is selected from CF 3 , C 1 -. 4 alkoxy substituted with 0-2 R 4b , C ⁇ _ 6 alkyl substituted with 0-2 R 4b , - (CH 2 ) r -C 3 _io carbocycle substituted with 0-2 R 4b , and -(CH 2 ) r -5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 3c is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, and phenyl;
  • R 3e at each occurrence, is selected from H, S0 2 NHR 3 ,
  • R 3f at each occurrence, is selected from: C -s alkyl substituted with 0-2 R la , C 2 _ 6 alkenyl substituted with 0-2 R la , C 2 - 6 alkynyl substituted with 0-2 R la , -(Co- 4 alkyl) -5-10 membered carbocycle substituted with 0-3 R la , and -(Co- 4 alkyl) -5-10 membered heterocycle substituted with 0-3 R la and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 3 ⁇ at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , - (CH 2 ) r -3-6 member
  • R 3 and R 3 ⁇ are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
  • (CR 3 R 3a ) r OR 2 F, CI, Br, I, C ⁇ _ alkyl, (CR 3 R 3a ) r CN, (CR 3 R 3 ) r N0 2 , (CR 3 R 3a ) r NR 2 R 2a , (CR 3 R 3a ) r C (0) R 2c , (CR 3 R 3a ) r NR 2 C(0)R 2b , (CR 3 R 3a ) r C (0) NR 2 R 2a ,
  • R 4a s selected from (CR 3 R 3 9) r N( ⁇ 0) R 2d R 2d , (CR 3 R 3 9) v -NR 2d C(0)R 2e , (CR 3 R 3 9) V -C (0)NR 2d R 2d ,
  • R 4a is selected from (CR 3 R 3 9) r NR 2d R 2d ,
  • R 5a at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 7 is selected from H, OH, C ⁇ _ 6 alkyl, C ⁇ _ 6 alkyl-C(O)-, C ⁇ _ 6 alkyl-O-, (CH 2 ) n -phenyl, C 1 - 4 alkyl-OC(O)-, C 6 - ⁇ o aryl-O-, C 6 - ⁇ o aryl-OC(O)-, C 6 - ⁇ o aryl-CH 2 -C(0)-, C 1 - 4 alkyl-C (O) O-C 1 - 4 alkyl-OC (0) - , C 6 - 10 aryl-C(0)0-Ci- alkyl-OC (0) - ,
  • R 8 at each occurrence, is selected from H, C - Q alkyl, and (CH 2 ) n -phenyl;
  • R 7 and R 8 when attached to the same nitrogen, combine to form a 5-10 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • 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;
  • p at each occurrence, is selected from 0, 1, and 2;
  • r at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6 ;
  • t at each occurrence, is selected from 0, 1, 2, and 3;
  • v at each occurrence, is selected from 1, 2, 3, 4, 5, and 6 ;
  • Z-A is other than NHC(O) -thienyl, NHCH 2 -thienyl, NHC (0) -benzothienyl, and NHCH 2 -benzothienyl;
  • ring M is a non-aromatic ring with at least one ring N
  • G-G;L is attached via a ring N
  • Z is at least two atoms in length
  • Y is other than phenyl or pyridyl .
  • the present invention provides a novel compound of Formula II:
  • ring M is a 5, 6, or 7 membered carbocycle or a 5 , 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0) p , N, and NZ 2 ;
  • ring M is substituted with 0-2 R la and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
  • ring P including P x , P 2 , and P 3 , is a 5 or 6 membered aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0) p , and N;
  • ring P including P 1# P 2 , and P 3 , is a 5 or 6 membered dihydro-aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0) p , and N;
  • ring P is substituted with 0-2 R la ;
  • one of P and M is -Z-A-B and the other -G ⁇ G;
  • G is a group of formula Ila or lib:
  • ring D including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
  • E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
  • ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2 R; alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds ;
  • A is selected from:
  • C 5 - 10 carbocycle substituted with 0-2 R 4 and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4 ;
  • Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R a and 0-2 R 4 : cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl , 1,3, 4-oxadiazolyl
  • Z is selected from a bond, CH 2 , CH 2 CH 2 , CH 2 0, OCH 2 , C(O), NH, CH 2 NH, NHCH 2 , CH 2 C(0), C(0)CH 2 , C(0)NH, NHC(O), NHC(0)CH 2 C(0)NH, S(0) 2 , CH 2 S(0) 2 , S(0) 2 (CH 2 ), S0 2 NH, and NHS0 , provided that Z does not form a N-S, NCH 2 N, NCH 2 0, or NCH 2 S bond with either group to which it is attached;
  • Z 2 is selected from H, C ⁇ _ alkyl, phenyl, benzyl, C(0)R 3b , S(0)R 3f , and S(0) 2 R 3f ;
  • R la at each occurrence, is selected from H, -(CH ) r -R lb , -(CH(CH 3 ) ) r -R lb , -(C(CH 3 ) 2 ) r -R lb , -0- (CR 3 R 3a ) r ⁇ R lb , -NR 2 -(CR 3 R a ) r -R lb , and -S- (CR 3 R 3a ) r -R lb , provided that R la forms other than an N-halo, N-S, O-O, or N-CN bond; alternatively, when two R la groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N,
  • this ring being substituted with 0-2 R 4b and comprising: 0-3 double ring bonds;
  • R ib ig selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, CI, Br, I, -CN, -CHO, CF 3 , OR 2 , NR 2 R 2a , C(0)R 2b , C0 2 R 2b , OC(0)R 2 , C0 2 R 2a , S(0) p R 2 , NR 2 (CH 2 ) r OR 2 , NR 2 C(0)R 2b , NR 2 C(0)NHR 2 , NR 2 C(0) 2 R 2a , OC(0)NR 2 R 2a , C(0)NR 2 R 2a , C(0)NR 2 (CH 2 ) r OR 2 , S0 2 NR 2 R 2a , NR 2 S0 2 R 2 , C 5 _ 6 carbocycle substituted with 0-2 R b , and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the
  • R 2 at each occurrence, is selected from H, CF 3 , CH 3 ,
  • R 2a at each occurrence, is selected from H, CF 3 , CH 3 ,
  • 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 b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from CF 3 , C 1 -. 4 alkoxy, CH 3 , CH 2 CH , CH 2 CH 2 CH , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, C 5 - 6 carbocycle substituted with 0-2 R b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0) p and substituted with 0-2 R 4b ;
  • R 2c is selected from CF 3 , OH, C 1 - 4 alkoxy, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, C 5 _ 6 carbocycle substituted with 0-2 R b , and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2d is selected from H, R 4c , C 1 - 4 alkyl substituted with 0-2 R c , - (CR 3 R 3a ) r -C 3 - 6 carbocycle substituted with 0-2 R 4c , and - (CR 3 R 3a ) r -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , provided that R 2d forms other than a N-halo, N-C-halo, S(0) p - halo, O-halo, N-S, S-N, S(0) p -S(0) p , S-O, O-N, O-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, R c , C 1 - 4 alkyl substituted with 0-2 R 4c , - (CR 3 R 3a ) r -C 3 _ 6 carbocycle substituted with 0-2 R 4c , and - (CR 3 R 3a ) r -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 3 at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, and phenyl;
  • R 3a at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, and phenyl;
  • R 3 and R 3a together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R 3 and R 3a are attached;
  • R 3c at each occurrence, is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, and phenyl;
  • R 3 9, at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl, cyclopropyl-methyl, benzyl , and phenyl ;
  • R 3 and R 3 ⁇ are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
  • R 4 a is selected from (CR 3 R 3 9) r N( ⁇ 0)R 2d R 2d ,
  • R 4a is selected from (CR 3 R 3 ⁇ ) r NR 2d R 2d , NR 2d C(0)R 2e , NR 2d C(0)NR 2d R 2d , NR 2d C (0) 0R 2d , NR 2d S0NR 2d R 2d , and NR 2d S0 2 R 2d , provided that at least one of R 2d and R 2e is alkyl substituted with at least one R 4c that is other than alkyl;
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, CI, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 ,
  • r at each occurrence, is selected from 0, 1, and 2;
  • v at each occurrence, is selected from 1, 2, and 3.
  • the present invention provides a novel compound, wherein:
  • ring M is substituted with 0-2 R la and is selected from the group :
  • ring P including P x , P 2 , P 3 , and P is selected from
  • one of P 4 and M 4 is -Z-A-B and the other -G 1 -G;
  • G is selected from the group:
  • R l a i s selected from H, R lb , CH(CH 3 )R lb , C(CH 3 ) 2 R lb , CH 2 R lb , and CH 2 CH 2 R lb , provided that R la forms other than an N- halo, N-S, or N-CN bond;
  • R la groups when two R la groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0) p , this ring being substituted with 0-2 R 4b and 0-3 ring double bonds;
  • R lb is selected from H, CH 3 , CH 2 CH 3 , F, Cl, Br, -CN, -CHO, CF 3 , OR 2 , NR 2 R 2a , C(0)R 2b , C0 2 R 2b , 0C(0)R 2 , C0 2 R 2a , S(0) p R 2 , NR 2 (CH 2 ) r OR 2 , NR 2 C(0)R 2b , C(0)NR 2 R 2a , S0 2 NR 2 R 2a , NR 2 S0 2 R 2 , phenyl substituted with 0-2 R 4b , and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b , provided that R lb forms other than an 0-0, N-halo, N-S, or N-CN bond;
  • A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R 4 ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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
  • Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R and 0-1 R 4 ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2, 3-oxadiazole, 1,2,4- oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2 , 5-thiadiazole, 1, 3, 4-thiadiazole, 1, 2 , 3-triazole, 1, 2 , 4-triazole, 1, 2, 5-triazole
  • 0-2 R b a benzyl substituted with 0-2 R b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2
  • R 2 at each occurrence, is selected from H, CF , CH , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-2 R b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • 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 b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from CF 3 , C ⁇ _ 4 alkoxy, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-2 R 4b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2c at each occurrence, is selected from CF 3 , OH, 0CH 3 ,
  • R 2d is selected from H, R 4c , C 1 -. 4 alkyl substituted with 0-2 R c , C 3 _ 6 carbocycle substituted with 0-2 R 4c , - (CR 3 R 3a )-C 3 - 6 carbocycle substituted with 0-2 R 4c , 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , and - (CR 3 R 3a ) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , provided that R 2d forms other than a N-halo, N-C-halo, S(0) p -halo, 0-halo, N- S, S-N, S(0)p-S(0) p , S-0,
  • R 2e is selected from H, R c , C 1 - 4 alkyl substituted with 0-2 R c , C 3 _ 6 carbocycle substituted with 0-2 R 4c , - (CR 3 R 3a ) -C 3 _ 6 carbocycle substituted with 0-2 R c , 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , and - (CR 3 R 3a ) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4 at each occurrence, is selected from H, (CH ) 0R 2 , CH 2 OR 2 , OR 2 , F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 , C(CH 3 ) 3 , -CN, N0 2 , NR 2 R 2a , CH 2 NR 2 R 2a , (CH 2 ) 2 NR 2 R 2a , C(0)R 2c , NR 2 C(0)R 2b , C(0)NR 2 R 2 , S0 2 NR 2 R 2a , CF 3 , and CF 2 CF 3 ;
  • R a is selected from (CH 2 ) r N ( ⁇ O) R 2d R 2d , (CH 2 ) v -NR 2d C (0) R 2e , (CH 2 ) v -NR 2d C(0)NR 2d R 2d , (CH 2 ) v -NR 2d C (0) OR 2d , and (CH 2 ) v -NR 2d S0 2 R 2d ;
  • R 4a is selected from (CH 2 ) r NR 2d R 2d , NR 2d C(0)R 2e , NR 2d C(0)NR 2d R 2d , NR 2d C (0) OR 2d , and
  • R 2d S0 2 R 2d provided that at least one of R 2d and R 2e is alkyl substituted with at least one R c that is other than alkyl;
  • R 4b and (CR 3 R 3a )5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 6 is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CN, N0 2 , NR 2 R 2a , CH 2 NR 2 R 2a , C(0)R 2b , CH 2 C(0)R 2b , NR 2 C(0)R 2b , S0 2 NR 2 R 2a , and NR 2 S0 2 C ⁇ _ 4 alkyl; and,
  • v at each occurrence, is selected from 1 and 2.
  • the present invention provides a novel compound, wherein: ring M is substituted with 0-2 R la and is selected from the group :
  • ring P including P 1# P 2 , P , and P is selected from
  • one of P and M 4 is -A-B and the other -G;
  • G is selected from the group:
  • G 1 is absent or is selected from CH 2 , CH 2 CH 2 , CH 2 0, OCH 2 , NH, CH 2 NH, NHCH 2 , CH 2 C(0), C(0)CH 2 , C(0)NH, NHC(O),
  • A is selected from piperidinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R 4 ;
  • B is selected from phenyl, pyridyl, pyrrolidino, N- pyrrolidino-carbonyl, morpholino, N-morpholino- carbonyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R 4a and 0-1 R 4 ;
  • R la is selected from H, R lb , C(CH 3 ) 2 R lb , and CH 2 R lb , provided that R la forms other than an N-halo, N-S, or N-CN bond;
  • R lb is selected from CH 3 , CH 2 CH 3 , F, Cl, Br, -CN, CF 3 , OR 2 , NR 2 R 2a , C(0)R 2b , C0 2 R 2b , C0 R 2a , S(0) p R 2 , C(0)NR 2 R 2a , S0 2 NR 2 R 2a , NR 2 S0 2 R 2 , and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b , provided that R lb forms other than an O-O, N-halo, N-S, or N-CN . bond;
  • R at each occurrence, is selected from H, CH 3 , CH 2 CH 3 ,
  • R 2a at each occurrence, is selected from H, CH 3 , CHCH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with
  • 0-1 R b and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R 4b ;
  • 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 0-1 R b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from 0CH 3 , OCH 2 CH 3 ,
  • OCH 2 CH 2 CH 3 OCH(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-1 R b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0) p and substituted with 0-1
  • R c at each occurrence, is selected from OH, OCH 3 , OCH CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-1 R b , and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R 4b ;
  • R 2d is selected from H, R c , C ⁇ _ 4 alkyl substituted with 0-2 R 4c , C 3 -g carbocycle substituted with 0-2 R 4c , -(CH 2 )-C 3 _ 6 carbocycle substituted with
  • R 4 at each occurrence, is selected from OH, OR 2 , CH 2 OR 2 , (CH 2 ) 2 OR 2 , F, Br, Cl, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ,
  • R 4a is selected from (CH 2 ) r N( ⁇ 0) R 2d R 2d , (CH 2 ) v -NR 2d C (0) R 2e , (CH 2 ) v -NR 2d C(0)NR 2d R 2d , (CH 2 ) v -NR 2d C (0) 0R 2d , and (CH 2 ) v -NR 2d S0 2 R 2d ;
  • R 4a is selected from (CH 2 ) r NR 2d R 2d , NR 2d C(0)R 2e , NR 2d C(0)NR 2d R 2d , NR 2d C (0) 0R 2d , and
  • R 2d S0 R 2d provided that at least one of R 2d and R 2e is alkyl substituted with at least one R c that is other than alkyl;
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CN, N0 2 , NR 2 R 2a , CH 2 NR 2 R 2a , C(0)R 2b , CH 2 C(0)R 2b , NR 2 C(0)R 2b , and S0NR 2 R 2a .
  • the present invention provides a novel compound, wherein:
  • ring M is substituted with 0-1 R la and is selected from the group :
  • ring P including P lf P , P 3 , and P 4 is selected from group :
  • one of P 4 and M 4 is -A-B and the other -G;
  • G is selected from:
  • A is selected from the group: piperidinyl, phenyl, 2- pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-C1- phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2- aminophenyl, and 2-methoxyphenyl;
  • B is selected from phenyl, pyridyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R 4a ;
  • R la is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 F, CH 2 C1,
  • R 2 at each occurrence, is selected from H, CH 3 , CH 2 CH 3 ,
  • R 2a at each occurrence, is selected from H, CH 3 , and CH 2 CH 3 ;
  • 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 0-1 R 4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S(0) p ;
  • R 2b at each occurrence, is selected from OH, OCH 3 , OCHCH 3 , CH 3 , and CH 2 CH 3 ;
  • R 2c at each occurrence, is selected from OH, OCH 3 , OCH 2 CH 3 , CH 3 , and CH 2 CH 3 ;
  • R 2d is selected from H, R c , C 1 -. 4 alkyl substituted with 0-2 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R 4c , phenyl substituted with 0-2 R 4c , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2
  • R c provided that R 2d forms other than a N-halo, N-C- halo, S(0) p -halo, O-halo, N-S, S-N, S(0) p -S(0) p , S-O, O-N, O-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, R 4c , C 1 -. 4 alkyl substituted with 0-2 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R 4c , phenyl substituted with 0-2 R c , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4a is selected from CH 2 N( ⁇ 0)R 2d R 2d , CH 2 NR 2d C (0) R 2e ,
  • 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R ;
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , NR 2 R 2a , CH 2 NR 2 R 2a , C(0)R 2b , CH 2 C(0)R 2b , NR 2 C(0)R 2b , and S0 2 NR 2 R 2a .
  • the present invention provides a novel compound, wherein the compound is selected from:
  • M 4 is -A-B
  • G is selected from:
  • A-B is selected from :
  • R 2d is selected from H, C 1 -. 4 alkyl substituted with 0-1 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R 4c , phenyl substituted with 0-2 R 4c , and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , provided that R 2d forms other than a N-halo, N-C-halo, S(0) p -halo, 0- halo, N-S, S-N, S(0) p -S(0) p , S-0, 0-N, 0-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, C 1 - 4 alkyl substituted with 0-1 R 4c , C 3 _ 6 cycloalkyl substituted with 0-2 R 4c , phenyl, substituted with 0-2 R c , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4a is selected from CH 2 N( ⁇ 0) R 2d R 2d , CH 2 NR 2d C (0) R 2e , CH 2 NR 2d C(0)OR 2d , and CH 2 NR 2d S0 2 R 2d ; and,
  • R 4 c i s selected from OH, 0CH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 0H,
  • the present invention provides a novel compound, wherein the compound is of the formula:
  • P 4 is -G
  • M 4 is -A-B
  • A-B is selected from:
  • R 2d is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH 2 CH 2 CH (CH 3 ) 2 , CH 2 - cyclopropyl, cyclopropyl, and cyclopentyl; and,
  • R 2e at each occurrence, is selected from CH 3 , CH 2 CH 3 ,
  • the present invention provides a novel compound, wherein the compound is selected from the group:
  • the present invention provides a novel compound, wherein the compound is of Formula Ilia, Illb, or IIIc:
  • ring M including M 1# M 2 , and, if present, M 3 , is phenyl or a 3-10 membered carbocyclic or 4-10 membered heterocyclic ring consisting of: carbon atoms and 1-4 heteroatoms selected from 0, S(0) p , N, and NZ 2 ;
  • ring M is substituted with 0-3 R la and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
  • one of P 4 and M is -Z-A-B and the other -G -G;
  • G is a group of formula Ila or lib:
  • ring D including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
  • E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
  • ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2 R; alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds ;
  • A is selected from:
  • C 5 - 10 carbocycle substituted with 0-2 R 4 and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4 ;
  • Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R a and 0-2 R 4 : cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, pipe
  • Z is selected from a bond, CH 2 , CH 2 CH , CH 2 0, OCH 2 , C(O), NH, CH 2 NH, NHCH 2 , CH 2 C(0), C(0)CH 2 , C(0)NH, NHC(O), NHC(0)NH, NHC(0)CH 2 C(0)NH, C(0)NHS(0) 2 , S(0) 2 ,
  • Z 2 is selected from H, C ⁇ _ 4 alkyl, phenyl, benzyl, C(0)R 3b , S(0)R 3f , and S(0) 2 R f ;
  • R la at each occurrence, is selected from H, -(CH 2 ) r -R lb ,
  • R la forms other than an N-halo, N-S, O-O, or N-CN bond; alternatively, when two R la groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N,
  • R 2 at each occurrence, is selected from H, CF 3 , CH ,
  • R 2a at each occurrence, is selected from H, CF 3 , CH 3 ,
  • 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 b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R b at each occurrence, is selected from CF 3 , C 1 -. 4 alkoxy, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, C 5 - 6 carbocycle substituted with 0-2 R b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2c is selected from CF 3 , OH, C 1 -. 4 alkoxy, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , benzyl, C 5 - 6 carbocycle substituted with 0-2 R 4b , and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2d is selected from H, R c , C ⁇ _ 4 alkyl substituted with 0-2 R 4c , - (CR 3 R 3a ) r -C 3 _ 6 carbocycle substituted with 0-2 R 4c , and - (CR 3 R 3a ) r -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , provided that R 2d forms other than a N-halo, N-C-halo, S (O p - halo, 0-halo, N-S, S-N, S(0) p -S(0) p , S-0, 0-N, 0-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, R c , C 1 -. 4 alkyl substituted with 0-2 R c , - (CR 3 R 3a ) r -C 3 - 6 carbocycle substituted with 0-2 R 4c , and - (CR 3 R 3a ) r -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 3 at each occurrence, is selected from H, CH 3 , CH CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, and phenyl;
  • R a at each occurrence, is selected from H, CH 3 , CHCH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, and phenyl;
  • R 3 and R 3a together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R 3 and R 3a are attached;
  • R 3c at each occurrence, is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, and phenyl;
  • R 3 9, at each occurrence, is selected from H, CH 3 , CHCH , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl, cyclopropyl-methyl, benzyl , and phenyl ;
  • R 3 and R 3 9 are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
  • R 4 a ig selected from (CR 3 R 3 9) r N( ⁇ 0) R 2d R 2d ,
  • R 4a is selected from (CR 3 R 3 9) r NR 2d R 2d , NR 2d C(0)R 2e , NR 2d C(0)NR 2d R 2d , NR 2d C (0) 0R 2d , NR 2d S0 2 NR 2d R 2d , and NR 2d S0 2 R 2d , provided that at least one of R 2d and R e is alkyl substituted with at least one R c that is other than alkyl;
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 ,
  • r at each occurrence, is selected from 0, 1, and 2;
  • v at each occurrence, is selected from 1, 2, and 3.
  • the present invention provides a novel compound, wherein:
  • ring M is substituted with 0-3 R la and 0-1 carbonyl group;
  • G is selected from the group:
  • G ⁇ is absent or is selected from (CR 3 R 3a ) 1 _ 3 ,
  • R la is selected from H, R lb , CH(CH 3 )R lb , C(CH 3 ) 2 R lb , CH 2 R lb , and CH 2 CH 2 R lb , provided that R la forms other than an N- halo, N-S, or N-CN bond;
  • R la groups when two R la groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0) p , this ring being substituted with 0-2 R 4b and 0-3 ring double bonds;
  • Rlb i s selected from H, CH 3 , CH 2 CH 3 , F, Cl, Br, -CN, -CHO, CF 3 , OR 2 , NR 2 R 2a , C(0)R 2b , C0 2 R 2b , OC(0)R 2 , C0 2 R 2a , S(0) p R 2 , NR 2 (CH 2 ) r OR 2 , NR 2 C(0)R 2b , C(0)NR 2 R a , S0NR 2 R 2a , NR 2 S0 2 R 2 , phenyl substituted with 0-2 R 4b , and 5-6
  • A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R 4 ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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 ,
  • Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R 4a and 0-1 R 4 ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3-oxadiazole, 1,2,4- oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2, 5-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2 , 3-triazole, 1, 2 , 4-triazole, 1, 2
  • R 2 at each occurrence, is selected from H, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , phenyl substituted with
  • 0-2 R 4b a benzyl substituted with 0-2 R 4b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R 2a at each occurrence, is selected from H, CF 3 , CH 3 ,
  • R 2 and R 2 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 b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from CF 3 , C ⁇ _ 4 alkoxy, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-2 R b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • R c at each occurrence, is selected from CF 3 , OH, OCH 3 ,
  • R 2 is selected from H, R c , C ⁇ _ 4 alkyl substituted with 0-2 R c , C 3 _ 6 carbocycle substituted with 0-2 R c , - (CR 3 R 3a ) -C 3 - 6 carbocycle substituted with 0-2 R c , 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , and - (CR 3 R 3a ) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2d forms other than a N-halo, N-C-halo, S(0) p -halo, 0-halo, N- S, S-N, S(0)p-S(0) p , S-O, 0-
  • R 2e is selected from H, R 4c , C ⁇ _ 4 alkyl substituted with 0-2 R c , C3.. 6 carbocycle substituted with 0-2 R 4 , - (CR 3 R 3 ) -C 3 - 6 carbocycle substituted with 0-2 R 4c , 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , and - (CR 3 R 3a ) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4 at each occurrence, is selected from H, (CH 2 ) 2 0R 2 , CH 2 OR 2 , OR 2 , F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 , C(CH 3 ) 3 , -CN, N0 2 , NR 2 R 2a , CH 2 NR 2 R 2a , (CH 2 ) 2 NR 2 R 2a , C(0)R 2c , NR 2 C(0)R 2b , C(0)NR 2 R 2a , S0 2 NR 2 R 2a , CF 3 , and
  • R 4a i s selected from (CH 2 ) r N( ⁇ 0) R 2d R 2d , (CH 2 ) v -NR 2d C (0) R 2e , (CH 2 ) v -NR 2d C(0)NR 2d R 2d , (CH 2 ) v -NR 2d C (0) OR 2d , and (CH 2 ) v -NR 2d S0 2 R 2d ;
  • R 4a is selected from (CH 2 ) r NR 2d R 2d ,
  • NR 2d C(0)R 2e NR 2d C(0)NR 2d R 2d , NR 2d C (0) 0R 2d , and NR 2d S0 R 2d , provided that at least one of R 2d and R 2e is alkyl substituted with at least one R 4c that is other than alkyl;
  • R b and (CR R a )5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b ;
  • NR 3 S0 2 -C ⁇ _4 alkyl NR 3 S0 2 CF 3 , NR 3 S0 2 -phenyl , S(0) p CF 3 , S(0) p -C ⁇ _ 4 alkyl, S (0) p -phenyl, CF 3 , phenyl substituted with 0-2 R 6 , naphthyl substituted with 0-2 R 6 , and benzyl substituted with 0-2 R 6 ;
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CN, N0 2 , NR 2 R 2a ,
  • v at each occurrence, is selected from 1 and 2.
  • the present invention provides a novel compound, wherein the compound is selected from:
  • J is selected from 0, S, NH, and NR la ;
  • G is selected from the group:
  • G x is absent or is selected from CH 2 , CH 2 CH 2 , CH 2 0, OCH 2 , NH, CH 2 NH, NHCH 2 , CH 2 C(0), C(0)CH 2 , C(0)NH, NHC (0) , NHC(0)NH, C(0)NHS(0) 2 , CH 2 S(0) 2 , S(0) 2 (CH 2 ), S0 2 NH, and NHS0 2 , provided that G ⁇ does not form a N-S, NCH 2 N, NCH 2 0, or NCH 2 S bond with either group to which it is attached;
  • A is selected from indolinyl, piperidinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R 4 ;
  • B is selected from phenyl, pyridyl, pyrrolidino, N- pyrrolidino-carbonyl, morpholino, N-morpholino- carbonyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R a and 0-1 R 4 ;
  • Rla is selected from H, R lb , C(CH 3 ) 2 R lb , and CH 2 R lb , provided that R la forms other than an N-halo, N-S, or N-CN bond;
  • R lb is selected from CH 3 , CH 2 CH 3 , F, Cl, Br, -CN, CF 3 , OR 2 , NR 2 R 2a , C(0)R 2b , C0 2 R 2b , C ⁇ 2 R 2a , S(0) p R 2 , C(0)NR 2 R 2a , S0 2 NR 2 R 2a , NR 2 S0 2 R 2 , and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b , provided that R lb forms other than an 0-0, N-halo, N-S, or N-CN bond;
  • R 2 at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , phenyl substituted with 0-1 R 4b , benzyl substituted with 0-1 R 4b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R 4b ;
  • R 2a at each occurrence, is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with
  • 0-1 R and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R 4b ;
  • 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 0-1 R b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from OCH 3 , OCH CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-1 R 4b , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R b ;
  • R 2c is selected from OH, 0CH , OCH 2 CH , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , benzyl, phenyl substituted with 0-1 R b , and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R b ;
  • R d is selected from H, R 4c , C 1 -. 4 alkyl substituted with 0-2 R 4c , C 3 _ 6 carbocycle substituted with 0-2 R c , -(CH )-C 3 _ 6 carbocycle substituted with
  • 0-2 R c 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R c , and -(CH 2 )-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4 at each occurrence, is selected from OH, OR 2 , CH 2 OR 2 , (CH 2 ) 2 OR 2 , F, Br, Cl, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 , C(CH 3 ) 3 , NR 2 R 2a , CH 2 NR 2 R 2a , (CH 2 ) 2 NR 2 R 2a , CF 3 , and CF 2 CF 3 ;
  • R 4 a i s selected from (CH 2 ) r N( ⁇ 0) R 2d R 2d , (CH 2 ) v -NR 2d C (0) R 2e , (CH 2 ) v -NR 2d C(0)NR d R 2d , (CH 2 ) v -NR 2d C (0) 0R 2d , and (CH 2 ) v -NR 2d S0 2 R 2d ;
  • R 4a is selected from (CH 2 ) r NR 2d R 2d ,
  • NR 2d C(0)R 2e NR 2 C(0)NR 2d R 2d , NR 2d C (0) 0R 2d , and NR 2d S0 2 R 2d , provided that at least one of R 2d and R 2e is alkyl substituted with at least one R 4c that is other than alkyl;
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CN, N0 2 , NR 2 R 2a , CH 2 NR 2 R 2a , C(0)R 2b , CH 2 C(0)R b , NR 2 C(0)R 2b , and S0 2 NR 2 R 2a .
  • the present invention provides a novel compound, wherein the compound is selected from:
  • J is selected from 0, S, NH, and NR la ;
  • M 4 is -Z-A-B
  • G is selected from:
  • G ⁇ is absent or is selected from CH 2 NH, NHCH 2 , CH 2 C(0), C(0)CH 2 , C(0)NH, NHC(O), NHC(0)NH, CH 2 S(0) 2 ,
  • A is selected from the group: indolinyl, piperidinyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C1- phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2- methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;
  • B is selected from phenyl, pyridyl, 1 , 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R 4a ;
  • R l a i s selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 F, CH 2 C1, Br, CH 2 Br, -CN, CH 2 CN, CF 3 , CH 2 CF 3 , OCH 3 , CH 2 OH, C(CH 3 ) 2 OH, CH 2 OCH 3 , NH 2 , CH 2 NH 2 , NHCH 3 , CH 2 NHCH 3 ,
  • R 2 at each occurrence, is selected from H, CH 3 , CHCH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , phenyl substituted with 0-1 R 4b , benzyl substituted with 0-1 R b , and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-1 R 4b ;
  • R 2a at each occurrence, is selected from H, CH 3 , and
  • 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 0-1 R b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0) p ;
  • R 2b at each occurrence, is selected from OH, OCH 3 , 0CHCH 3 , CH 3 , and CH 2 CH 3 ;
  • R 2c at each occurrence, is selected from OH, OCH 3 , OCH CH 3 , CH 3 , and CH 2 CH 3 ;
  • R d is selected from H, R 4c , C 1 - 4 alkyl substituted with 0-2 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R 4c , phenyl substituted with 0-2 R 4c , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2d forms other than a N-halo, N-C- halo, S(0) p -halo, O-halo, N-S, S-N, S(0) p -S(0) p , S-O, O-N, O-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, R c , C 1 -. 4 alkyl substituted with 0-2 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R 4 , phenyl substituted with 0-2 R 4c , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4c , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4a is selected from CH 2 N( ⁇ 0) R 2d R 2d , CH 2 NR 2d C (0) R 2e ,
  • R 5 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p and substituted with 0-2 R 4b.
  • R 6 at each occurrence, is selected from H, OH, OR 2 , F, Cl, CH 3 , CH 2 CH 3 , NR 2 R 2a , CH 2 NR 2 R 2a , C(0)R 2b , CH 2 C(0)R 2b , NR 2 C(0)R 2b , and S0 2 NR 2 R 2a .
  • the present invention provides a novel compound, wherein the compound is selected from:
  • G is selected from:
  • A-B is selected from:
  • R d is selected from H, C 1 - 4 alkyl substituted with 0-1 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R c , phenyl substituted with 0-2 R 4c , and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , provided that R 2d forms other than a N-halo, N-C-halo, S(0) p -halo, 0- halo, N-S, S-N, S(0) p -S(0) p , S-0, 0-N, O-S, or 0-0 moiety;
  • R 2e at each occurrence, is selected from H, C ⁇ _ 4 alkyl substituted with 0-1 R c , C 3 _ 6 cycloalkyl substituted with 0-2 R c , phenyl, substituted with 0-2 R c , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) p , provided that R 2e forms other than a C(0)-halo or C(0)-S(0) p moiety;
  • R 4a i s selected from CH 2 N( ⁇ 0)R 2d R 2d , CH 2 NR 2d C (0) R 2e , CH 2 NR 2d C(0)0R 2d , and CH 2 NR 2d S0 2 R 2d ; and, R 4c is selected from OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 ,
  • the present invention provides a novel compound, wherein the compound is selected from:
  • P 4 is -G
  • A-B is selected from:
  • R 2d is selected from H, CH 3 , CH 2 CH , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH 2 CH 2 CH (CH 3 ) 2 , CH 2 - cyclopropyl, cyclopropyl, and cyclopentyl; and,
  • R 2e at each occurrence, is selected from CH 3 , CH 2 CH 3 ,
  • the present invention provides a novel compound, wherein the compound is selected from the group:
  • the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
  • the present invention provides a novel method for treating 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 present invention provides a novel method, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
  • the present invention provides a novel method, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction,
  • the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder
  • the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
  • the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is compound of the present invention or a pharmaceutically acceptable salt thereof and the second therapeutic agent is at least one agent selected from a second factor Xa inhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent.
  • the present invention provides a novel method, wherein the second therapeutic agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase .
  • the second therapeutic agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide,
  • the present invention provides a novel method, wherein the second therapeutic agent is at least one anti-platelet agent.
  • the present invention provides a novel method, wherein the anti-platelet agent is aspirin and clopidogrel.
  • the present invention provides a novel method, wherein the anti-platelet agent is clopidogrel .
  • the present invention provides a novel article of manufacture, comprising:
  • composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
  • the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
  • the present invention provides a novel article of manufacture, comprising:
  • composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
  • the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
  • the present invention provides novel compounds as described above for use in therapy.
  • the present invention provides the use of novel compounds as described above for the manufacture of a medicament for the treatment of a thromboembolic disorder.
  • the compounds herein described may have asymmetric centers .
  • the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.
  • the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.
  • 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 in general, does not cover groups such as N-halo, S(0)H, and S0 2 H.
  • 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 .
  • amines on the compounds of this invention can be converted to amine N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
  • an oxidizing agent e.g., MCPBA and/or hydrogen peroxides
  • all shown and claimed amines are considered to cover both the shown amine and its N-oxide (N ⁇ O) derivative.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C ⁇ _ 6 alkyl is intended to include Ci, C 2 , C 3 , C 4 , C 5 , and CQ 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 ⁇ _ 6 alkoxy is intended to include Ci, C 2 , C 3 , C 4 , C 5 , and C 6 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 , Cs , and C 7 cycloalkyl groups.
  • Alkenyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl .
  • C 2 _ 6 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkenyl groups.
  • Alkynyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl .
  • C 2 - 6 Alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , and C ⁇ 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 residue” 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 ring, any of which may be saturated, partially unsaturated, or unsaturated
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane,
  • bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane) .
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a trycyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge .
  • 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 ring heteroatoms independently selected from the group consisting of N, 0 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 (i.e., N ⁇ O and S(0) p ).
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined) .
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that 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 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, 0 and S.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined) .
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O)p) .
  • bridged rings are also included in the definition of heterocycle.
  • a bridged ring occurs when one or more atoms (i.e., C, 0, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a trycyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl , benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 , 5, 2-dithiazinyl, dihydrofuro [2 , 3-i>] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl
  • 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, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that 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, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 18th ed. , Mack Publishing Company, Easton, PA, 1990, p 1445, the disclosure of which is hereby incorporated by reference.
  • prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form.
  • the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
  • Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs the present invention 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 the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxy1, 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 the present invention.
  • “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. It is preferred that there presently recited compounds do not contain a N-halo, S(0) 2 H, or S(0)H group.
  • 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.
  • treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state .
  • Therapeutically effective amount is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit factor Xa.
  • “Therapeutically effective amount” is also intended to include an amount of the combination of compounds claimed that is effective to inhibit factor Xa.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul . 1984, 22:27-55, occurs when the effect (in this case, inhibition of factor Xa) 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 sub-optimal concentrations of the compounds . Synergy can be in terms of lower cytotoxicity, increased antithrombotic 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 the present invention of formula I where B is imidazole can be prepared as shown in Scheme 2.
  • Commercially available imidazole 2-carboxaldehyde can be used as the starting material.
  • Reductive amination, followed by protection of the amino group can produce the imidazole intermediate 2.
  • Ullman coupling of imidazole 2 with iodide 3 can give the biaryl A-B precursor 4, which can be coupled with 5 using standard coupling conditions to provide 6.
  • Deprotection of the CBZ group, followed by reaction with acid chlorides, carbamoyl chloride, sulfonyl chlorides, and isocyanates can provide compounds of the invention with structures 7, 8, 9, and 10.
  • other compounds of the present invention where B is an imidazole derivative could be prepared as shown in Scheme 3 using 2-aminomethylimidazole (JOC, 43 (8), 1978, 1603) as the starting material.
  • Scheme 2 2-aminomethylimidazole
  • Additional Z-linkers to the A-B intermediates can be synthesized by the chemical manipulation of the amino functionality (Scheme 6) of the compounds described above.
  • A-B intermediates with various Z- linkers can be synthesized by the methods shown in Scheme 7.
  • the iodo-ester intermediate can be subjected to Ullman and/or Suzuki coupling methodologies to afford A-B intermediates .
  • These intermediates in turn can be homologated via the Arndt Eistert methodology to afford other A-B intermediates.
  • the ester functionality can be reduced to the alcohol that in turn can be converted to a variety of A-B intermediates by procedures known to those skilled in the art.
  • Non-aromatic intermediates as shown in Scheme 8 can be synthesized via procedures known to those skilled in the art . These intermediates can than be further manipulated to incorporate R a via procedures previously described.
  • the compounds of this invention and the intermediates described above wherein the B group contains an oxidizable group can be oxidized, e.g. N to N-oxide.
  • Schemes 2-11 describe how to make the A-B moieties of the present invention and how to couple them to prepare compounds of the present invention.
  • the Z group may or may not be present depending on how the A-B group is coupled.
  • the coupling portion of the A-B group could (a) be displaced by the incoming Z or M group, (b) become the Z group, or (c) be incorporated into ring M.
  • the remaining portions of the compounds of the present invention, G-Gx-P-M-Z, G-G ⁇ M-P-Z, G-G 1 -P-M, G-Gi-M-P, G ⁇ - M-Z, and G-Gi-M can be prepared using methods known to those of ordinary skill in the art.
  • G is a ring substituted with a basic moiety
  • one of ordinary skill in the art can look to US 5,939,418, US 5,925,635, US 6,057,342, US 6,187,797, US 6,020,357, US 6,060,491, US 6,191,159, W098/57951, W099/32454 WOOO/059902, WO01/32628, WO00/39131, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, and USSN 60/278,165 for starting materials and intermediates to form the present G-G -P-M-Z, G-G ⁇ M-P-Z, G-G i -P-M-Z-A, and/or G- G ⁇ M-P-Z-A groups to which the present B and/or A-B groups can be coupled.
  • G is a ring substituted with a non-basic group
  • one of ordinary skill in the art can look to US' 5,998,424, WO00/39131, WOOO/059902, WO01/32628, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, and USSN 60/278,165 for starting materials and intermediates to form the present G-G -P-M-Z, G-Gx-M-P-Z, G-Gi-P-M-Z-A, and/or G-Gi-M-P-Z-A groups to which the present B and/or A-B groups can be coupled.
  • G is a bicyclic moiety
  • one of ordinary skill in the art can look to W098/57951 WO00/039108, WO00/39131, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, and USSN 60/278,165 for starting materials and intermediates to form the present G-Gi-P-M-Z, G-Gi-M-P-Z, G-Gi-P-M-Z-A, and/or G- G ⁇ -M-P-Z-A groups to which the present B and/or A-B groups can be coupled.
  • Scheme 13 illustrates some of the numerous imidazole, triazole, and tetrazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications.
  • V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide.
  • U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide.
  • Scheme 14 shows some of the numerous pyrazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications.
  • Scheme 15 depicts some of the numerous oxazole, thiazole, isoxazole, oxadiazole, and thiadiazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications.
  • V is nitro, amino, ester, or acid.
  • Scheme 16 illustrates two intermediates useful for making a compound of the present invention wherein ring P is fused to ring M.
  • Scheme 16 also illustrates a number of bicyclic compounds that can be made from these intermediates or derivatives thereof. These intermediates and their modification are described in the above-noted patents and publications.
  • Scheme 17 depicts another intermediate useful for making a compound of the present invention wherein ring P is fused to ring M.
  • Scheme 17 also illustrates a number of bicyclic compounds that can be made from this intermediate or derivatives thereof (e.g., the corresponding cyclohexenone) .
  • U is OH or morpholine and V is H or C(0)R ⁇ a .
  • This intermediate, derivatives thereof, and their modification are described in the above-noted patents and publications.
  • Scheme 18 shows another intermediate useful for making a compound of the present invention wherein ring P is fused to ring M.
  • Scheme 18 also illustrates a number of bicyclic compounds that can be made from this intermediate or derivatives thereof. This intermediate, derivatives thereof, and their modification are described in the above- noted patents and publications.
  • Scheme 19 illustrates a number of other bicyclic rings that are considered to be part of the present bicyclic group, rings P-M.
  • Scheme 19 also describes a method of converting the shown rings to compounds of the present invention. As one of ordinary skill in the art would recognize, this method would be applicable to other heterobicyclics not shown.
  • Scheme 21 depicts some of the numerous 6-membered aromatic ring intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications.
  • V is nitro, protected sulfonamide, or ester group and is a precursor of group Z of the present invention.
  • Benzo fused dihydro-pyridone intermediates of the present invention can be prepared from readily available starting materials as shown in Scheme 22.
  • the compounds of this invention with general structure of Formula I can be synthesized by using similar methods as described previously and by those skilled in the art.
  • One diastereomer of a compound of Formula I may display better activity compared with the others.
  • the following stereochemistries are considered to be a part of the present invention.
  • racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 pp or using enantiomerically pure acids and bases.
  • a chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E. Ace . Chem. Res . 2000, 33 , 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.
  • thromboembolic disorders are a circulatory disease caused by blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation) .
  • blood clots i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation
  • thromboembolic disorders as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
  • thromboembolic disorders also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • thrombosis includes occlusion (e.g. after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty) .
  • the thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, atrial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy.
  • the anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.
  • the effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate.
  • the rate of factor Xa hydrolysis of chromogenic substrate S2222 (Diapharma/Chromogenix, West Chester, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was 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, Ki .
  • 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 m for substrate hydrolysis was 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, IN) 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.
  • Ki 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 Ki of ⁇ 10 ⁇ M.
  • Preferred compounds of the present invention have Ki's of ⁇ 1 ⁇ M. More preferred compounds of the present invention have Ki's of ⁇ 0.1 uM. Even more preferred compounds of the present invention have Ki's of ⁇ 0.01 uM. Still more preferred compounds of the present invention have Ki's of ⁇ 0.001 uM.
  • a number of compounds of the present invention were found to exhibit Ki's of ⁇ 10 uM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors .
  • 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 that 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
  • the compounds of the present invention may also be useful as inhibitors of serine proteases, notably human thrombin, Factor Vila, Factor IXa, Factor XIa, urokinase, 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, Factor Vila, Factor IXa, Factor XIa, urokinase, 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, cat
  • Some compounds of the present invention were 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.
  • vi tro 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, TX
  • 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, IN) 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, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm that 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.
  • thromboembolic condition or disease Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki of less than 10 ⁇ m, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.
  • the compounds are administered to a mammal in a therapeutically effective amount.
  • therapeutically effective amount it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat a thromboembolic condition or disease.
  • the compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents.
  • administered in combination or “combination therapy” it is meant that a compound of the present invention 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.
  • Additional therapeutic agents include other anticoagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type) , cardiac glycosides, diruetics, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal) , anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti-anxiety agents, anti-proliferative agents, anti-tumor agents, anti- ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid receptor antagonist) , anti- infective agents, anti-viral agents, anti-bacterial agents
  • anticoagulant agents or coagulation inhibitory agents
  • warfarin and heparin either unfractionated heparin or any commercially available low molecular weight heparin
  • synthetic pentasaccharide synthetic pentasaccharide
  • direct acting thrombin inhibitors including hirudin and argatrobanas 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, for example 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, droxica , diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • aspirin acetylsalicyclic acid or ASA
  • piroxicam are preferred.
  • Suitable platelet inhibitory agents include lib/Ilia antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban) , thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g., dipyridamole) , and pharmaceutically acceptable salts or prodrugs thereof.
  • lib/Ilia antagonists e.g., tirofiban, eptifibatide, and abciximab
  • thromboxane-A2-receptor antagonists e.g., ifetroban
  • thromboxane-A2-synthetase inhibitors e.g., ifetroban
  • PDE-III inhibitors e.g., dipyridamole
  • pharmaceutically acceptable salts or prodrugs thereof e.g.,
  • anti-platelet agents or platelet inhibitory agents
  • platelet inhibitory agents is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P 2 Y 1 and P 2 Y 12 ' with P 2 ⁇ 2 being even more preferred.
  • Preferred P 2 Y 12 receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use.
  • 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, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof.
  • Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal ⁇ -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.
  • thrombolytics or fibrinolytic agents denote agents that lyse blood clots (thrombi) .
  • agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK) , lanoteplase (nPA) , factor Vila inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors) , alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof.
  • anistreplase refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 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 .
  • Suitable anti-arrythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone) ; Class II agents (such as carvadiol and propranolol) ; Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide) ; Class IV agents (such as ditiazem and verapamil) ; K + channel openers such as I A h inhibitors, and I Ku r inhibitors (e.g., compounds such as those disclosed in WO01/40231) .
  • Class I agents such as propafenone
  • Class II agents such as carvadiol and propranolol
  • Class III agents such as sotalol, dofetilide, amiodarone, azimilide and ibutilide
  • Class IV agents such as ditiazem and verapamil
  • K + channel openers such as I A h inhibitors, and I Ku r
  • Suitable anti-hypertensive agents for use in combination with the compounds of the present invention include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil) ; diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone) ; renin inhibitors; ACE inhibitors (e.g., captopril, zof
  • NEP neutral endopeptidase
  • vasopepsidase inhibitors dual NEP-ACE inhibitors
  • suitable calcium channel blockers (L- type or T-type) for use in combination with the compounds of the present invention include diltiazem, verapamil, nifedipine, amlodipine and mybefradil.
  • suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
  • Suitable diruetics for use in combination with the compounds of the present invention include: chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, and spironolactone.
  • suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include sprionolactone and eplirinone .
  • suitable phospodiesterase inhibitors for use in combination with the compounds of the present invention include: PDE III inhibitors (such as cilostazol) ; and PDE V inhibitors (such as sildenafil) .
  • Suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.
  • HMG-CoA reductase inhibitors e.g., pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin)
  • ZD-4522 a.k.a.
  • rosuvastatin, or atavastatin or visastatin) ) ; squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran) ; ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414) .
  • Suitable anti-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g., metformin) ; glucosidase inhibitors (e.g., acarbose) ; insulins (including insulin secretagogues or insulin sensitizers) ; meglitinides (e.g., repaglinide) ; sulfonylureas (e.g., glimepiride, glyburide and glipizide) ; biguanide/glyburide combinations (e.g., glucovance) , thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR- gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those
  • suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.
  • suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2 inhibitors) ; aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and/or rofecoxib.
  • PTK protien tyrosine kinase
  • cyclooxygenase inhibitors including NSAIDs, and COX-1 and/or COX-2 inhibitors
  • suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.
  • suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol .
  • suitable anti-coagulants for use in combination with the compounds of the present invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin) .
  • suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibitors (such as those disclosed in WO00/59506) .
  • Suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate .
  • Suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.
  • Suitable anti-ulcer and gastroesophageal reflux disease agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.
  • Administration of the compounds of the present invention i.e., a first therapeutic agent in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent) , preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each (i.e., a synergistic combination) .
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses.
  • Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated.
  • Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone.
  • 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.
  • Compounds of the present invention may further be useful as diagnostic agents and adjuncts.
  • the present compounds may be useful in maintaining whole and fractionated blood in the fluid phase such as required for analytical and biological testing.
  • the present invention also encompasses an article of manufacture.
  • article of manufacture is intended to include, but not be limited to, kits and packages.
  • the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic disorder (as defined previously) .
  • the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat a thromboembolic disorder.
  • the article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
  • the first container is a receptacle used to hold a pharmaceutical composition.
  • This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
  • First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation) , or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
  • the second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
  • the package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
  • the package insert is located on the outside of the second container.
  • the package insert is physically attached via tape, glue, staple, or another method of attachment.
  • it can be adjacent to or touching the outside of the second container without being physically attached.
  • the package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container.
  • the information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration) .
  • the package insert specifically recites the indications for which the pharmaceutical composition has been approved.
  • the package insert may be made of any material on which a person can read information contained therein or thereon.
  • the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
  • 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.
  • 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.
  • 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.
  • Such 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.
  • Dosage forms (pharmaceutical compositions) 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.
  • 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, 18th ed. , Mack
  • 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.
  • one active ingredient may be enteric coated.
  • 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 that affects 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 low- viscosity 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.
  • Part B Preparation of 1- (4-iodophenyl) -3- (4-morpholinyl) - 5, 6-dihydro-2 ( 1H) -pyridinone 6- [4-Iodophenyl] -1,4,5, 6-tetrahydropyrazolo- [3 , 4-c] - pyridin-7-one (85.17 g,282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) were dissolved into CHCI 3 (750 mL) and refluxed for 3% hours. The reaction mixture was poured over ice and then quenched further with water.
  • Part C Preparation of 1- (4-iodophenyl) -4- (trifluoroacetyl) -2, 3-piperidinedione 4-Dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved into CH 2 C1 2 (130 mL) and cooled to 0°C. Trifluoroacetic anhydride (4.54 g, 32.01 mmol) was added and the mixture was stirred at 0°C for 30 min. A solution of the above morpholine-enamine from part B (10.25 g, 26.68 mmol) in CH 2 C1 2 (370 mL) was added slowly. The reaction mixture was warmed to room temperature and stirred overnight.
  • the reaction mixture was concentrated and purified by silica gel chromatography using 0%-50% ethyl acetate/hexane gradient to isolate the intermediate.
  • the intermediate was dissolved in 20% HCI (50 mL) and diethyl ether (200 mL) and stirred at room temperature overnight. It was then quenched with water, extracted with ether (3x100 mL) , washed with brine (1x100 mL) , and dried (Na 2 S0 4 ) . The residue was re-dissolved in petroleum ether and the undissolved solid was filtered off. The filtrate was concentrated to afford 9.99 g of the desired product (78%) .
  • Part D Preparation of 1- [4-methoxyphenyl] -3- trifluoromethyl-6- [4-iodophenyl]-l, 4,5,6- tetrahydropyrazolo- [3, 4-c] -pyridin-7-one 1- (4-iodophenyl) -4- (trifluoroacetyl) -2, 3-piperidinedione from Part C (10.0 g, 24.3 mmol) and 4- methoxyphenylhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in HCI (IN, 200 mL) and methanol (400 mL) .
  • 2-Imidazolecarboxyaldehyde (5.0 g, 52.0 mmol) was suspended in 200 mL of methanol. Methylamine (20 mL of 33% solution in methanol) was added. After stirred for 15 minutes, NaBH (3.95 g, 0.10 mol) was added portion-wise. The reaction mixture was then heated at 50°C for 2 h under N . The solvent was removed. The solid was washed with CH 2 C1 2 and filtered. The CH 2 C1 2 solution was dried over MgS0 4 , concentrated, and dried under vacuum to give the methylamine as a yellow oil. This oil was dissolved in a 1:1 solution of CH 2 C1 2 and THF.
  • Part F Preparation of benzyl (1- ⁇ 4- [1- (4-methoxyphenyl) -7- methylene-3- (trifluoromethyl) -1,4, 5, 7-tetrahydro- 6H- pyrazolo [3, 4-c]pyridin-6-yl]phenyl ⁇ -Iff-imidazol-2-yl)methyl (methyl) carbamate
  • Part B Preparation of ethyl 6- (4-iodophenyl) -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxylate
  • Example 1 and triethylamine (74 mL, 0.53 mol) at reflux in toluene (400 mL) for 24 h.
  • the reaction mixture was cooled, washed with water, and dried (Na 2 S0 4 ) . It was concentrated and chromatographed with 1:1 EtOAc/hexane to afford 28.8 g (71%) of the ester-iodo product.
  • 2-Imidazolecarboxaldehyde (50.0 g, 52.5 mmol) and MeOH (700 mL) were added together in a 2L round-bottomed flask. A solution of methylamine in EtOH (200 mL of 33%) was added. The mixture was stirred at RT under N 2 for 30 minutes and NaBH 4 (37 g, 100 mmol) was added portionwise in 35 minutes. The resulting mixture was stirred at RT for 1 h, then heated at 55 2 C for 2 h. The solvents were removed in vacuo. The residue was washed with CH 2 C1 and filtered. The filtrate was washed with brine, dried over MgS0 4 .
  • Part E Preparation ethyl 6- [4- (2- ⁇ [acetyl (methyl) amino]methyl ⁇ -Iff-imidazol-1-yl)phenyl] -l-(4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxylate
  • Product from Part D 500 mg, 0.40 mmol
  • Part B Preparation of 6- [4- (2- ⁇ [ethylcarbonyl (methyl) amino]methy ⁇ -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-OXO-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
  • Part B Preparation of 1- (4-methoxyphenyl) -6- ⁇ 4- [2- ( ⁇ methyl [ (methylamino) carbonyl] -amino ⁇ methyl) -lff-imidazol- 1-yl]phenyl ⁇ -7-oxo-4,5,6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
  • Part A Preparation of ethyl 6-[4-(2- ⁇ [ (methoxycarbonyl) (methyl) amino]methyl ⁇ -Iff-imidazol-1-yl)phenyl] -1- (4- ethoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- ⁇ ]pyridine-3-carboxylate
  • Example 7 (25 mg, 0.036 mmol) was suspended in CHC1 (5 mL) . Triethylamine (36 mg, 0.36 mmol) was added, followed by ethyl chloroformate (4.3 mg, 0.04 mmol). The mixture was stirred at room temperature under N for 18 h. The solvent was removed in vacuo . The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H 2 0/CH 3 CN gradient with 0.05% TFA) to give 18 mg of the final product as the TFA salt. MS (ES + ) : 544.5, (M+H) + . !
  • Part B Preparation of l-(4-Methoxyphenyl) -6- [4- (2- ⁇ [methyl (methylsulfonyl) amino] -methyl ⁇ -Iff-imidazol-1-yl)phenyl] -7- oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt
  • MS (ES + ) 550.4, (M+H) + . !
  • Example 16 6-[4-(2- ⁇ [ [ (3, 5-dimethyl-4-isoxazolyl) sulfonyl] (methylamino]methyl ⁇ -Iff-imidazol-1-yl)phenyl] -1- (4-methoxyphenyl) ⁇ 7-oxo-4,5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt
  • Example 17 1- (4-Methoxyphenyl) -6- [4- (2- ⁇ [methyl (phenylsulfonyl) amino] - methyl ⁇ -Iff-imidazol-1-yl)phenyl] -7-oxo-4, 5, 6, 7-tetrahydro- lff-pyrazolo [3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
  • Part B Preparation of 1- (4-methoxyphenyl) -7-oxo-6- (4- ⁇ 2- [ (propylamino)methyl] -Iff-imidazol-1-yl ⁇ phenyl) -4, 5, 6,7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, bis (trifluoroacetic acid) salt
  • Part B Preparation of 6- (4- ⁇ 2- [ (isopropylamino)methyl] -lff- imidazol-1-yl ⁇ phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5, 6,7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, bis (trifluoroacetic acid) salt
  • Part B Preparation of 6- ⁇ 4- [2- (aminomethyl) -Iff-imidazol-1- yl]phenyl ⁇ -1- (4-methoxyphenyl) -7-oxo-4,5,6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide
  • N- [2- (aminomethyl) ] -lff-imidazole bis (hydrochloric acid) salt (333 mg, 1.96 mmol)
  • the product from Part B of Example 18 500 mg, 1.2 mmol
  • Cul 186 mg, 0.98 mmol
  • K 2 C0 3 1.082 g, 7.84 mmol
  • the mixture was degassed and then heated at 130°C under N 2 for 4 h.
  • the mixture was cooled and aqueous NH 4 0H was added.
  • the mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc.
  • Part C Preparation of. 1- (4-methoxyphenyl) -6- (4- ⁇ 2- [ (methylamino)methyl] -Iff-imidazol-1-yl ⁇ phenyl) -3-
  • Part D Preparation of JV-[(l- ⁇ 4-[l-(4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-1,4,5, 7-tetrahydro-6ff-pyrazolo [3,4- c] pyridin-6-yl] phenyl ⁇ -Iff-imidazol-2-yl) ethyl] - N- methylacetamide trifluoroacetic acid salt

Abstract

The present application describes substituted-aminomethyl substituted compounds and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.

Description

TITLE Substituted Amino Methyl Factor Xa Inhibitors
FIELD OF THE INVENTION
This invention relates generally to substituted- aminomethyl substituted compounds, 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.
BACKGROUND OF THE INVENTION U.S. Patent Nos. 3,365,459, 3,340,269, and 3,423,414 illustrate anti-inflammatory inhibitors of the following formula:
Figure imgf000002_0001
wherein A is 2-3 carbon atoms, X can be 0, and R1 and R3 can be substituted or unsubstituted aromatic groups. None of these patents, however, exemplify or suggest compounds of the present invention.
US 5,342,851 depicts thiazole platelet aggregation inhibitors including those of the following formula:
Figure imgf000002_0002
wherein A is a linker, B can be a linker or a ring, Q is a ring or an amino group, R, Rlf and R3 are a variety of groups. This patent, however, does not exemplify or suggest compounds of the present invention. WO00/39131 describes heterobicyclic Factor Xa inhibitors of which the following is an example formula:
Figure imgf000003_0001
wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclic moiety and B is a basic group or a cyclic moiety. Compounds specifically described in WO00/39131 are not considered to be part of the present invention.
W098/28269, W098/28282, W099/32454, US 6,020,357, and US 6,271,237 describe Factor Xa inhibitors of the following formula:
Figure imgf000003_0002
wherein ring M is a heterocycle, Z is a linker, A is a ring, B is a basic or cylic group, D is a basic moiety, and E is a ring. Compounds specifically described in W098/28269, W098/28282, W099/32454, US 6,020,357, and US 6,271,237 are not considered to be part of the present invention. 098/57951 describes Factor Xa inhibitors of the following formula:
Figure imgf000003_0003
wherein ring M can be a variety of heterocycles and rings
D-E represent a heterobicyclic group. Compounds specifically described in W098/57951 are not considered to be part of the present invention. W098/57934 and US 6,060,491 describe Factor Xa inhibitors of the following formula:
Figure imgf000004_0001
wherein ring M is a 6-membered heteroaryl, Z is a linker, A is a ring, B is a basic or cylic group, D is a basic moiety, and E is a ring. Compounds specifically described in W098/57934 and US 6,060,491 are not considered to be part of the present invention.
W098/57937 and US 5,998,424 describe Factor Xa inhibitors of the following formula:
Figure imgf000004_0002
wherein ring M is a variety of rings, ring D is an aromatic ring, and R and E are non-basic groups. Compounds specifically described in W098/57937 and US 5,998,424 are not considered to be part of the present invention.
WO99/50255 and US 6,191,159 describe pyrazoline and triazoline Factor Xa inhibitors of the following formulas :
Figure imgf000004_0003
Compounds specifically described in WO99/50255 and US 6,191,159 are not considered to be part of the present invention. WO00/59902 describes Factor Xa inhibitors of the following formula:
Figure imgf000004_0004
wherein ring M can be a variety of rings all of which are substituted with Z-A-B, Z is a linker, A is a ring, B is a sulfonyl-containing heterobicycle, and rings D-E represent a heterobicyclic group or a 6-membered ring. Compounds specifically described in WO00/59902 are not considered to be part of the present invention.
WO01/32628 describes cyano-pyrroles, cyano-imidazoles, cyano-pyrazoles, and cyano-triazoles that are Factor Xa inhibitors. Compounds specifically described in WO01/32628 are not considered to be part of the present invention. O01/05784 describes Factor Xa inhibitors of the following formulas:
Figure imgf000005_0001
wherein Z is C or N, G is a mono- or bicyclic ring M, A is a linker, B is a basic or cyclic group. Compounds specifically described in WO01/05784 are not considered to be part of the present invention. WOOO/39108 describes Factor Xa inhibitors of the following formula:
Figure imgf000005_0002
wherein ring M can be a variety of heterocycles and rings D-E represent a heterobicyclic group. Compounds specifically described in WOOO/39108 are not considered to be part of the present invention.
WO01/19798 describes factor Xa inhibitors of the following formula:
A-Q-D-E-G-J-X wherein A, D, G, and X can be phenyl or heterocycle. However, none of the presently claimed compounds are exemplified or suggested in WO01/19798.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common 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 5 formation of prothro binase complex (factor Xa, factor V,
Ca2+ 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
10 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.
15 Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors. In addition, it is also desirable to find new compounds with
20 improved pharmacological characteristics compared with known factor Xa inhibitors. For example, it is preferred to find new compounds with improved factor Xa inhibitory activity and selectivity for factor Xa versus other serine proteases (i.e., trypsin). It is also desirable and
25 preferable to find compounds with advantageous and improved characteristics in one or more of the following categories: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages
30. and/or once-daily dosing) ; (c) factors which decrease blood concentration peak-to-trough characteristics (e.g., clearance and/or volume of distribution) ; (d) factors that increase the concentration of active drug at the receptor (e.g., protein binding, volume of distribution); (e) factors that decrease the liability for clinical drug-drug interactions (e.g., cytochrome P450 enzyme inhibition or induction); (f) factors that decrease the potential for adverse side-effects (e.g., pharmacological selectivity beyond serine proteases, potential chemical or metabolic reactivity, and limited CNS penetration) ; and, (g) factors that improve manufacturing costs or feasibility (e.g., difficulty of synthesis, number of chiral centers, chemical stability, and ease of handling) .
SUMMARY OF THE INVENTION Accordingly, the present invention provides novel substituted-aminomethyl substituted compounds that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides 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. The present invention provides a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder
The present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
The present invention provides novel compounds for use in therapy.
The present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed substituted-aminomethyl substituted compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] In an embodiment, the present invention provides a novel compound of formula I: P4-P-M-M4
I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
M is a 3-10 membered carbocycle or a 4-10 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, N, and NZ2;
ring M is substituted with 0-3 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
P is fused onto ring M and is a 5, 6, or 7 membered carbocycle or a 5, 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, and N;
ring P is substituted with 0-3 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
alternatively, ring P is absent and P is directly attached to ring M;
one of P4 and M4 is -Z-A-B and the other -G^G, provided that P4 and M4 are attached to different rings when ring P is present;
G is a group of formula Ila or lib:
Figure imgf000009_0001
Ila lib
ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p;
ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1-2 R;
alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, wherein the 5-6 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and has 0-3 ring double bonds;
R is selected from H, CX-4 alkyl, F, CI, Br, I, OH, 0CH3, OCH2CH3, 0CH(CH3)2, 0CH2CH2CH3, CN, C (=NR8) NR7R9 , NHC(=NR8)NR7R9, ONHC ( =NR8 ) NR7R9 , NR8CH(=NR7), NH2 , NH(Cι_3 alkyl), N(Cι_3 alkyl)2, C(=NH)NH2, CH2NH2 , CH2NH(Cι_3 alkyl), CH2N(Cι_3 alkyl)2, CH2CH2NH2 , CH2CH2NH(Cι_3 alkyl), CH2CH2N(Cι_3 alkyl)2,
(CR8R9)tC(0)H, (CR8R9)tC(0)R2 , (CR8R9) tNR7R8, (CR8R9)tC(0)NR7R8, (CR8R9)tNR7C(0)R7, (CR8R9)tOR3, (CR8R9)tS(0)pNR7R8, (CR8R9)tNR7S(0)pR7, (CR8R9)tSR3, (CR8R9)tS(0)R3, (CR8R9)tS(0)2R3, and OCF3 ;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is selected from:
C3-10 carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4;
B is Y or X-Y, provided that Z and B are attached to different atoms on A;
X is selected from - (CR2R2a) χ-4-, -CR2 (CR2R2b) (CH2) t-, -C(0)-, -C(=NRlb)-, -CR2(NRlbR2)-, -CR2(OR2)-, -CR2(SR2)-, -C(0)CR2R2a-, -CR2R2aC(0) , -S-, -S(0)-,
-S(0)2-, -SCR2R2a-, -S(0)CR2R2a-, -S (0) 2CR2R2a- , -CR2R2aS-, -CR2R2aS(0)-, -CR2R2aS(0)2-, -S(0)2NR2-, -NR2S(0)2-, -NR2S(0)2CR2R2a-, -CR2R2aS (0) 2NR2- , -NR2S(0)2NR2-, -C(0)NR2-, -NR2C(0)-, -C (0) NR2CR2R2a- , -NR2C(0)CR2R2a-, -CR2R2aC (0) NR2- , -CR2R2aNR2C (0) - ,
-NR2C(0)0-, -0C(0)NR2-, -NR2C (0)NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2aO-, and -OCR2R2a-;
Y is selected from: C3_ιo carbocycle substituted with 1 R4a and 0-2 R4, and,
5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of
N, 0, and S(0)p and substituted with 1 R4a and 0-2 R4;
G1 is absent or is selected from (CR3R3a)1-5,
(CR3R3a) 0-2CR3=CR3 (CR3R3a) 0-2 , (CR3R3a) o-2C≡C (CR3R3 ) 0-2 , (CR3R3a)uC(0) (CR3R3a)w, (CR3R3a)uC(0)0(CR3R3a)w, (CR3R3a)uOC(0) (CR3R3a)w, (CR3R3a)u0(CR3R3a)w, (CR3R3a)uN3b(CR3R3a)w, (CR3R ) UC (0)N3b (CR3R3a) w,
(CR3R3a)uN3bC(0) (CR3R3a)w, (CR3R3a) U0C (0) N3b (CR3R3a)w- (CR3R3a)uN3bC(0)0(CR3R3a)w, (CR3R3a) uN3bC (0) N3b (CR3R3a) w, (CR3R3a)uN3bC(S)N3b(CR3R3a)w, (CR3R3a) US (CR3Ra) w, (CR3R3a)uS(0) (CR3R3a)w, (CR3R3a)uS(0)2(CR3R )w, (CR3R a) US (0) N3b (CR3R3a) w, (CR3R3 ) uN3bS (0) 2 (CR3R3a) w, (CR3R3a) US (0) 2N3b (CR3R3a) w, (CR3R3a) uN3bS (0) 2N3b (CRR3a) w, (CR3R3a)uNR3e(CR3R3a)w, (CR3R3a)uC(0) (CR3R3 )uC(0) (CR3R3a)w, (CR3R3a) uNR3b (CR3R3a) UC (0) NR3b (CR3R3a) w, (CR3R3a)uNR3bC(0) (CR3R3a)uC(0) (CR3R a)w, (CR3R3a) UC (0) (CR3R3a) UC (0) NR3b (CR3R3a) w, (CR3R3a) uNR3bC (0) (CR3R3a) UC (0)NR3b (CR3R3a) w, (CR3R3a)uS(0)NR3bC(0) (CR3R3a)w, (CR3R3a)uC(0)NR3bS(0)2(CR3R3a)w, and
(CR3R3a)uS(0)2NR3bC(0)NR3bCR3R3a)w, wherein u + w total 0, 1, 2, 3, or 4 , provided that G;L does not form a N- S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
Z is selected from a bond, - (CR3R3e) 1_4- ,
(CR3R3e qO(CR3R3e)qi, (CR3R3e)qNR3 (CR3R3e)qi, (CR3R3e qC(0) (CR3R3e)gi, (CR3R3e) qC (0) 0 (CR3R3e) qι , (CR3R3e qOC(O) (CR3R3e)qi, (CR3R3e) qC (0) NR b (CR3R3e) ql , (CR3R3e qNR3bC(0) (CR3R3e)gi, (CR3R3e) q0C (0) 0 (CR3R e) qι , (CR3R3e qOC(0)NR3b(CR3R3e)qι, (CR3R3e qNR3bC(0)0(CR3R3e)qι, (CR3R3e qNR3bC(0)NR3b(CR3R3e)qi, (CR3R3e qC(0) (CR3R3e)qC(0) (CR R3e)ql, (CR3R3e qNR3b(CR3R3e)qC(0)NR3b(CR3R3e)qi, (CR3R3e qNR3bC(0) (CR3R3e)qC(0) (CR3R3e)qι, (CR R3e qC(0) (CR3R3e)qC(0)NR b(CR3R3e)qi, (CR3R3 qNR3bC(0) (CR3R3e)gC(0)NR3b(CR3R3e)ql, (CR3R3e qS(CR3R e)ql, (CR3R3e)qS(0) (CR3R e)ql, (CR3R3e qS(0)2(CR3R3e)gi, (CR3R3e) qS02NR3b (CR R3e) gi , (CR3R3e qNR3 S02(CR3R3e)qi, (CR3R3e qS(0)NR3bC(0) (CR3R3e)qι, (CR3R3e gC(0)NR3bS(0)2(CR3R3e)qi, and (CR3R3e qNR3bS02NRb(CR3R3e)qι, wherein q + ql total 0, 1, 2, 3, or 4, provided that Z does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
Z2 is selected from H, S(0)2NHR3b, C(0)R3b, C(0)NHR3b,
C(0)OR3f, S(0)R3f, S(0)2R3f, Cι-6 alkyl substituted with 0-2 Rla, C2_6 alkenyl substituted with 0-2 Rla, C2_6 alkynyl substituted with 0-2 Rla, - (Co-4 alkyl) - cycloalkyl substituted with 0-3 Rla, -(Co-4 alkyl) - heterocycle substituted with 0-3 Rla, - (C0-4 alkyl) - aryl substituted with 0-3 Rla, and, - (C0-4 alkyl) - heteroaryl substituted with 0-3 Rla;
Rl , at each occurrence, is selected from H, - (CR3R3a) r-Rlb,
- (CR3R3a) r-CR3RlbRlb, - (CR3R3 ) r-0- (CR3R3a) r-Rlb,
- (CR3R3 ) r-NR2- (CR3R3a) r-Rlb,
- (CR3R3a) r-S (0)p- (CR3R a) r-Rlb, -(CR3R3a)r-C02- (CR3R3a)r-Rlb,
-(CR3R3a)r-C(0)NR2- (CR3R3a) r-Rlb,
-(CR3R3a)r-C(0)-(CR3R3 )r-Rlb, -C2_6 alkenylene-Rlb,
-C2_5 alkynylene-Rlb, and - (CR3R3a) r-C (=NRlb)NR3Rlb, provided that Rla forms other than an N-halo, N-S, 0- 0, or N-CN bond; alternatively, when two Rla groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N,
0, and S(0)p, this ring being substituted with 0-2 R4b and comprising: 0-3 double bonds;
Rib is selected from H, Cι_3 alkyl, F, CI, Br, I, -CN, -N02 , -CHO, (CF2)rCF , (CR3R3a)r0R2, NR2R2 , C(0)R2b, C02R2b, OC(0)R2, CH(CH2OR2)2, (CF2 ) rC02R2a, S(0)pR2b, NR2 (CH2)rOR2, C(=NR2c)NR2R2a, NR2C(0)R2b, NR2C (0)NR2R2a, NR2C(0)2R2a, OC(0)NR2R2a, C(0)NR2R2a, C (0) NR2 (CH2) rOR2 , Sθ2NR2R2a, NR2S02R2, C (0) NR2S02R2 , C3-6 carbocycle substituted with 0-2 R4b, and 5-10 membered heterocycle substituted with 0-2 Rb and consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) , provided that
Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond and provided that S(0)PR2 forms other than S(0)2H or S(0)H;
R2, at each occurrence, is selected from H, CF3, Cι_6 alkyl, benzyl, - (CH2) r-C3_ιo carbocycle substituted with 0-2 R4b, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, Cι_6 alkyl, benzyl, - (CH2) r-C3_ιo carbocycle substituted with 0-2 R4b, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3 , C1-4 alkoxy, C1-6 alkyl substituted with 0-2 R4b, - (CH2) r-C3_ιo carbocycle substituted with 0-2 R4b, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, Cι_4 alkoxy, Cι_6 alkyl, - (CH2) r-C3_ιo carbocycle substituted with 0-2 R4b, and -(CH )r-5-10 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, Rc, Cι_6 alkyl substituted with 0-2 R4c, - (CR3R3a) r-C3_ιo carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p- halo, 0-halo, N-S, S-N, S(0)p-S(0)p, S-O, O-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R4c, Cι_6 alkyl substituted with 0-2 Rc, - (CR3R3 ) r-C3-ιo carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R3, at each occurrence, is selected from H, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
R3a, at each occurrence, is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R3 and R a are attached, and 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R3b, at each occurrence, is selected from CF3, C1-.4 alkoxy substituted with 0-2 R4b, Cι_6 alkyl substituted with 0-2 R4b, - (CH2)r-C3_io carbocycle substituted with 0-2 R4b, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R3c, at each occurrence, is selected from CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, Ci-4 alkyl-phenyl , and C(=0)R3c;
R3e, at each occurrence, is selected from H, S02NHR3,
S02NR3R3, C(0)R3, C(0)NHR3, C(0)OR3f, S(0)R3f, S(0)2R3f, Ci-6 alkyl substituted with 0-2 Rla, C2_6 alkenyl substituted with 0-2 Rla, C2_6 alkynyl substituted with
0-2 Rla, -(Co-4 alkyl) -5-10 membered carbocycle substituted with 0-3 Rla, and -(Co-4 alkyl) -5-10 membered heterocycle substituted with 0-3 Rla and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p;
R3f, at each occurrence, is selected from: C -s alkyl substituted with 0-2 Rla, C2_6 alkenyl substituted with 0-2 Rla, C2-6 alkynyl substituted with 0-2 Rla, -(Co-4 alkyl) -5-10 membered carbocycle substituted with 0-3 Rla, and -(Co-4 alkyl) -5-10 membered heterocycle substituted with 0-3 Rla and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p; R3^, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, - (CH2 ) r-3-6 membered carbocycle, and -(CH )r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p;
alternatively, when R3 and R3^ are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
R4, at each occurrence, is selected from H, =0,
(CR3R3a)rOR2, F, CI, Br, I, Cι_ alkyl, (CR3R3a)rCN, (CR3R3 )rN02, (CR3R3a)rNR2R2a, (CR3R3a) rC (0) R2c, (CR3R3a)rNR2C(0)R2b, (CR3R3a) rC (0) NR2R2a,
(CR3R3a)rNR2C(0)NR2R2a, (CR3R3a) rC (=NR2) NR2R2a, (CR3R3a)rC(=NS(0) R5a)NR2R2a, (CR3R3a) rNHC (=NR2) NR2R2a, (CR3R3a)rC(0)NHC(=NR2)NR2R2a, (CR3R3a) rS0 NR2R2a, (CR3R3a)rNR2S02NR2R2a, (CR3R a) rNR2S02-Ci- alkyl, (CR3R3a)rNR2S02R5a, (CR3R3a) rS (0) pR5a,
(CR3R3a)r(CF2)rCF3, NHCH2Rlb, 0CH2Rlb, SCH2Rlb, N(CH2)2(CH2)tRlb, 0(CH2)2(CH2)tRlb, S (CH2 ) 2 (CH2) tRlb, (CR3R3a) r-5-6 membered carbocycle substituted with 0-1 R5, and a (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R5;
R4a s selected from (CR3R39)rN(→0) R2dR2d, (CR3R39)v-NR2dC(0)R2e, (CR3R39) V-C (0)NR2dR2d,
(CR3R39)v-NR2dC(0)NR2dR2d, (CR3R39) v-NR2dC (0) 0R2d, ( CR3R39 ) v- S02NR2dR2d , ( CR3R39 ) v-NR2dS02NR2dR2d , (CR3R39)v-C(0)NR2dS02R2d, (CR3R39) v-NR2dS02R2d, and (CR3R39)v-S(0)pR2d, provided that S(0)pR2d forms other than S(0)2H or S(0)H;
alternatively, R4a is selected from (CR3R39)rNR2dR2d,
NR2dC(0)R2e, C(0)NR2dR2d, NR2dC (0) NR2dR2d, NR2dC (0) OR2d, S02NR2dR2d, NR2dS02NR2dR2d, C (0) NR2 S02R2d, NR2dS02R2d, and S(0)pR2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl, provided that S(0)pR2d forms other than S(0)2H or S(0)H;
R b, at each occurrence, is selected from H, =0, (CH2)rOR3, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, Cι_4 alkyl,
(CH2)rCN, (CH2)rN02, (CH2)rNR3R3a, (CH2 ) rC (0) R3 , (CH2)rC(0)OR3c, (CH2)rNR C(0)R3a, (CH2 ) r-C (0)NR R3a, (CH2)rNR3C(0)NR3R3a, (CH2 ) r-C (=NR3) NR3R3a, (CH2 ) rNR3C ( =NR3 ) NR3R3a, (CH2 ) rS02NR3R3a , (CH2)rNR3S02NR3R3 , (CH2 ) rNR3S02-Cι_ alkyl,
( CH2 ) rNR3 S02CF3 , ( CH2 ) rNR3 S02 -phenyl , ( CH2 ) r S ( 0 ) pCF3 , (CH2)rS(0)p-Cι_4 alkyl, (CH2) rS (0)p-phenyl, and (CH2)r(CF2)rCF3;
R4c, at each occurrence, is selected from =0, (CR3R3a) r0R2, (CR3R3 )rF, (CR3R3 )rBr, (CR3R3a)rCl, (CR3R3a) rCF3 , C1-4 alkyl, (CR3R3a)rCN, (CR3R3a) rN02 , (CR3R3a) rNR2R2a, (CR3R3a) rN (→O) R2R2a, (CR3R3 ) rC (0) R2c, (CR3R3a) rNR2C (0) R2b, (CR3R3a) rC (0)NR2R2a, (CR3R3a)rN=CHOR3, (CR3R3a) rC (0) NH (CH2 ) 2NR2R2a, (CR3R3a)rNR2C(0)NR2R2a, (CR3R3a) rC (=NR2 ) NR2R2a, (CR3R3a)rNHC(=NR2)NR2R2a, (CR3R3a) rS02NR2R2a, (CR3R3a)rNR2S02NR2R2a, (CR3R3 ) rC (0) NHS02-Cι_ alkyl, (CR3R3a)rNR2S02R5a, (CR3R3a)rS(0)pR a, (CF2)rCF3, (CR3R3a)rC3_ιo carbocycle substituted with 0-2 R4b, and (CR3R3a) r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, Cι_6 alkyl, =0, (CH2)rOR3, F, CI, Br, I, -CN, N02 , (CH2 ) rNR3R3a, (CH2)rC(0)R3, (CH2)rC(0)OR3c, (CH2 ) rNR3C (0) R3a, (CH2)rC(0)NR3R3a, (CH2)rNR3C(0)NR3R3a, (CH2 ) rCH (=N0R3d) , (CH )rC(=NR3)NR3R3a, (CH2 ) rNR3C (=NR3 ) NR3R3a, (CH2 ) rS02NR3R3a, (CH2 ) rNR3S02NR3R3a, (CH2)rNR3S02-Cι_4 alkyl, (CH2) rNR3Ξ02CF3 , (CH2)rNR3S02-phenyl, (CH2) rS (0)pCF3 , (CH2)rS(0)p-Cι_4 alkyl, (CH2) rS (0)p-phenyl, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R5a, at each occurrence, is selected from Cι_6 alkyl,
(CH2)rOR3, (CH2)rNR3R3a, (CH2 ) rC (0) R3 , (CH2 ) rC (0) 0R3c, (CH2)rNR3C(0)R3a, (CH2 ) rC (0) NR3R3a, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6, provided that R5a does not form a S-N or S(0)p-C(0) bond;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, Cι-4 alkyl, CN, N02 , (CH2) rNR2R2a, (CH2) rC (0) R2b, NR2C(0)R2b, NR2C(0)NR2R2a, C(=NH)NH2, NHC(=NH)NH2, S0NR2R2a, NR2S0NR2R2a, and NR2S02Cι_ alkyl;
R7, at each occurrence, is selected from H, OH, Cι_6 alkyl, Cι_6 alkyl-C(O)-, Cι_6 alkyl-O-, (CH2)n-phenyl, C1-4 alkyl-OC(O)-, C6-ιo aryl-O-, C6-ιo aryl-OC(O)-, C6-ιo aryl-CH2-C(0)-, C1-4 alkyl-C (O) O-C1-4 alkyl-OC (0) - , C6-10 aryl-C(0)0-Ci- alkyl-OC (0) - ,
C1-6 alkyl-NH2-C(0)-, phenyl-NH2-C (0) - , and phenyl C1-4 alkyl-C (0)-;
R8, at each occurrence, is selected from H, C -Q alkyl, and (CH2)n-phenyl;
alternatively, R7 and R8, when attached to the same nitrogen, combine to form a 5-10 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R9, at each occurrence, is selected from H, Cι_6 alkyl, and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6 ;
t, at each occurrence, is selected from 0, 1, 2, and 3; v, at each occurrence, is selected from 1, 2, 3, 4, 5, and 6 ; and,
provided that when ring M is phenyl and is substituted 1,2 by M4 and P and G]_ is present, then Z-A is other than NHC(O) -thienyl, NHCH2-thienyl, NHC (0) -benzothienyl, and NHCH2-benzothienyl;
further provided that when (a) P is absent, (b) ring M is a non-aromatic ring with at least one ring N, (c) G-G;L is attached via a ring N, and (d) Z is at least two atoms in length, then Y is other than phenyl or pyridyl .
[2] In a preferred embodiment, the present invention provides a novel compound of Formula II:
Figure imgf000022_0001
II or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M, including P1# P2 , M1# and M , is a 5, 6, or 7 membered carbocycle or a 5 , 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, N, and NZ2;
ring M is substituted with 0-2 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds; ring P, including Px, P2, and P3 , is a 5 or 6 membered aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, and N;
alternatively, ring P, including P1# P2 , and P3 , is a 5 or 6 membered dihydro-aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, and N;
ring P is substituted with 0-2 Rla;
one of P and M is -Z-A-B and the other -Gι~G;
G is a group of formula Ila or lib:
Figure imgf000023_0001
Ila lib
ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p;
ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2 R; alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds ;
R is selected from H, C^ alkyl, F, CI, OH, 0CH3 , OCH2CH3 , OCH(CH3)2, CN, C(=NH)NH2, C(=NH)NHOH, C (=NH) NH0CH3 , NH2, NH(Cι_3 alkyl), N(Cι_3 alkyl)2, C(=NH)NH2, CH2NH2 , CH2NH(Cι_3 alkyl), CH2N(Cι_3 alkyl)2, (CR8R9) tNR7R8, C(0)NR7R8, CH2C(0)NR7R8, S(0)2R3, S(0)pNR7R8, CH2S(0)pNR7R8, and 0CF3 ;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is selected from:
C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4;
X is selected from - (CR2R2a) X-4-, -C(0)-, -C(=NRlb)-,
-CR2(NRlbR2)-, -C(0)CR2R2a-, -CR2R2aC(0) , -C(0)NR2-, -NR2C(0)-, -C(0)NR2CR2R2a-, -NR2C (0) CR2R2a- , -CR2R2aC(0)NR2-, -CR2R2aNR2C (0) - , -NR2C (0) NR2- , -NR2-,
-NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2aO-, and -OCR2R2a-; Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R a and 0-2 R4: cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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 ;
Z is selected from a bond, CH2 , CH2CH2, CH20, OCH2, C(O), NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)CH2C(0)NH, S(0)2, CH2S(0)2, S(0)2(CH2), S02NH, and NHS0 , provided that Z does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
Z2 is selected from H, Cι_ alkyl, phenyl, benzyl, C(0)R3b, S(0)R3f, and S(0)2R3f;
Rla, at each occurrence, is selected from H, -(CH )r-Rlb, -(CH(CH3) )r-Rlb, -(C(CH3)2)r-Rlb, -0- (CR3R3a) r~Rlb, -NR2-(CR3R a)r-Rlb, and -S- (CR3R3a) r-Rlb, provided that Rla forms other than an N-halo, N-S, O-O, or N-CN bond; alternatively, when two Rla groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N,
0, and S(0)p, this ring being substituted with 0-2 R4b and comprising: 0-3 double ring bonds;
Rib ig selected from H, CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, F, CI, Br, I, -CN, -CHO, CF3 , OR2, NR2R2a, C(0)R2b, C02R2b, OC(0)R2, C02R2a, S(0)pR2, NR2 (CH2 ) rOR2 , NR2C(0)R2b, NR2C(0)NHR2, NR2C(0)2R2a, OC(0)NR2R2a, C(0)NR2R2a, C(0)NR2(CH2)rOR2, S02NR2R2a, NR2S02R2, C5_6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CF3 , CH3 ,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, a C5-.6 carbocyclic-CH2-group substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb ;
R2a, at each occurrence, is selected from H, CF3, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3, C1-.4 alkoxy, CH3 , CH2CH , CH2CH2CH , CH(CH3)2, CH2CH2CH2CH , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, CH3 , CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5_6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R c, - (CR3R3a) r-C3-6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p- halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, O-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R4c, - (CR3R3a) r-C3_6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R3, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
R3a, at each occurrence, is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R3 and R3a are attached;
R3c, at each occurrence, is selected from CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl; R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2-phenyl, CH2CH2-phenyl, and C(=0)R3c;
R39, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclopropyl-methyl, benzyl , and phenyl ;
alternatively, when R3 and R3^ are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
R4, at each occurrence, is selected from H, =0, OR2,
CH2OR2, (CH2)2OR2, F, Cl, Br, I, C1-4 alkyl, -CN, N02 , NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, C(0)R2c, NR2C(0)R2b, C(0)NR2R2 , S02NR2R2a, S(0)pR5 , CF3 , CF2CF3 , 5-6 membered carbocycle substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R5;
R 4a is selected from (CR3R39) rN(→0)R2dR2d,
(CR3R39)v-NR2dC(0)R2e, (CR3R39)v-NR2dC(0)NR2dR2d, (CR3R39)v-NR2dC(0)0R2d, (CR3R3^) v-NR2dS02NR2dR2d, and (CR3R39)v-NR2dS02R2d;
alternatively, R4a is selected from (CR3R3^)rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) 0R2d, NR2dS0NR2dR2d, and NR2dS02R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R4c that is other than alkyl; R b, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, CI, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)OR3 , CH2C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a,
CH2C(0)NR3R3a, NR3C(0)NR3R3a, CH2NR3C (0) NR3R3a, C(=NR3)NR3R3a, CH2C(=NR3)NR3R3a, NR3C (=NR3 ) NR3R3a, CH2NR3C(=NR3)NR3R3a, S0 NR R a, CH2S0 NR3R3a, NR3S0 NR R3a, CH NR3S02NR3R3a, NR3S02-Ci-4 alkyl, CH2NR3S0 -Cι_4 alkyl, NR3S02CF3, CH2NR3S02CF3 ,
NR3S02 -phenyl, CH2NR3S02 -phenyl, S(0)PCF3, CH2S(0)PCF3, S(0)p-Cι-4 alkyl, CH2S (0)p-Cι_4 alkyl, S (0)p-phenyl , CH2S(0)p-phenyl, CF3, and CH2-CF3;
R c, at each occurrence, is selected from =0, (CR3R3a) r0R2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a) rCF3, C1-4 alkyl, (CR3R3a)rCN, (CR3R3a) rN02 , (CR3R3a) rNR2R2a, (CR3R3a) rN (→O) R2R2a, (CR3R3a) rC (0) R2c, (CR3R3a)rNR2C(0)R2b, (CR3R3a)rC(0)NR2R2a, (CR3R3a)rNR2C(0)NR2R2a, (CR3R3a) rS02NR2R2a,
(CR3R3a) rNR2S02NR2R2a, (CR3R3a) rNR2S02R5a, (CR3R3a)rS(0)pR5a, (CF2)rCF3, (CR3R3a) rC3_ιo carbocycle substituted with 0-2 R b, and (CR3R3a) r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N,
0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH20R3 , F, Cl, -CN, N02 , NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)OR3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R a, NR3C (O) NR3R a, CH(=NOR3d), C(=NR3)NR3R3a, NR3C (=NR3 ) NR3R3a, S02NR3R3a, NR3S02NR3R3a, NR3S02-Ci_4 alkyl, NR3S0 CF3, NR3S0 - phenyl, S(0)pCF3, S(0)p-Cι-4 alkyl, S (0)p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, CI, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 ,
CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, -CN, N02 , NR2R2a,
CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b,
NR2C(0)NR2R2a, C(=NH)NH2, NHC(=NH)NH2, S02NR2R2a,
NR2S02NR2R2a, and NR2S0 Cι_ alkyl;
r, at each occurrence, is selected from 0, 1, and 2; and,
v, at each occurrence, is selected from 1, 2, and 3.
[3] In another preferred embodiment, the present invention provides a novel compound, wherein:
ring M is substituted with 0-2 Rla and is selected from the group :
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000035_0003
Figure imgf000035_0004
Figure imgf000035_0002
Figure imgf000036_0001
ring P, including Px, P2 , P3 , and P is selected from
Figure imgf000036_0002
Figure imgf000037_0001
36
Figure imgf000038_0001
one of P4 and M4 is -Z-A-B and the other -G1-G;
G is selected from the group:
Figure imgf000038_0002
Figure imgf000038_0004
Figure imgf000038_0003
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
absent or is selected from (CR3R3a)1_3,
(CR3R3a)uC(0) (CR3R3a)w, (CR3R3a)uO(CR3R3a)w, (CR3R3a)uNR3b(CR3R3a)w, (CR3R3a) UC (0) NR (CR3R3a) w, (CR R3a)uNR3bC(0) (CR3R3 )w, (CR3R3a)uNR3bC(0) (CR3R3a)uC(0)NR3b(CR3R3a)w, (CR3R3a)uS(CR R3a)w; (CR R3a) US (0) (CR3R3a)w,
(CR3R3a)uS(0)2(CR3R3a)w, (CR3R3a)uS(0)NR3b(CR R3a)w,
(CR3R3a)u NR3 S(0)2(CR3R3a)w, and
(CR3R3a)uS(0)2NR3b(CR3R3a)w, wherein u + w total 0, 1, or 2, provided that G does not form a N-S, NCH2N,
NCH20, or NCH2S bond with either group to which it is attached;
Rla is selected from H, Rlb, CH(CH3)Rlb, C(CH3)2Rlb, CH2Rlb, and CH2CH2Rlb, provided that Rla forms other than an N- halo, N-S, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 R4b and 0-3 ring double bonds;
Rlb is selected from H, CH3 , CH2CH3 , F, Cl, Br, -CN, -CHO, CF3, OR2, NR2R2a, C(0)R2b, C02R2b, 0C(0)R2, C02R2a, S(0)pR2, NR2(CH2)rOR2, NR2C(0)R2b, C(0)NR2R2a, S02NR2R2a, NR2S02R2, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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, indolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
X is selected from -C(O)-, -C(=NRlb)-, -C(0)NR2-,
-NR2C(0)-, -NR2C(0)CR2R2a-, -NR2C (O)NR2- , and 0;
Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R and 0-1 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2, 3-oxadiazole, 1,2,4- oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2 , 5-thiadiazole, 1, 3, 4-thiadiazole, 1, 2 , 3-triazole, 1, 2 , 4-triazole, 1, 2, 5-triazole, 1 , 3 , 4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; R2, at each occurrence, is selected from H, CF3, CH3 ,
CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with
0-2 Rb, a benzyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
R4b;
R2 , at each occurrence, is selected from H, CF , CH , CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3, Cι_4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, 0CH3,
OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3, CH2CH2CH3 , CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R4c, C1-.4 alkyl substituted with 0-2 R c, C3_6 carbocycle substituted with 0-2 R4c, - (CR3R3a)-C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rc, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R c, C3_6 carbocycle substituted with 0-2 R4c, - (CR3R3a) -C3_6 carbocycle substituted with 0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rc, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from H, (CH ) 0R2, CH2OR2, OR2, F, Cl, Br, I, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN, N02, NR2R2a, CH2NR2R2a, (CH2) 2NR2R2a, C(0)R2c, NR2C(0)R2b, C(0)NR2R2 , S02NR2R2a, CF3 , and CF2CF3;
R a is selected from (CH2 ) rN (→O) R2dR2d, (CH2) v-NR2dC (0) R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2) v-NR2dC (0) OR2d, and (CH2)v-NR2dS02R2d;
alternatively, R4a is selected from (CH2) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) OR2d, and
NR2dS02R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3,
CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN,
N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)OR3c, CH2-C(0)OR3c, NR C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH2-C(0)NR3R3a, S02NR3R3a, CH2S02NR3R3a, NR3S02-Cι_ alkyl, CH2NR3S02-Cι_ alkyl, NR3S0 -phenyl, CH2NR3S02- phenyl, S(0)pCF3, CH2S(0)pCF3, S(0)p-Cι_4 alkyl, CH S(0)p-Cι-4 alkyl, S (0)p-phenyl, CH2S (0)p-phenyl, and CF3;
R4c, at each occurrence, is selected from =0, OR2, (CR3R3a)OR2, F, (CR3R3a)F, Br, (CR3R3a)Br, Cl, (CR3R3a)Cl, CF3, (CR3R3a)CF3, Cι_ alkyl, -CN, (CR3R3a)CN, N02, (CR3R3a)N0 , NR2R2a, (CR3R3a) NR2R2a,
N(→0)R2R2a, (CR3R3a)N(→0)R2R2a, C(0)R2c, (CR3R3a)C(0)R2c, NR2C(0)R2b, (CR3R3a) NR2C (0) R2b,
C(0)NR2R2a, (CR3R3a)C(0)NR2R2a, NR2C (0) NR2R2a, (CR3R3a)NR2C(0)NR2R2a, S02NR2R2a, (CR3R3a) S02NR2R2a, NR2S0NR2R2a, (CR3R3a)NR2S02NR2R2a, NR2S0 R5a,
(CR3R3a)NR2S02R5a, S(0)pR5a, (CR3R3a) S (0) pR5a, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 R4b, (CR3R3a)C3_ιo carbocycle substituted with 0-2 R4b, 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
R4b, and (CR3R3a)5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH , CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)0R3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S0NR3R3a, NR3S02-Cι_4 alkyl, NR3S02CF3, NR3S0 -phenyl , S(0)pCF3, S(0)p-Ci_4 alkyl, S (0)p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, S02NR2R2a, and NR2S02Cι_4 alkyl; and,
v, at each occurrence, is selected from 1 and 2.
[4] In another preferred embodiment, the present invention provides a novel compound, wherein: ring M is substituted with 0-2 Rla and is selected from the group :
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
ring P, including P1# P2, P , and P is selected from
Figure imgf000052_0002
Figure imgf000053_0001
one of P and M4 is -A-B and the other -G;
G is selected from the group:
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
G1 is absent or is selected from CH2 , CH2CH2, CH20, OCH2 , NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O),
CH2S(0) , S(0) (CH2), S02NH, and NHS02 , provided that Gλ does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
A is selected from piperidinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4;
B is selected from phenyl, pyridyl, pyrrolidino, N- pyrrolidino-carbonyl, morpholino, N-morpholino- carbonyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a and 0-1 R4;
Rla is selected from H, Rlb, C(CH3)2Rlb, and CH2Rlb, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
Rlb is selected from CH3, CH2CH3 , F, Cl, Br, -CN, CF3 , OR2, NR2R2a, C(0)R2b, C02R2b, C0 R2a, S(0)pR2, C(0)NR2R2a, S02NR2R2a, NR2S02R2, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an O-O, N-halo, N-S, or N-CN . bond;
R , at each occurrence, is selected from H, CH3 , CH2CH3 ,
CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3, CHCH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with
0-1 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from 0CH3, OCH2CH3,
OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-1 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p and substituted with 0-1
R4b;
R c, at each occurrence, is selected from OH, OCH3, OCH CH3 , OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-1 Rb, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2d, at each occurrence, is selected from H, R c, Cι_4 alkyl substituted with 0-2 R4c, C3-g carbocycle substituted with 0-2 R4c, -(CH2)-C3_6 carbocycle substituted with
0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety; R2e, at each occurrence, is selected from H, R c, Cι_4 alkyl substituted with 0-2 R c, C _6 carbocycle substituted with 0-2 R4c, -(CH2)-C3_6 carbocycle substituted with 0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and -(CH )-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from OH, OR2, CH2OR2, (CH2)2OR2, F, Br, Cl, I, CH3 , CH2CH3 , CH2CH2CH3,
CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, CF3 , and CF2CF3 ;
R4a is selected from (CH2) rN(→0) R2dR2d, (CH2) v-NR2dC (0) R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2 ) v-NR2dC (0) 0R2d, and (CH2)v-NR2dS02R2d;
alternatively, R4a is selected from (CH2) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) 0R2d, and
NR2dS0 R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl;
Rb, at each occurrence, is selected from H, =0, OR3,
CH20R3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S0 -Ci-4 alkyl, NR3S02 -phenyl, S(0)p-Ci-4 alkyl, S (0)p-phenyl, and CF3 ;
R4c, at each occurrence, is selected from =0, OR2, CH2OR2,
F, Br, Cl, CF3, Cι-4 alkyl, -CN, N02, NR2R2a, CH2NR2R2 ,
N(→0)R2R2a, CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c,
NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0)NR2R2a,
S0NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2S0 R5a, S(0)pR5a, CH2S(0)pR5a, CF3, CF2CF3 , C3_6 carbocycle substituted with 0-2 R4b, (CH2)C3_6 carbocycle substituted with 0-2 Rb, 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, and (CH2)-5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_ alkyl, NR3S02-phenyl, S(0)p-Cι-4 alkyl, S (0) p-phenyl , CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, and S0NR2R2a.
[5] In another preferred embodiment, the present invention provides a novel compound, wherein:
ring M is substituted with 0-1 Rla and is selected from the group :
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
ring P, including Plf P , P3, and P4 is selected from group :
Figure imgf000064_0001
one of P4 and M4 is -A-B and the other -G;
G is selected from:
Figure imgf000065_0001
Figure imgf000066_0001
A is selected from the group: piperidinyl, phenyl, 2- pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-C1- phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2- aminophenyl, and 2-methoxyphenyl;
B is selected from phenyl, pyridyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a; Rla is selected from H, CH3, CH2CH3, CH2CH2CH3, CH2F, CH2C1,
Br, CH2Br, -CN, CH2CN, CF3 , CH2CF3 , OCH3 , CH2OH,
C(CH3)2OH, CH2OCH3, NH2 , CH2NH2 , NHCH3 , CH2NHCH3 , N(CH3)2, CH2N(CH3)2, C02H, COCH3 , C02CH3 , CH2C0 CH3 ,
SCH3, CH2SCH3, S(0)CH3, CH2S(0)CH3, S(0)2CH3,
CH2S(0)2CH3, C(0)NH2, CH2C(0)NH2, S02NH2 , CH2S02NH2,
NHS02CH3, CH2NHS02CH3, pyridin-2-yl , pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N- oxide, pyridin-4-yl-N-oxide, imidazol-1-yl, CH2- imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N,N- dimethylaminomethyl-oxazol-2-yl , 1,2,3, 4-tetrazol-l- yl, l,2,3,4-tetrazol-5-yl, CH2-1, 2 , 3 , 4-tetrazol-l-yl, and CH2-1, 2, 3 , 4-tetrazol-5-yl, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3 , CH2CH3,
CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 Rb, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3, and CH2CH3;
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 0-1 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S(0)p; R2b, at each occurrence, is selected from OH, OCH3, OCHCH3, CH3, and CH2CH3;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3 , CH3, and CH2CH3;
R2d, at each occurrence, is selected from H, R c, C1-.4 alkyl substituted with 0-2 R c, C3_6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
R c, provided that R2d forms other than a N-halo, N-C- halo, S(0)p-halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, O-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R4c, C1-.4 alkyl substituted with 0-2 R c, C3_6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4a is selected from CH2N(→0)R2dR2d, CH2NR2dC (0) R2e,
CH2NR2dC(0)NR2dR2d, CH2NR2dC (0) OR2d, and CH2NR2dS02R2d;
R4b, at each occurrence, is selected from H, =0, OR3,
CH20R3, F, Cl, CH3, CH2CH3, NR3R3a, CH2NR3R3a, C(0)R3, C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02 -phenyl, S(0)2CH3, S (0) 2 -phenyl, and CF3 ;
R4c, at each occurrence, is selected from =0, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3,
CH(CH3)2, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH(CH3)2, F, Br, Cl, CF3 , NR2R2a, CH2NR2R2a, N(→0)R2R2a, CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0) NR2R2 , S02NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2S02R5a,
S(0)pR5a, CH2S(0)pR5a, CF3, cyclopropyl substituted with 0-1 R4b, cyclobutyl substituted with 0-1 R4b, cyclopentyl substituted with 0-1 Rb, phenyl substituted with 0-1 Rb, -CH2-cyclopropyl substituted with 0-1 Rb, -CH2-cyclobutyl substituted with 0-1 R4b,
-CH -cyclopentyl substituted with 0-1 R4b, benzyl substituted with 0-2 Rb, 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, and (CH2)-
5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R ;
R5, at each occurrence, is selected from H, =0, CH3,
CH2CH3, OR3, CH2OR3, F, Cl, NR3R3a, CH2NR3R3a, C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R a, S02NR3R3a, NR3S02-Ci-4 alkyl, NR3S02 -phenyl, S(0)2-CH3, S (0) 2 -phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, and S02NR2R2a.
[6] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from:
Figure imgf000070_0001
Figure imgf000071_0001
70
Figure imgf000072_0001
is -G;
M4 is -A-B;
G is selected from:
Figure imgf000073_0001
A-B is selected from :
Figure imgf000074_0001
R2d, at each occurrence, is selected from H, C1-.4 alkyl substituted with 0-1 Rc, C3_6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0- halo, N-S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R4c, C3_6 cycloalkyl substituted with 0-2 R4c, phenyl, substituted with 0-2 Rc, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4a is selected from CH2N(→0) R2dR2d, CH2NR2dC (0) R2e, CH2NR2dC(0)OR2d, and CH2NR2dS02R2d; and,
R 4c is selected from OH, 0CH3, OCH2CH3 , OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, CH20H,
CH2OCH3, CH20CH2CH3, CH2OCH2CH2CH3 , CH20CH (CH3) 2 , F, Br, Cl, CF3, NR2R2a, CH2NR2R2 , C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0) NR2R2 , S02NR2R2a, CH2S02NR2R2a, NR2S0 R5a, CH2NR2S02R5a, S(0)pR5a, and CH2S(0)pR5a.
[7] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is of the formula:
Figure imgf000075_0001
P4 is -G;
M4 is -A-B;
A-B is selected from:
Figure imgf000076_0001
R2d, at each occurrence, is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl; and,
R2e, at each occurrence, is selected from CH3, CH2CH3,
CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl. [8] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from the group:
N- [ (l-{4- [1- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6- yl] phenyl} -lff-imidazol-2-yl) methyl] -N-methylacetamide ;
N- [ (l-{4- [1- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6H-pyrazolo [3 , 4-c]pyridin-6- yl] phenyl} -1H-imidazol-2-yl) methyl] -N-methylacetamide;
methyl (l-{4- [1- (4-methoxyphenyl) -7-oxo-3-
(trifluoromethyl) -1,4,5, 7-tetrahydro-6ff-pyrazolo [3,4- c]pyridin-6-yl]phenyl}-lff-imidazol-2-yl)methyl (methyl) carbamate;
N- [ (l-{4- [1- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6H-pyrazolo [3 , 4-c]pyridin-6- yl] phenyl} -Iff-imidazol-2-yl) methyl] -N- methylmethanesulfonamide;
N- [ ( l- { 4- [ l- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6H-pyrazolo [3 , 4-c]pyridin-6- yl] phenyl}-Iff-imidazol-2-yl) methyl] -N, 3, 5-trimethyl-4- isoxazolesulfonamide;
6- [4- (2-{ [acetyl (methyl) amino]methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
6-[4-(2-{ [ethylcarbonyl (methyl) amino]methyl} -Iff-imidazol- l-yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide; 6- [4- (2-{ [n-propylcarbonyl (methyl) amino] methyl }-lff- imidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3- carboxamide;
6- [4- (2-{ [i-propylcarbonyl (methyl) amino] methyl} -lff- imidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3- carboxamide;
6- [4- (2-{ [i-butylcarbonyl (methyl) amino] methyl }-lff- imidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3- carboxamide;
1- (4-methoxyphenyl) -6-{4-[2-( {methyl [
(methylamino) carbonyl] -amino}methyl ) -lff-imidazol-1- yl] phenyl} -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxamide;
methyl (1- {4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl] phenyl } -lff-imidazol-2-yl ) methyl (methyl ) carbamate ;
ethyl (l-{4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl ] henyl } -lff-imidazol-2-yl ) methyl (methyl ) carbamate;
1- (4-methoxyphenyl) -6- [4-(2-{ [methyl
(methylsulfonyl) amino] -methyl} -Iff-imidazol-1- yl)phenyl] -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3, 4- c] pyridine-3-carboxamide; - (4-methoxyphenyl) -6- [4- (2-{ [methyl (n- propylsulfonyl) amino] -methyl} -Iff-imidazol-1- yl) phenyl] -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c] pyridine-3-carboxamide;
-[4-(2-{ [ [ (3, 5-dimethyl-4-isoxazolyl) sulfonyl] (methyl) - amino]methyl}-lff-imidazol-l-yl)phenyl] -1- (4- methoxyphenyl ) -7-oxo-4, 5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c]pyridine-3-carboxamide;
- (4-methoxyphenyl) -6-[4-(2-{ [methyl (phenylsulfonyl) amino] methyl } -lff-imidazol-1-yl) phenyl] -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4 -c] pyridine-3-carboxamide;
- [4- (2-{ [acetyl (ethyl) amino] methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
- [4- (2-{ [acetyl (n-propyl) amino] methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
- [4- (2-{ [acetyl (n-propyl) amino] methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
- [4- (2-{ [ethylcarbonylamino] methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6- yl] phenyl} -Iff-imidazol-2-yl) methyl] -N-methylacetamide; N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl ] phenyl } -Iff-imidazol-2-yl ) methyl ] -N- methylpropanamide;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c] pyridin-6- yl ] phenyl } -Iff-imidazol-2-yl) methyl ] -N- methylbutanamidetrifluoroacetic acid salt;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c] pyridin-6- yl] phenyl }-lff-imidazol-2-yl) methyl] -N, 2- dimethylpropanamide ;
N- [ (1- {4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl ] phenyl } -Iff-imidazol-2-yl ) methyl ] -N- methylcyclopropanecarboxamide ;
methyl (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl ] phenyl} -lff-imidazol-2-yl ) methyl (methyl ) carbamate;
N-ethyl-N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7- oxo-1, 4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl ] phenyl } -Iff-imidazol-2-yl ) methyl ] acetamide;
N-isopropyl-N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-l, 4,5, 7-tetrahydro-6ff- pyrazolo [3 , 4-c]pyridin-6-yl]phenyl}-lff-imidazol-2- yl ) methyl ] acetamide ; N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo[3, 4-c]pyridin-6- yl ] phenyl } -lff-imidazol-2-yl ) methyl ] -N-propylacetamide;
1- (4-methoxyphenyl) -6- [2 ' - ( {methyl [ (methylamino) carbonyl] - amino}methyl) -1,1' -biphenyl-4-yl] -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -6- (2 ' - { [methyl (methylsulfonyl) mino] - methyl }-l, 1' -biphenyl-4-yl) -7-oxo-4, 5,6, 7-tetrahydro- lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
N- (2-{4-[3-cyano-l- (4-methoxyphenyl) -7-oxo-l, 4, 5,7- tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6-yl] -1- piperidinyl }benzyl) -N-methylacetamide ;
6- [1- (2-{ [acetyl (methyl) amino] methyl}phenyl) -4- piperidinyl] -1- (4-methoxyphenyl) -7-oxo-4 ,5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -6- [1- (2-{ [methyl
(methylsulfonyl) amino] methyl }phenyl) -4-piperidinyl] -7- oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3 , -c] pyridine-3- carboxamide;
6- (4-{2- [ (dimethylnitroryl) methyl] -Iff-imidazol-1- yl}phenyl) -1- (4-methoxyphenyl) -3- (trifluoromethyl) - 1,4,5, 6-tetrahydro-7ff-pyrazolo [3 , 4-c] pyridin-7-one;
1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2 '-{ [bis (2- hydroxyethyl) amino] methyl}-l, 1' -biphenyl-4-yl) -3- ( trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pryazolo [3, 4- c]pyridin-7-one; 1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2 ' -{ [ (3-aminopropyl) (methyl) amino] methyl }-l, 1' -biphenyl-4-yl) -3- ( trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pryazolo [3 , 4- c]pyridin-7-one;
6- (2'-{ [ (2-hydroxyethyl) (methyl) amino] methyl}-l, 1 ' - biphenyl-4-yl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pryazolo [3 , 4-c]pyridine-3-carboxamide;
6- (2'-{ [bis (2-hydroxyethyl) amino] methyl }-l, 1 ' -biphenyl-4- yl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pryazolo [3 , 4-c]pyridine-3-carboxamide;
6- (2 ' -{ [ (3-aminopropyl) (methyl) amino] methyl }-l, 1' -biphenyl- 4-yl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pryazolo [3 , 4-c] pyridine-3-carboxamide;
6- (2'-{ [ (2-hydroxyethyl) (methyl) amino] methyl }-l, 1'- biphenyl-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) - 1,4,5, 6-tetrahydro-lff-pryazolo [3 , -c]pyridin-7-one;
or a pharmaceutically acceptable salt form thereof.
[9] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is of Formula Ilia, Illb, or IIIc:
Figure imgf000082_0001
Ilia Illb IIIc or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M, including M1# M2 , and, if present, M3, is phenyl or a 3-10 membered carbocyclic or 4-10 membered heterocyclic ring consisting of: carbon atoms and 1-4 heteroatoms selected from 0, S(0)p, N, and NZ2;
ring M is substituted with 0-3 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
one of P4 and M is -Z-A-B and the other -G -G;
G is a group of formula Ila or lib:
Figure imgf000083_0001
Ila lib
ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p;
ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2 R; alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds ;
R is selected from H, Cλ- alkyl, F, Cl, OH, 0CH3 , OCH2CH3 , OCH(CH3)2, CN, C(=NH)NH2, C(=NH)NH0H, C (=NH) HOCH3 , NH2, NH(Cι_3 alkyl), N(Cι_3 alkyl)2, C(=NH)NH2, CH2NH2 , CH2NH(Cι_3 alkyl), CH2N(Cι_3 alkyl)2, (CR8R9) tNR7R8, C(0)NR7R8, CH2C(0)NR7R8, S(0)2R3, S(0)pNR7R8, CH2S(0)pNR7R8, and OCF3 ;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is selected from:
C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4 ;
X is selected from - (CR2R2a) . - , -C(0)-, -C(=NRlb)-,
-CR2(NRlbR2)-, -C(0)CR2R2a-, -CR2R2aC(0), -C(0)NR2-, -NR2C(0)-, -C(0)NR2CR2R2a-, -NR2C (0) CR2R2a- , -CR2R2aC(0)NR2-, -CR2R2aNR2C (0) - , -NR2C (0) NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2 O-, and -0CR2R2a- ; Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 Ra and 0-2 R4: cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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 ;
Z is selected from a bond, CH2, CH2CH , CH20, OCH2 , C(O), NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)NH, NHC(0)CH2C(0)NH, C(0)NHS(0)2, S(0)2,
CH2S(0) , S(0) (CH2), S02NH, and NHS02 , provided that Z does not form a N-S, NCHN, NCH20, or NCH2S bond with either group to which it is attached;
Z2 is selected from H, Cι_4 alkyl, phenyl, benzyl, C(0)R3b, S(0)R3f, and S(0)2R f;
Rla, at each occurrence, is selected from H, -(CH2)r-Rlb,
-(CH(CH3) )r-Rlb, -(C(CH3)2)r-Rl , -0- (CR3R3a) r-Rlb, -NR2-(CR3R3a)r-Rlb, and -S- (CR3R3a) r-Rlb, provided that
Rla forms other than an N-halo, N-S, O-O, or N-CN bond; alternatively, when two Rla groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N,
0, and S(0)p, this ring being substituted with 0-2 R4b and 0-3 ring double bonds;
Rlb is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, -CN, -CHO, CF3 , OR2, NR2R2a, C(0)R2b, C02R2b, OC(0)R2, C02R2a, S(0)pR2, NR2 (CH2) rOR2 , NR2C(0)R2b, NR2C(0)NHR2, NR2C(0)2R2a, OC(0)NR2R2a, C(0)NR2R2a, C(0)NR2(CH2)rOR2, S02NR2R2 , NR2S02R2, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CF3 , CH ,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5_6 carbocycle substituted with 0-2 Rb, a C5-6 carbocyclic-CH2-group substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
Rb, at each occurrence, is selected from CF3, C1-.4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3 , OH, C1-.4 alkoxy, CH3, CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R c, Cι_4 alkyl substituted with 0-2 R4c, - (CR3R3a) r-C3_6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, provided that R2d forms other than a N-halo, N-C-halo, S (Op- halo, 0-halo, N-S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-.4 alkyl substituted with 0-2 R c, - (CR3R3a) r-C3-6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R3, at each occurrence, is selected from H, CH3, CH CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
R a, at each occurrence, is selected from H, CH3 , CHCH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R3 and R3a are attached;
R3c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl; R3d, at each occurrence, is selected from H, CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2-phenyl, CH2CH2-phenyl, and C(=0)R3c;
R39, at each occurrence, is selected from H, CH3 , CHCH , CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclopropyl-methyl, benzyl , and phenyl ;
alternatively, when R3 and R39 are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
R4, at each occurrence, is selected from H, =0, OR2,
CH2OR2, (CH2)2OR2, F, Cl, Br, I, C1-4 alkyl, -CN, N0 , NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, C(0)R2c, NR2C(0)R2b, C(0)NR2R2a, S02NR2R2a, S(0)pR5a, CF3 , CF2CF3, 5-6 membered carbocycle substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R5;
R 4a ig selected from (CR3R39) rN(→0) R2dR2d,
(CR3R39)v-NR2dC(0)R2e, (CR3R39) v-NR2dC (0) NR2dR2d, (CR3R39)v-NR2dC(0)OR2d, (CR3R39) v-NR2dS02NR2dR2d, and (CR3R3£f)v-NR2dS02R2d;
alternatively, R4a is selected from (CR3R39) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) 0R2d, NR2dS02NR2dR2d, and NR2dS02R2d, provided that at least one of R2d and R e is alkyl substituted with at least one Rc that is other than alkyl; R b, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)OR3c,
CH2C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH2C(0)NR3R3a, NR C(0)NR3R3a, CH2NR3C (0) NR3R3a, C(=NR3)NR3R3a, CH2C(=NR3)NR3R3a, NR C (=NR3 ) NR3R3a, CH2NR3C(=NR3)NR3R3a, S02NR3R3a, CH2S02NR3R3a, NR3S02NR3R3a, CH2NR3S0 NR3R3 , NR3S02-Ci-4 alkyl,
CH2NR3S02-Cι_4 alkyl, NR3S02CF3, CH2NR3S02CF3, NR3S02 -phenyl, CH2NR3S02 -phenyl, S(0)PCF3, CH2S(0)pCF3, S(0)p-Cι_4 alkyl, CH S (0)p-Cι_4 alkyl, S (0) p-phenyl, CH2S(0) p-phenyl, CF3 , and CH2-CF3;
R4c, at each occurrence, is selected from =0, (CR3R3a) rOR2 , (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a) rCF3 , C1-4 alkyl, (CR3R3a)rCN, (CR3R3a) rN0 , (CR R3a) rNR2R2a, (CR3R3a) rN(→0) R2R2a, (CR3R3a) rC (0) R2c, (CR3R3a)rNR2C(0)R2b, (CR3R3a) rC (0) NR2R2a,
(CR3R3a)rNR2C(0)NR2R2a, (CR3R3 ) rS0 NR2R2a, (CR3R3a) rNR2S02NR2R2a, (CR3R3a) rNR2S02R5a, (CR3R3a)rS(0)pR5a, (CF2)rCF3, (CR3R3a) rC3_ι0 carbocycle substituted with 0-2 R4b, and (CR3R3a) r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3, F, Cl, -CN, N02 , NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)OR3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, NR3C (0) NR3R3a, CH(=NOR3d), C(=NR3)NR3R3a, NR3C (=NR3 ) NR3R3a, S02NR3R3a, NR3S02NR3R3a, NR3S02-Cι_ alkyl, NR3S0 CF3, NR3S02- phenyl, S(0)pCF3, S(0)p-Cι_ alkyl, S (0) p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3 , CH2CH3 , CH2CH2CH , CH(CH3)2, CH2CH2CH2CH3 ,
CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, -CN, N02 , NR2R2a,
CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b,
NR2C(0)NR2R2a, C(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S02Cι_ alkyl;
r, at each occurrence, is selected from 0, 1, and 2; and,
v, at each occurrence, is selected from 1, 2, and 3.
[10] In another preferred embodiment, the present invention provides a novel compound, wherein:
ring M, including M1# M2 , and, if present, M3 , is selected from phenyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1, 2, 3-triazole, 1, 2 , 4-triazole, 1, 3 , 4-triazole, 1,2,3- oxadiazole, 1, 2 , 4-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2, 3, 4-tetrazole, 1, 2 , 3 , 5-tetrazole, pyran, thiopyran, thiopyran=l, 1-dioxide, pyridine, pyrimidine, pyridazine, pyrazine, 1, 2 , 3-triazine, 1, 2, 4-triazine, 1, 2 , 3 , 4-tetrazine, dihydro-pyrrole, dihydro-furan, dihydro-thiophene, dihydro-pyrazole, dihydro-imidazole, dihydro-isoxazole, dihydro-oxazole, dihydro-isothiazole, dihydro-thiazole, dihydro-1, 2 , 3- triazole, dihydro-1, 2 , 4-triazole, dihydro-1, 3 , 4- triazole, dihydro-1, 2 , 3-oxadiazole, dihydro-1, 2, 4- oxadiazole, dihydro-1, 3 , 4-oxadiazole, dihydro-1, 2 , 3- thiadiazole, dihydro-1, 2 , 4-thiadiazole, dihydro-1, 3 , 4- thiadiazole, dihydro-1, 2 , 3 , 4-tetrazole, dihydro-
1, 2 , 3 , 5-tetrazole, dihydro-pyran, dihydro-thiopyran, dihydro-thiopyran=1 , 1-dioxide, dihydro-pyridine, dihydro-pyrimidine, dihydro-pyridazine, dihydro- pyrazine, dihydro-1, 2 , 3-triazine, dihydro-1, 2 , 4- triazine, dihydro-1, 2 , 3 , 4-tetrazine, cyclopentene, cyclopentane, cyclohexene, cyclohexane, tetrahydro- pyrrole, tetrahydro-furan, tetrahydro-thiophene, tetrahydro-thiophene-1, 1-dioxide, tetrahydro-pyrazole, tetrahydro-imidazole, tetrahydro-isoxazole, tetrahydro-oxazole, tetrahydro-isothiazole, tetrahydro-thiazole, tetrahydro-1, 2 , 3-triazole, tetrahydro-1, 2 , 4-triazole, tetrahydro-1, 3 , 4-triazole, tetrahydro-1, 2 , 3-oxadiazole, tetrahydro-1, 2,4- oxadiazole, tetrahydro-1, 3 , 4-oxadiazole, tetrahydro- 1, 2 , 3-thiadiazole, tetrahydro-1, 2 , 4-thiadiazole, tetrahydro-1, 3 , 4-thiadiazole, tetrahydro-1, 2,3,4- tetrazole, tetrahydro-1, 2 , 3 , 5-tetrazole, tetrahydro- pyran, tetrahydro-thiopyran, tetrahydro-thiopyran-1, 1- dioxide, tetrahydro-pyridine, tetrahydro-pyrimidine, tetrahydro-pyridazine, tetrahydro-pyrazine, tetrahydro-1, 2 , 3-triazine, tetrahydro-1, 2 , 4-triazine, and tetrahydro-1, 2,3, 4-tetrazine;
ring M is substituted with 0-3 Rla and 0-1 carbonyl group; G is selected from the group:
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
95
Figure imgf000097_0001
Figure imgf000098_0001
Gι is absent or is selected from (CR3R3a)1_3,
(CR3R3a)uC(0) (CR3R3a)w, (CR3R3a)uO(CR3R3a)w, (CRR3a)uNR3b(CR3R3a)w, (CR3R3a) UC (O) NR3b (CR3R3a) w, (CR3R3 )uNR3bC(0) (CR3R3a)w,
(CR3R3a)uNR3bC(0) (CR3R3a)uC(0)NR3b(CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(0) (CR3R3a)w, (CR3R3a)uS(0)2(CR3R3a)w, (CR3R3a)uS(0)NR3b(CR3R3a)w, (CR3R3a)uNR3bS(0)2(CR3R3a)w, (CR3R3a) US (0) 2NR3b(CR3R3a) w, and (CR3R3a)uC(0)NR3bS(0)2(CR3R3a)w, wherein u + w total 0, 1, or 2 , provided that G1 does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
Rla is selected from H, Rlb, CH(CH3)Rlb, C(CH3)2Rlb, CH2Rlb, and CH2CH2Rlb, provided that Rla forms other than an N- halo, N-S, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 R4b and 0-3 ring double bonds; Rlb is selected from H, CH3, CH2CH3 , F, Cl, Br, -CN, -CHO, CF3, OR2, NR2R2a, C(0)R2b, C02R2b, OC(0)R2, C02R2a, S(0)pR2, NR2(CH2)rOR2, NR2C(0)R2b, C(0)NR2R a, S0NR2R2a, NR2S02R2, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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, indolinyl, indolyl, benzimidazolyl , benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
X is selected from -C(O)-, -C(=NRlb)-, -C(0)NR2-,
-NR2C(0)-, -NR2C(0)CR2R2a-, -NR2C (0) NR2- , and 0;
Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-1 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3-oxadiazole, 1,2,4- oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2, 5-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2 , 3-triazole, 1, 2 , 4-triazole, 1, 2 , 5-triazole, 1, 3 , 4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
R2 , at each occurrence, is selected from H, CF3 , CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with
0-2 R4b, a benzyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3 , CH3 ,
CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2 , 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 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3 , Cι_4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
Rc, at each occurrence, is selected from CF3, OH, OCH3,
OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3, CH2CH2CH3 , CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and
5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2 , at each occurrence, is selected from H, Rc, Cι_4 alkyl substituted with 0-2 R c, C3_6 carbocycle substituted with 0-2 R c, - (CR3R3a) -C3-6 carbocycle substituted with 0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-O, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R4c, Cι_4 alkyl substituted with 0-2 R c, C3..6 carbocycle substituted with 0-2 R4 , - (CR3R3 ) -C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rc, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from H, (CH2)20R2, CH2OR2, OR2, F, Cl, Br, I, CH3 , CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN, N02, NR2R2a, CH2NR2R2a, (CH2) 2NR2R2a, C(0)R2c, NR2C(0)R2b, C(0)NR2R2a, S02NR2R2a, CF3 , and
CF2CF3 ;
R4a is selected from (CH2) rN(→0) R2dR2d, (CH2) v-NR2dC (0) R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2 ) v-NR2dC (0) OR2d, and (CH2)v-NR2dS02R2d;
alternatively, R4a is selected from (CH2) rNR2dR2d,
NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) 0R2d, and NR2dS0 R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R4c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3,
CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)0R3c,
CH2-C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH -C(0)NR3R3a, S02NRR a, CH2S02NR3R3a, NR3S02-Cι_4 alkyl, CH2NR3S02-Cι_ alkyl, NR3S02-phenyl, CH2NR3S02- phenyl, S(0)pCF3, CH2S(0)PCF3, S(0)p-Cι_4 alkyl, CH2S(0)p-Cι-4 alkyl, S (0)p-phenyl, CH2S (0) p-phenyl, and CF3 ;
Rc, at each occurrence, is selected from =0, OR2, (CRR3a)OR2, F, (CR3R3a)F, Br, (CR3R3 )Br, Cl, (CR3R3a)Cl, CF3, (CR3R3a)CF3, Cι_ alkyl, -CN, (CR3R3 )CN, N02, (CR3R3a)N02, NR2R2a, (CR3R3a) NR2R2a,
N(→0)R2R2a, (CR3R3a)N(→0)R2R2a, C(0)R2c,
(CR3R3a)C(0)R2c, NR2C(0)R2b, (CR3R3a) NR2C (0) R2b, C(0)NR2R2a, (CR3R3a)C(0)NR2R2a, NR2C (0) NR2R2a,
(CR3R3a)NR2C(0)NR2R2 , S02NR2R2a, (CR3R3a) S02NR2R2a, NR2S02NR2R2a, (CR3R3a) NR2S0NR2R2a, NR2S02R5a,
(CR3R3a)NR2S02R5a, S(0)pR5a, (CR3R3a) S (0) pR5a, CF3 , CF2CF3, C3-10 carbocycle substituted with 0-2 R4b,
(CR3R3a)C3_ιo carbocycle substituted with 0-2 R4b, 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
Rb, and (CR R a)5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH20R3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH C(0)R3, C(0)0R3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a,
NR3S02-Cι_4 alkyl, NR3S02CF3, NR3 S02 -phenyl , S(0)pCF3, S(0)p-Cι_4 alkyl, S (0)p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a,
CH2NR2R2 , C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, S02NR2R2a, and NR2S0 Cι_4 alkyl; and,
v, at each occurrence, is selected from 1 and 2.
[11] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from:
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000108_0002
Figure imgf000108_0003
J is selected from 0, S, NH, and NRla;
G is selected from the group:
Figure imgf000109_0001
Figure imgf000110_0001
Gx is absent or is selected from CH2, CH2CH2, CH20, OCH2, NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC (0) , NHC(0)NH, C(0)NHS(0)2, CH2S(0)2, S(0)2(CH2), S02NH, and NHS02, provided that Gλ does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
A is selected from indolinyl, piperidinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4;
B is selected from phenyl, pyridyl, pyrrolidino, N- pyrrolidino-carbonyl, morpholino, N-morpholino- carbonyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 Ra and 0-1 R4; Rla is selected from H, Rlb, C(CH3)2Rlb, and CH2Rlb, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
Rlb is selected from CH3, CH2CH3, F, Cl, Br, -CN, CF3 , OR2, NR2R2a, C(0)R2b, C02R2b, Cθ2R2a, S(0)pR2, C(0)NR2R2a, S02NR2R2a, NR2S02R2, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with
0-1 R , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from OCH3, OCH CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 Rb;
R2c, at each occurrence, is selected from OH, 0CH , OCH2CH , OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-1 Rb, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 Rb;
Rd, at each occurrence, is selected from H, R4c, C1-.4 alkyl substituted with 0-2 R4c, C3_6 carbocycle substituted with 0-2 R c, -(CH )-C3_6 carbocycle substituted with
0-2 Rc, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(Op-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety; R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3_6 carbocycle substituted with 0-2 R , -(CH2)-C3_6 carbocycle substituted with
0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from OH, OR2, CH2OR2, (CH2)2OR2, F, Br, Cl, I, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, NR2R2a, CH2NR2R2a, (CH2) 2NR2R2a, CF3 , and CF2CF3 ;
R 4a is selected from (CH2) rN(→0) R2dR2d, (CH2) v-NR2dC (0) R2e, (CH2)v-NR2dC(0)NRdR2d, (CH2 ) v-NR2dC (0) 0R2d, and (CH2)v-NR2dS02R2d;
alternatively, R4a is selected from (CH2) rNR2dR2d,
NR2dC(0)R2e, NR2 C(0)NR2dR2d, NR2dC (0) 0R2d, and NR2dS02R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R4c that is other than alkyl;
Rb, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, -CN, N02, NR3R3a, CH2NRR3a, C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR S02-Cι_ alkyl, NR3S02-phenyl, S(0)p-Ci-4 alkyl, S (0)p-phenyl , and CF3 ;
R c, at each occurrence, is selected from =0, OR2, CHOR2, F, Br, Cl, CF3, C1-4 alkyl, -CN, N02 , NR2R2a, CH2NR2R2a,
N(→0)R2R2 , CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c,
NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0)NR2R2a,
S02NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2S0 R5a,
S(0)pR5a, CH2S(0)pR5a, CF3, CF CF3, C3_6 carbocycle substituted with 0-2 R4b, (CH2)C3_6 carbocycle substituted with 0-2 Rb, 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb, and (CH2)-5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3 , C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S0 -phenyl , S(0)p-Ci_4 alkyl, S (0) p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)Rb, NR2C(0)R2b, and S02NR2R2a. [12] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from:
Figure imgf000116_0001
Figure imgf000117_0001
J is selected from 0, S, NH, and NRla;
Figure imgf000117_0002
M4 is -Z-A-B;
G is selected from:
Figure imgf000118_0002
Figure imgf000118_0001
Figure imgf000118_0004
Figure imgf000118_0003
NH2
Figure imgf000118_0005
Figure imgf000119_0001
Figure imgf000119_0003
Figure imgf000119_0002
Figure imgf000119_0004
Gλ is absent or is selected from CH2NH, NHCH2 , CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)NH, CH2S(0)2,
S(0)2(CH2), S02NH, and NHS02 , provided that G1 does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
A is selected from the group: indolinyl, piperidinyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C1- phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2- methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;
B is selected from phenyl, pyridyl, 1 , 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a;
Rla is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH2F, CH2C1, Br, CH2Br, -CN, CH2CN, CF3 , CH2CF3 , OCH3 , CH2OH, C(CH3)2OH, CH2OCH3, NH2 , CH2NH2 , NHCH3 , CH2NHCH3 ,
N(CH3)2, CH2N(CH3)2, C0 H, COCH3 , C0 CH3 , CH2C02CH3 , SCH3, CH2SCH3, S(0)CH3, CH2S(0)CH3, S(0)2CH3, CH2S(0)2CH3, C(0)NH2, CH2C(0)NH2, S02NH2 , CH2S02NH2, NHS02CH3, CH2NHS02CH3, pyridin-2-yl , pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N- oxide, pyridin-4-yl-N-oxide, imidazol-1-yl, CH2- imidazol-1-yl, 4-methyl-oxazol-2-yl , 4-N,N- dimethylaminomethyl-oxazol-2-yl, 1,2,3, 4-tetrazol-l- yl, l,2,3,4-tetrazol-5-yl, CH2-1, 2 , 3 , 4-tetrazol-l-yl , and CH2-1, 2 , 3 , 4-tetrazol-5-yl, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3, CHCH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 Rb, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3 , and
CH2CH3 ; 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 0-1 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from OH, OCH3, 0CHCH3 , CH3, and CH2CH3;
R2c, at each occurrence, is selected from OH, OCH3, OCH CH3, CH3, and CH2CH3;
Rd, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R c, C3_6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C- halo, S(0)p-halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, O-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-.4 alkyl substituted with 0-2 R c, C3_6 cycloalkyl substituted with 0-2 R4 , phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety; R4a is selected from CH2N(→0) R2dR2d, CH2NR2dC (0) R2e,
CH2NR2dC(0)NR2dR2d, CH2NR2dC (0) OR2d, and CH2NR2dS02R2d;
R4b, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3 , NR3R3a, CH2NR3R3a, C(0)R3, C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3Ra, NR3S02-phenyl, S(0)2CH3, S (0) 2-phenyl , and CF3 ;
R4c, at each occurrence, is selected from =0, OH, 0CH3 , OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH20H, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH(CH3)2, F, Br, Cl, CF3 , NR2R2a, CH2NR2R2a, N(→0)R2R2 , CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0)NR2R2a, S02NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2S02R5a,
S(0)pR5a, CH2S(0)pR5a, CF3, cyclopropyl substituted with 0-1 R4b, cyclobutyl substituted with 0-1 R4b, cyclopentyl substituted with 0-1 Rb, phenyl substituted with 0-1 Rb, -CH -cyclopropyl substituted with 0-1 R4b, -CH2-cyclobutyl substituted with 0-1 R4b,
-CH2-cyclopentyl substituted with 0-1 Rb, benzyl substituted with 0-2 Rb, 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, and (CH2)-
5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b. R5, at each occurrence, is selected from H, =0, CH3,
CH2CH3, OR3, CH2OR3, F, Cl, NR3R3a, CH2NR3R a, C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_ alkyl, NR3S02-phenyl, S(0)2-CH3, S (0) -phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, and S02NR2R2a.
[13] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from:
Figure imgf000123_0001
Figure imgf000123_0002
G is selected from:
Figure imgf000124_0001
A-B is selected from:
Figure imgf000125_0001
Rd, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R c, C3_6 cycloalkyl substituted with 0-2 R c, phenyl substituted with 0-2 R4c, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0- halo, N-S, S-N, S(0)p-S(0)p, S-0, 0-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, Cι_4 alkyl substituted with 0-1 R c, C3_6 cycloalkyl substituted with 0-2 R c, phenyl, substituted with 0-2 Rc, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4a is selected from CH2N(→0)R2dR2d, CH2NR2dC (0) R2e, CH2NR2dC(0)0R2d, and CH2NR2dS02R2d; and, R4c is selected from OH, OCH3, OCH2CH3 , OCH2CH2CH3,
OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH (CH3) 2 , F, Br, Cl, CF3, NR2R2a, CH2NR2R2a, C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0)NR2R2a, S02NR2R2a, CH2S0NR2R2a, NR2S02R5a, CH2NR2S02R5a, S(0)pR5a, and CH2S(0)pR5a.
[14] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from:
Figure imgf000126_0001
P4 is -G; and
A-B is selected from:
Figure imgf000127_0001
R2d, at each occurrence, is selected from H, CH3, CH2CH , CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl; and,
R2e, at each occurrence, is selected from CH3, CH2CH3,
CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl. [15] In another preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from the group:
N- [4- (2- { [acetyl (methyl) amino]methyl}-lH-imidazol-l-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- ( trifluoromethyl) - 1H-pyrazole-5-carboxamide;
N- [4- (2-{ [acetyl (methyl) amino]methyl}-lH-imidazol-l-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (methylsulfonyl) - 1H- yrazole-5-carboxamide;
N- [4- (2- { [methylsulfonylamino] methyl} -lff-imidazol-1-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (methylsulfonyl) - 1H-pyrazole-5-carboxamide;
N- [4- (2- { [methylsulfonylamino] methyl} -1H-imidazol-1-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (aminocarbonyl) - lH-pyrazole-5-carboxamide;
5-{ [5- (2-{ [acetyl (methyl) amino] methyl } -1H-imidazol-1-yl) - 2, 3-dihydro-lH-indol-1-yl] carbonyl }-l- (3-amino-l , 2- benzisoxazol-5-yl) -lH-pyrazole-3-carboxamide;
1- (3-amino-l, 2-benzisoxazol-5-yl) -5-{ [5- (2-{ [methyl
(methylsulfonyl) amino]methyl}-lH-imidazol-l-yl) -2 , 3- dihydro-lH-indol-1-yl] carbonyl }-lH-pyrazole-3- carboxamide;
2- (3-aminobenzo [d] isoxazol-5-yl) -5-trifluoromethyl-2H- pyrazole-3-carboxylic acid (1- {2- [ (acetylmethylamino) - methyl ] phenyl} -piperidin-4-yl ) amide ; 2- (3-aminobenzo [d] isoxazol-5-yl) -5-trifluoromethyl-2H- pyrazole-3-carboxylic acid (l-{2-[
(methanesulfonylmethyl-amino) methyl] phenyl }piperidin-
4-yl) amide;
2- (4-methoxyphenyl) -5-trifluoromethyl-2H-pyrazole-3- carboxylic acid [1- (2-{ [ (2-hydroxyethyl) methylamino] - me hyl}phenyl ) piperidin-4-yl] amide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating 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.
In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
In another embodiment, the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder
In another embodiment, the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is compound of the present invention or a pharmaceutically acceptable salt thereof and the second therapeutic agent is at least one agent selected from a second factor Xa inhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent.
In another preferred embodiment, the present invention provides a novel method, wherein the second therapeutic agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase .
In another preferred embodiment, the present invention provides a novel method, wherein the second therapeutic agent is at least one anti-platelet agent.
In another preferred embodiment, the present invention provides a novel method, wherein the anti-platelet agent is aspirin and clopidogrel.
In another preferred embodiment, the present invention provides a novel method, wherein the anti-platelet agent is clopidogrel .
In another embodiment, the present invention provides a novel article of manufacture, comprising:
(a) a first container;
(b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
(c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic disorder.
In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
In another embodiment, the present invention provides a novel article of manufacture, comprising:
(a) a first container;
(b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
(c) a package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a thromboembolic disorder.
In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. In another embodiment, the present invention provides novel compounds as described above for use in therapy.
In another embodiment, the present invention provides the use of novel compounds as described above for the manufacture of a medicament for the treatment of a thromboembolic disorder.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
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. All tautomers of shown or described compounds are also considered to be part of the present invention.
Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole. Preferably, the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.
The term "substituted, " as used herein, 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. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N) . The present invention, in general, does not cover groups such as N-halo, S(0)H, and S02H.
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.
When any variable (e.g., R6) 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.
In cases wherein there are amines on the compounds of this invention, these can be converted to amine N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed amines are considered to cover both the shown amine and its N-oxide (N→O) derivative.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Cι_6 alkyl, is intended to include Ci, C2, C3, C4, C5, and CQ 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+l) ) . 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. Cι_6 alkoxy, is intended to include Ci, C2 , C3, C4, C5, and C6 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, Cs , and C7 cycloalkyl groups. Alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl . C2_6 alkenyl is intended to include C2, C3, C4, C5, and C6 alkenyl groups. "Alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl . C2-6 Alkynyl is intended to include C2, C3, C4, C5, and Cβ 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. As used herein, "carbocycle" or "carbocyclic residue" 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 ring, any of which may be saturated, partially unsaturated, or unsaturated
(aromatic) . Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane,
[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl . As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane) . A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a trycyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge .
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 ring heteroatoms independently selected from the group consisting of N, 0 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 (i.e., N→O and S(0)p). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined) . The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that 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. 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, 0 and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined) . The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p) . It is to be noted that total number of S and 0 atoms in the aromatic heterocycle is not more than 1. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, 0, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a trycyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl , benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 , 5, 2-dithiazinyl, dihydrofuro [2 , 3-i>] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, 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, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl , 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.
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.
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, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that 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, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 18th ed. , Mack Publishing Company, Easton, PA, 1990, p 1445, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention 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 the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxy1, 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 the present invention. "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. It is preferred that there presently recited compounds do not contain a N-halo, S(0)2H, or S(0)H group.
"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., =0) group, then 2 hydrogens on the atom are replaced. As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state .
"Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit factor Xa. "Therapeutically effective amount" is also intended to include an amount of the combination of compounds claimed that is effective to inhibit factor Xa. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul . 1984, 22:27-55, occurs when the effect (in this case, inhibition of factor Xa) 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 sub-optimal concentrations of the compounds . Synergy can be in terms of lower cytotoxicity, increased antithrombotic effect, or some other beneficial effect of the combination compared with the individual components .
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 (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
The compounds of the present invention of formula I (Scheme 1) where P is not fused onto ring M could be prepared as outlined in Scheme 2 to Scheme 8 and via standard methods known to those skilled in the art.
Scheme 1 P4—P—M—M4 = G-Gi P—M—Z-A-B
Formula I
The compounds of the present invention of formula I where B is imidazole can be prepared as shown in Scheme 2. Commercially available imidazole 2-carboxaldehyde can be used as the starting material. Reductive amination, followed by protection of the amino group can produce the imidazole intermediate 2. Ullman coupling of imidazole 2 with iodide 3 can give the biaryl A-B precursor 4, which can be coupled with 5 using standard coupling conditions to provide 6. Deprotection of the CBZ group, followed by reaction with acid chlorides, carbamoyl chloride, sulfonyl chlorides, and isocyanates can provide compounds of the invention with structures 7, 8, 9, and 10. Similarly, other compounds of the present invention where B is an imidazole derivative could be prepared as shown in Scheme 3 using 2-aminomethylimidazole (JOC, 43 (8), 1978, 1603) as the starting material. Scheme 2
Figure imgf000145_0001
Scheme 3
Figure imgf000146_0001
Compounds of formula I where B is a phenyl derivative can be prepared as shown in Scheme 4. Suzuki coupling of iodide 19 with boronic acid 20 can afford the biaryl intermediate 21, which can be coupled with 5 through standard coupling conditions to give 22. Reductive animation, followed by reactions with acid chlorides, carbamates, sulfonyl chlorides, and isocyanates can provide compounds of this invention having structures 23-26. Scheme 4
Figure imgf000147_0001
Aminopyridyl and aminopyrimidyl A-B analogs (see structures in Scheme 5) can be prepared using routes similar to those of Scheme 4. Scheme 5
Figure imgf000148_0001
Additional Z-linkers to the A-B intermediates can be synthesized by the chemical manipulation of the amino functionality (Scheme 6) of the compounds described above.
Scheme 6
"• A-B.
Figure imgf000148_0002
R = I, OH,
SH or S02C1
Other possible A-B intermediates with various Z- linkers can be synthesized by the methods shown in Scheme 7. The iodo-ester intermediate can be subjected to Ullman and/or Suzuki coupling methodologies to afford A-B intermediates . These intermediates in turn can be homologated via the Arndt Eistert methodology to afford other A-B intermediates. Alternatively, the ester functionality can be reduced to the alcohol that in turn can be converted to a variety of A-B intermediates by procedures known to those skilled in the art. Scheme 7
Figure imgf000149_0001
Non-aromatic intermediates as shown in Scheme 8 can be synthesized via procedures known to those skilled in the art . These intermediates can than be further manipulated to incorporate Ra via procedures previously described.
Scheme 8
Figure imgf000149_0002
A-B
The compounds of formula I (Scheme 1) where P is fused onto ring M can be prepared as outlined in Schemes 9 to 11 and via standard methods known to those skilled in the art. The halogenated intermediates illustrated in these Schemes can be subjected to the Ullman or the Suzuki coupling methodologies to afford the intermediates shown. Further elaboration of these intermediates using the methods described above and by those skilled in the art should provide compounds of the present invention.
Scheme 9
Figure imgf000150_0001
29
27
Scheme 10
Figure imgf000150_0002
30
20 31
Scheme 11
Figure imgf000150_0003
The compounds of this invention and the intermediates described above wherein the B group contains an oxidizable group can be oxidized, e.g. N to N-oxide.
Schemes 2-11 describe how to make the A-B moieties of the present invention and how to couple them to prepare compounds of the present invention. In the above Schemes, the Z group may or may not be present depending on how the A-B group is coupled. The coupling portion of the A-B group could (a) be displaced by the incoming Z or M group, (b) become the Z group, or (c) be incorporated into ring M. The remaining portions of the compounds of the present invention, G-Gx-P-M-Z, G-G^M-P-Z, G-G1-P-M, G-Gi-M-P, G^- M-Z, and G-Gi-M, can be prepared using methods known to those of ordinary skill in the art. All of the following patents and publications are incorporated herein by reference. For compounds wherein ring P is absent and ring M is a 5-, 6-, or 7-membered ring, one of ordinary skill in the art can look to US 5,939,418, US 5,925,635, US
6,057,342, US 6,187,797, US 6,020,357, US 6,060,491, US 5,998,424, US 6,191,159, W098/57951, W099/32454, WO00/039108, WOOO/059902, WO01/32628, WO01/005785, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, and USSN 09/887,936 for starting materials and intermediates to which the present B and/or A-B groups can be coupled. For compounds wherein ring P is fused to ring M (i.e., a bicyclic moiety is present) , one of ordinary skill in the art can look to WO00/39131, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, USSN 60/278,165, and USSN 09/887,850 for starting materials and intermediates to which the present B and/or A-B groups can be coupled.
For compounds wherein G is a ring substituted with a basic moiety, one of ordinary skill in the art can look to US 5,939,418, US 5,925,635, US 6,057,342, US 6,187,797, US 6,020,357, US 6,060,491, US 6,191,159, W098/57951, W099/32454 WOOO/059902, WO01/32628, WO00/39131, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, and USSN 60/278,165 for starting materials and intermediates to form the present G-G -P-M-Z, G-G^M-P-Z, G-Gi-P-M-Z-A, and/or G- G^M-P-Z-A groups to which the present B and/or A-B groups can be coupled. For compounds wherein G is a ring substituted with a non-basic group, one of ordinary skill in the art can look to US' 5,998,424, WO00/39131, WOOO/059902, WO01/32628, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, and USSN 60/278,165 for starting materials and intermediates to form the present G-G -P-M-Z, G-Gx-M-P-Z, G-Gi-P-M-Z-A, and/or G-Gi-M-P-Z-A groups to which the present B and/or A-B groups can be coupled. For compounds wherein G is a bicyclic moiety, one of ordinary skill in the art can look to W098/57951 WO00/039108, WO00/39131, USSN 09/892,319, USSN 60/313,552, USSN 60/246,108, USSN 60/246,125, USSN 60/292,665, USSN 60/278,173, and USSN 60/278,165 for starting materials and intermediates to form the present G-Gi-P-M-Z, G-Gi-M-P-Z, G-Gi-P-M-Z-A, and/or G- G^-M-P-Z-A groups to which the present B and/or A-B groups can be coupled. For compounds wherein A is an indoline or similar bicycle, one of ordinary skill in the art can look to WO01/005785 for starting materials and intermediates to which the present B group can be coupled or from which the present A-B groups can be formed. Scheme 12 illustrates some of the numerous pyrrole intermediates that can be used to prepare compounds of the present invention (Rz is the point of attachment for Z-A-B and can be H, a protecting group, a group modifiable to Z or Z-A, Z, Z-A, or A) . These intermediates are described in the above- noted patents and publications.
Scheme 12
Figure imgf000153_0001
Scheme 13 illustrates some of the numerous imidazole, triazole, and tetrazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. In Scheme 13, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide. In Scheme 13, U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide.
Scheme 13
NH2
Figure imgf000154_0001
Scheme 14 shows some of the numerous pyrazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. Scheme 14
Figure imgf000155_0001
Scheme 15 depicts some of the numerous oxazole, thiazole, isoxazole, oxadiazole, and thiadiazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. In Scheme 15, V is nitro, amino, ester, or acid.
Scheme 15
Figure imgf000156_0001
Scheme 16 illustrates two intermediates useful for making a compound of the present invention wherein ring P is fused to ring M. Scheme 16 also illustrates a number of bicyclic compounds that can be made from these intermediates or derivatives thereof. These intermediates and their modification are described in the above-noted patents and publications.
Scheme 16
tla
Figure imgf000157_0001
Figure imgf000157_0002
Figure imgf000157_0003
Scheme 17 depicts another intermediate useful for making a compound of the present invention wherein ring P is fused to ring M. Scheme 17 also illustrates a number of bicyclic compounds that can be made from this intermediate or derivatives thereof (e.g., the corresponding cyclohexenone) . In Scheme 17, U is OH or morpholine and V is H or C(0)R^a. This intermediate, derivatives thereof, and their modification are described in the above-noted patents and publications.
Scheme 17
Figure imgf000158_0001
Scheme 18 shows another intermediate useful for making a compound of the present invention wherein ring P is fused to ring M. Scheme 18 also illustrates a number of bicyclic compounds that can be made from this intermediate or derivatives thereof. This intermediate, derivatives thereof, and their modification are described in the above- noted patents and publications.
Scheme 18
Figure imgf000159_0001
n = 0-2 n 0-1 n = 0-1
Figure imgf000159_0002
Scheme 19 illustrates a number of other bicyclic rings that are considered to be part of the present bicyclic group, rings P-M. Scheme 19 also describes a method of converting the shown rings to compounds of the present invention. As one of ordinary skill in the art would recognize, this method would be applicable to other heterobicyclics not shown. Scheme 19
Figure imgf000160_0001
sieves
Figure imgf000160_0002
solvent / mol . sieves
Figure imgf000160_0003
Other useful pyrazole intermediates wherein G^ is an amide are exemplified in Scheme 20. Compounds of the present invention wherein the G^ group is other than an amide can be easily manipulated to other linker functionalities according to the methodologies known in the art, including the methodologies outlined in W098/28269 and W098/28282, the contents of both are incorporated herein by reference .
Scheme 20
Figure imgf000161_0001
Me3Al Ψ** G —G
Figure imgf000161_0002
Scheme 21 depicts some of the numerous 6-membered aromatic ring intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. In Scheme 21, V is nitro, protected sulfonamide, or ester group and is a precursor of group Z of the present invention. Scheme 21
Figure imgf000162_0001
Benzo fused dihydro-pyridone intermediates of the present invention can be prepared from readily available starting materials as shown in Scheme 22.
Scheme 22
Figure imgf000162_0002
Other benzo-bicyclics can also be obtained as shown in Schemes 23 and 24.
Scheme 23
Figure imgf000163_0001
Scheme 24
Figure imgf000164_0001
When M is a non-aromatic ring, the compounds of this invention with general structure of Formula I can be synthesized by using similar methods as described previously and by those skilled in the art. One diastereomer of a compound of Formula I may display better activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.
Figure imgf000165_0001
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 pp or using enantiomerically pure acids and bases. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E. Ace . Chem. Res . 2000, 33 , 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.
UTILITY The compounds of this invention are inhibitors of factor Xa and are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals (i.e., factor Xa-associated disorders). In general, a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation) . The term "thromboembolic disorders" as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart. The term "thromboembolic disorders" as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (e.g. after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty) . The thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, atrial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.
The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Diapharma/Chromogenix, West Chester, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was 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, Ki .
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, Km, for substrate hydrolysis was 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, IN) 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 was used to calculate Ki values: (vo-vs)/vs = I/(Ki (1+ S/Km) ) where : v0 is the velocity of the control in the absence of inhibitor; vs is the velocity in the presence of inhibitor; I is the concentration of inhibitor;
Ki is the dissociation constant of the enzyme : inhibitor complex; S is the concentration of substrate; Km is the Michaelis constant. Compounds tested in the above assay are considered to be active if they exhibit a Ki 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 uM. Even more preferred compounds of the present invention have Ki's of <0.01 uM. Still more preferred compounds of the present invention have Ki's of <0.001 uM. Using the methodology described above, a number of compounds of the present invention were found to exhibit Ki's of <10 uM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors .
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 that 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.
The compounds of the present invention may also be useful as inhibitors of serine proteases, notably human thrombin, Factor Vila, Factor IXa, Factor XIa, urokinase, 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.
Some compounds of the present invention were 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 vi tro inhibition constants were determined by the method described by Kettner et al . in 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, TX) was 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, IN) 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, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm that 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. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki of less than 10 μm, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors. 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 the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat a thromboembolic condition or disease.
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" it is meant that a compound of the present invention 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. Additional therapeutic agents include other anticoagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type) , cardiac glycosides, diruetics, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal) , anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti-anxiety agents, anti-proliferative agents, anti-tumor agents, anti- ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid receptor antagonist) , anti- infective agents, anti-viral agents, anti-bacterial agents, and anti-fungal agents.
Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin (either unfractionated heparin or any commercially available low molecular weight heparin) , synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and argatrobanas well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.
The term anti-platelet agents (or platelet inhibitory agents) , as used herein, denotes agents that inhibit platelet function, for example 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, droxica , diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) and piroxicam are preferred. Other suitable platelet inhibitory agents include lib/Ilia antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban) , thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g., dipyridamole) , and pharmaceutically acceptable salts or prodrugs thereof. The term anti-platelet agents (or platelet inhibitory agents) , as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y1 and P2Y12' with P2 χ2 being even more preferred. Preferred P2Y12 receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use. 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, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-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.
The term thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics) , as used herein, denote agents that lyse blood clots (thrombi) . Such agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK) , lanoteplase (nPA) , factor Vila inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors) , alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, 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 EP 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 .
Examples of suitable anti-arrythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone) ; Class II agents (such as carvadiol and propranolol) ; Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide) ; Class IV agents (such as ditiazem and verapamil) ; K+ channel openers such as IAh inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in WO01/40231) . Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil) ; diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone) ; renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril) ; AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan) ; ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat, gemopatrilat and nitrates). Examples of suitable calcium channel blockers (L- type or T-type) for use in combination with the compounds of the present invention include diltiazem, verapamil, nifedipine, amlodipine and mybefradil. Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
Examples of suitable diruetics for use in combination with the compounds of the present invention include: chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, and spironolactone.
Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include sprionolactone and eplirinone . Examples of suitable phospodiesterase inhibitors for use in combination with the compounds of the present invention include: PDE III inhibitors (such as cilostazol) ; and PDE V inhibitors (such as sildenafil) .
Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin) ) ; squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran) ; ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414) .
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g., metformin) ; glucosidase inhibitors (e.g., acarbose) ; insulins (including insulin secretagogues or insulin sensitizers) ; meglitinides (e.g., repaglinide) ; sulfonylureas (e.g., glimepiride, glyburide and glipizide) ; biguanide/glyburide combinations (e.g., glucovance) , thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR- gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1 (GLP-1) , and dipeptidyl peptidase IV (DP4) inhibitors .
Examples of suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline. Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2 inhibitors) ; aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and/or rofecoxib.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene. Examples of suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol . Examples of suitable anti-coagulants for use in combination with the compounds of the present invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin) . Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibitors (such as those disclosed in WO00/59506) .
Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate .
Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.
Examples of suitable anti-ulcer and gastroesophageal reflux disease agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.
Administration of the compounds of the present invention (i.e., a first therapeutic agent) in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent) , preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each (i.e., a synergistic combination) . A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. It is preferred that at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses. Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated. Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone. 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 . 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. Compounds of the present invention may further be useful as diagnostic agents and adjuncts. For example, the present compounds may be useful in maintaining whole and fractionated blood in the fluid phase such as required for analytical and biological testing. The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic disorder (as defined previously) . In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat a thromboembolic disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation) , or any other container used to manufacture, hold, store, or distribute a pharmaceutical product. The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration) . Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
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.
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. 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.
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.
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.
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. 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. 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. 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. 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.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
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 .
Suitable pharmaceutical carriers are described in Remington ' s Pharmaceutical Sciences, 18th ed. , Mack
Publishing Company, Easton, PA, 1990, a standard reference text in this field.
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.
Where the compounds of the present invention 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.
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.
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.
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 that affects 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 low- viscosity 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.
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. Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are afforded for illustration of the invention and are not intended to be limiting thereof.
Example 1 JV- [ (l-{4- [l-(4-Mβthoxyphenyl)-7-oxo-3- (trifluoromethyl) - 1,4, 5,7-tetrahydro-6Jϊ-pyrazolo[3f 4-c]pyridin-6-yl]phenyl}- 1H-imidazol-2-yl) ethyl] -N-methylacetamide, trifluoroacetic acid salt
Figure imgf000186_0001
Part A: Preparation of 6- [4-Iodophenyl] -1,4,5, 6- tetrahydropyrazolo- [3, 4-c] -pyridin-7-one 4-Iodoaniline (45.82 g, 209.2 mmol) and triethylamine
(65.61 mL, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0°C. 5-Bromovaleryl chloride (50. Og, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred overnight. It was then cooled to 0°C and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated and then re-dissolved in ethyl acetate (500 mL) and 3N HCI (500 mL) , extracted with ethyl acetate (2x250 mL) , washed with IN HCI (3x250 mL) , washed with brine (1x250 mL) , and dried (Na2S04) . Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent afforded 51.03 g of the desired product (81%). XHNMR (CDC13) δ 7.70 (d, 2H) , 7.03
(d, 2H) , 3.62 (t, 2H) , 2.56 (t, 2H) , 2.50-1.88 (m, 4H) ppm.
Part B: Preparation of 1- (4-iodophenyl) -3- (4-morpholinyl) - 5, 6-dihydro-2 ( 1H) -pyridinone 6- [4-Iodophenyl] -1,4,5, 6-tetrahydropyrazolo- [3 , 4-c] - pyridin-7-one (85.17 g,282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) were dissolved into CHCI3 (750 mL) and refluxed for 3% hours. The reaction mixture was poured over ice and then quenched further with water. It was extracted with CHC13 (3x400 mL) , washed with brine (1x400 mL) , dried (MgS04) , and concentrated. This residue was dissolved in morpholine (400 mL) and refluxed overnight. The reaction mixture was concentrated and purified by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent to afford 68 g of the morpholine-enamine (63%). 1 NMR (CDC13) δ 7.68 (d, 2H) , 7.11 (d, 2H) , 5.66 (t, 1H) , 3.82 (t, 4H) , 3.77 (t, 2H) , 2.89 (t, 4H) , 2.53-2.47 (m, 2H) ppm.
Part C: Preparation of 1- (4-iodophenyl) -4- (trifluoroacetyl) -2, 3-piperidinedione 4-Dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved into CH2C12 (130 mL) and cooled to 0°C. Trifluoroacetic anhydride (4.54 g, 32.01 mmol) was added and the mixture was stirred at 0°C for 30 min. A solution of the above morpholine-enamine from part B (10.25 g, 26.68 mmol) in CH2C12 (370 mL) was added slowly. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated and purified by silica gel chromatography using 0%-50% ethyl acetate/hexane gradient to isolate the intermediate. The intermediate was dissolved in 20% HCI (50 mL) and diethyl ether (200 mL) and stirred at room temperature overnight. It was then quenched with water, extracted with ether (3x100 mL) , washed with brine (1x100 mL) , and dried (Na2S04) . The residue was re-dissolved in petroleum ether and the undissolved solid was filtered off. The filtrate was concentrated to afford 9.99 g of the desired product (78%) . iHNMR (CDCI3) δ 7.77 (d, 2H) , 7.11 (d, 2H) , 3.93 (t, 2H) , 2.92 (t, 2H) ppm. Part D: Preparation of 1- [4-methoxyphenyl] -3- trifluoromethyl-6- [4-iodophenyl]-l, 4,5,6- tetrahydropyrazolo- [3, 4-c] -pyridin-7-one 1- (4-iodophenyl) -4- (trifluoroacetyl) -2, 3-piperidinedione from Part C (10.0 g, 24.3 mmol) and 4- methoxyphenylhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in HCI (IN, 200 mL) and methanol (400 mL) . The mixture was refluxed overnight. The reaction mixture was cooled to room temperature and quenched with water. It was extracted with ethyl acetate, washed with brine, and dried (Na2S04) . Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent afforded the desired pyrazole 9.28 g (74%). ENMR (CDC13) δ 7.69 (d, 2H) , 7.45 (d, 2H) , 7.06 (d, 2H) , 6.92 (d, 2H) , 4.11 (t, 2H) , 3.81 (s, 3H) , 3.15 (t, 2H) ppm; Mass Spec (M+H)+ 514.3.
Part E: Preparation of benzyl 1H-imidazol-2-yl-methyl- (methyl) carbamate
2-Imidazolecarboxyaldehyde (5.0 g, 52.0 mmol) was suspended in 200 mL of methanol. Methylamine (20 mL of 33% solution in methanol) was added. After stirred for 15 minutes, NaBH (3.95 g, 0.10 mol) was added portion-wise. The reaction mixture was then heated at 50°C for 2 h under N . The solvent was removed. The solid was washed with CH2C12 and filtered. The CH2C12 solution was dried over MgS04, concentrated, and dried under vacuum to give the methylamine as a yellow oil. This oil was dissolved in a 1:1 solution of CH2C12 and THF. To it was added Et3N (7.94 mL, 57.0 mmol) and benzylchloroformate (7.4 mL, 52.0 mmol). The mixture was stirred at room temperature under N2 for 1 h. The solvent was removed and the residue was partitioned between EtOAc and H20. The EtOAc layer was washed with brine, dried over MgS0 , and concentrated. The mixture was refluxed with 15 mL of TFA for 30 minutes to convert most of the bis-acylated byproduct to the desired product. The TFA was removed. It was dissolved in EtOAc and washed with Saturated aqueous NaHC03 and brine. The mixture was dried over MgS04, concentrated, and chromatographed with 1:1 EtOAc/hexane to give 6.56 g off-white solid (51.4% yield). MS (AP+) : 246.3, (M+H) + . ifflIMR (CDCl3 ) : δ 7.35 (s, 6H) , 6.90 (s, 1H) , 5.14 (s, 2H) , 4.48 (s, 2H) , 3.00 (s, 3H) .
Part F: Preparation of benzyl (1- {4- [1- (4-methoxyphenyl) -7- methylene-3- (trifluoromethyl) -1,4, 5, 7-tetrahydro- 6H- pyrazolo [3, 4-c]pyridin-6-yl]phenyl} -Iff-imidazol-2-yl)methyl (methyl) carbamate
benzyl 1H-imidazol-2-ylmethyl (methyl) carbamat (1.17 g, 4.76 mmol) from Part E, 1- [2-trifluoroacetamidomethyl- phenyl] -3-trifluoromethyl-6- [4-Iodo-2-fluorophenyl] -
1, 4, 5, 6-tetrahydropyrazolo- [3 , 4-c] -pyridin-7-one from Part D (1.63 g, 3.18 mmol), Cul (0.12 g, 20%), K2C03 (0.66 g, 4.76 mmol), 1, 10-phenanthroline (56 mg, 20%) were added together with 100 mL of DMSO. The mixture was degassed and then heated at 130°C under N2 for 12 h. The mixture was cooled and aqueous NH4OH (200 mL of of 10% NH40H) was added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgS0 , concentrated, and chromatographed with EtOAc to give 1.34 g of the desired product (66.9%). MS (ES+) : 631.3, (M+H)+. Part G: Preparation of 1- (4-methoxyphenyl) -6- (4- {2- [ (methylamino)methyl] -Iff-imidazol-1-yl}phenyl) -3- (trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pyrazolo [3,4- c]pyridin-7-one bis (trifluoroacetic acid) salt
Bnzyl (l-{4- [1- (4-methoxyphenyl) -7-methylene-3- (trifluoromethyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3 , 4- c] pyridin-6-yl ] phenyl} -IH-imidazol-2-yl ) methyl (methyl) carbamate (100 mg) was heated with 5 mL of TFA at 80°C for 1 h. The solvent was removed and dried under vacuum. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 20.0 mg of the desired product as the bis-TFA salt. MS (ES+) : 497.5, (M+H)+. !HNMR (CDC13) :δ 7.53-7.39 (m, 6H) , 7.27 (s, IH) , 7.20 (s,
IH) , 6.95 (d, 2H) , 4.25 (s, 2H) , 4.23 (t, 2H) , 3.84 (s, 3H) , 3.22 (t, 2H) , 2.74 (s, 3H) .
Part H: Preparation of JV- [ (l-{4- [1- (4- ethoxyphenyl) -7-oxo- 3- (trifluoromethyl) -1,4, 5, 7-tetrahydro-6ff-pyrazolo[3,4- c]pyridin-6-yl]phenyl} -Iff-imidazol-2-yl)methyl] -iV- methylacetamide, trifluoroacetic acid salt
The crude product Part G (100 mg, 0.20 mmol) was dissolved in CH2C12 (10 mL) . Triethylamine (0.11 mL, 0.80 mmol) was added, followed by acetyl chloride (0.03 mL, 0.40 mmol).
The mixture was stirred at room temperature under N for 2 h. It was diluted with CH2C12 and washed with H20 and brine. The organic solution was then dried over MgS0 and concentrated. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a
H20/CH3CN gradient with 0.05% TFA) to give 20.0 mg of the desired product as the TFA salt. MS (ES+) : 539.5, (M+H)+. XHNMR (CDCI3) :δ 7.58-7.44 (m, 7H) , 7.17 (s, IH) , 6.95 (d,
2H) , 4.61 (s, 2H) , 4.23 (t, 2H) , 3.83 (s, 3H) , 3.23 (t, 2H) , 3.18 (s, 3H) , 2.08 (s, 3H) .
Example 2
N- [ (l-{4- [1- (4- ethoxyphenyl) -7-OXO-3- (trifluoromethyl) -
1,4,5, 7-tetrahydro-6H-pyrazolo [3, 4-c]pyridin-6-yl]phenyl} - lH-imidazol-2-yl)methyl] -N-methylacetamide, trifluoroacetic acid salt
Figure imgf000191_0001
The crude product from Part G of Example 1 (100 mg, 0.20 mmol) was dissolved in CH2C12 (10 mL) . Methyl isocyanate (26.0 mg, 2.0 mmol) was added and the mixture was stirred at room temperature under N2 for 1/2 h. It was diluted with CH2C12 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 20.0 mg of the desired product as the
TFA salt. MS (ES+) : 554.5, (M+H)+. XHNMR (CDCl3):δ 7.56
(s, 3H) , 7.45 (d, 3H) , 7.31 (s, IH) , 7.19 (s, IH) , 6.96 (d,
2H) , 4.59 (s, 2H) , 4.23 (t, 2H) , 3.84 (s, 3H) , 3.23 (t,
2H) , 2.98 (s, 3H) , 2.70 (s, 3H) . Example 3
Methyl (l-{4- [1- (4-methoxyphenyl) -7-oxo-3-
(trifluoromethyl) -1,4,5, 7-tetrahydro-6ff-pyrazolo [3,4- c]pyridin-6-yl]phenyl} -Iff-imidazol-2-yl) ethyl
(methyl) carbamate, trifluoroacetic acid salt
Figure imgf000192_0001
The crude product from Part G of Example 1 (120 mg, 0.24 mmol) was dissolved in CHC1 (10 mL) . Triethylamine (0.15 L, 1.08 mmol) was added, followed by methyl chloroformate (0.075 mL, 0.96 mmol). The mixture was stirred at room temperature under N2 for 1 h. It was diluted with CH2C12 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 32.5 mg of the desired product as the TFA salt. MS (ES+) : 555.2, (M+H) + . 1-HNMR (DMSO, 90°C): δ 7.64 (s, IH) , 7.58 (m, 4H) , 7.50 (d, 2H) , 7.01 (d, 2H) , 4.60 (s, 2H) , 4.15 (t, 2H) , 3.81 (s, 3H) , 3.50 (s, 3H) , 3.15 (t, 2H) , 2.75 (s, 3H) .
Example 4
N- [ (l-{4- [1- (4-Methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl]phenyl} -
Iff-imidazol-2-yl)methyl] -N-methylmethanesulfonamide, trifluoroacetic acid salt
Figure imgf000193_0001
The crude product from Part G of Example 1 (200 mg, 0.40 mmol) was dissolved in CH2C12 (10 mL) . Triethylamine (0.25 mL, 1.6 mmol) was added, followed by methanesulfonyl chloride (0.06 mL, 0.80 mmol). The mixture was stirred at room temperature under N for 2 h. It was diluted with
CH2C12 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05%
TFA) to give 50.0 mg of the desired product as the TFA salt. MS (ES+) : 575.4, (M+H)+. iHNMR (CDC13 ) : δ 7.57-7.44
(m, 7H) , 7.25 (s, IH) , 6.96 (d, 2H) , 4.68 (s, 2H) , 4.22 (t, 2H) , 3.83 (s, 3H) , 3.22 (t, 2H) , 2.88 (s, 3H) , 2.81 (s, 3H) .
Example 5
N- [ (l- {4- [1- (4-Methoxyphenyl) -7-OXO-3- (trifluoromethyl) - l, 4, 5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl] phenyl} - lff-imidazol-2-yl)methyl] -JV, 3, 5-trimethyl-4- isoxazolesulf onamide, trifluoroacetic acid salt
Figure imgf000194_0001
This compound was prepared using the same methods as described in Example 4. MS (ES+) : 656.4, (M+H) + . 1BNMR (CD3OD) :δ 7.79 (s, IH) , 7.71 (s, IH) , 7.61 (m, 4H) , 7.46
(d, 2H) , 6.99 (d, 2H) , 4.59 (s, 2H) , 4.21 (t, 2H) , 3.82 (s, 3H) , 3.20 (t, 2H) , 2.79 (s, 3H) , 2.49 (s, 3H) , 2.23 (s, 3H) .
Example 6
6-[4-(2-{ [Acetyl (methyl)amino]methyl}-lff-imidazol-l- yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000194_0002
Part A: Preparation of ethyl (2Z) -chloro [ (4- methoxyphenyl)hydrazono] ethanoate
To p-anisidine (16 g, 0.129 mol) in cone. HCL (40 mL) , 100 mL) H20, cooled to -5°C and sodium nitrite (9.4 g, 0.136 mol) in H20 (60 mL) was added. The reaction mixture was stirred at -5°C for 20 min and a mixture of ethylchloroacetoacetate (22 g, 0.133 mol), ethanol (100 mL) , sodiumacetate (32 g, 0.389 mmol), and H20 (400 mL) was added. The reaction was allowed to warm up to room temperature and stirred for 2h. The product precipitated as a black solid. It was filtered and dried (30 g) . 1HNMR (CDC13) δ 8.28 (s, IH) , 7.18 (d, 2H) , 6.90 (d, 2H) , 4.41 (q, 2H) , 3.80 (s, 3H) , 1.42 (t, 3H) ppm.
Part B: Preparation of ethyl 6- (4-iodophenyl) -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxylate
The product of Part A (30 g, 0.117 mol) was stirred with 1- ( 4-iodophenyl) -3- (4-morpholinyl) -5, 6-dihydro-2 (IH) - pyridinone (29.9 g, 0.078 mol) prepared in Part B of
Example 1 and triethylamine (74 mL, 0.53 mol) at reflux in toluene (400 mL) for 24 h. The reaction mixture was cooled, washed with water, and dried (Na2S04) . It was concentrated and chromatographed with 1:1 EtOAc/hexane to afford 28.8 g (71%) of the ester-iodo product. Mass Spec (M+H)+ 517.9; ifflSIMR (CDCl3) δ 7.70 (d, 2H) , 7.47 (d, 2H) ,
7.09 (d, 2H) , 6.93 (d, 2H) , 4.49 (q, 2H) , 4.18 (t, 2H) , 3.81 (s, 3H) , 3.37 (t, 2H) , 1.45 (t, 3H) ppm.
Part C: Preparation of 2- (methylaminomethyl) imidazole
2-Imidazolecarboxaldehyde (50.0 g, 52.5 mmol) and MeOH (700 mL) were added together in a 2L round-bottomed flask. A solution of methylamine in EtOH (200 mL of 33%) was added. The mixture was stirred at RT under N2 for 30 minutes and NaBH4 (37 g, 100 mmol) was added portionwise in 35 minutes. The resulting mixture was stirred at RT for 1 h, then heated at 552C for 2 h. The solvents were removed in vacuo. The residue was washed with CH2C1 and filtered. The filtrate was washed with brine, dried over MgS04. It was concentrated and dried under vacuum to give 42.7 g of the desired product as a yellow oil. iHNMR (CDC13) δ 6.95 (s, 2H) , 3.85 (s, 2H) , 2.42 (s, 3H) ppm.
Part D: Preparation of ethyl 1- (4-methoxyphenyl) -6- (4- {2- [
(methylamino)methyl] -Iff-imidazol-1-yl}phenyl) -7-oxo-
4,5, 6, 7-tetrahydro-lff-pyrazolo [3, 4-c] pyridine-3-carboxylate 2- (methylaminomethyl) imidazole (2.22 g, 20 mmol), the product from Part B (5.17 g, 10 mmol), Cul (1.9 g, 10 mmol), K2C03 (5.53 g, 40 mmol) were added together with 60 mL of DMSO. The mixture was degassed and then heated at
130°C under N2 for 4 h. The mixture was cooled and aqueous NH4OH (10 mL) was added. The mixture was filtered through
Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed with MeOH:CHCl3 (2% to 4% to 7%) to give 2.1 g of the desired product (41.2%). MS (ES+) : 501.5, (M+HJ + ^HNMR (CDC13) δ
7.49-7.44 (m, 6H) , 7.09 (d, IH) , 7.01 (d, IH) , 6.96-6.91 (m, 2H) , 4.47 (q, 2H) , 4.19 (t, 2H) , 3.82 (s, 3H) , 3.71 (s, 2H) , 3.37 (t, 2H) , 2.4 (s, 3H) , 1.44 (t, 3H) ppm.
Part E: Preparation ethyl 6- [4- (2- { [acetyl (methyl) amino]methyl} -Iff-imidazol-1-yl)phenyl] -l-(4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxylate Product from Part D (500 mg, 0.40 mmol) was acylated with acetyl chloride (66 mg, 0.84 mmol) in CH2C12 (10 mL) and Et3N (120 mg, 1.68 mmol) to give the desired product. The crude product was purified by flash chromatography to give the final product (89 mg) . MS (ES+) : 543.5, (M+H) + . -HNMR (CDC13) δ 7.58-7.44 (m, 7H) , 7.09 (d, IH) , 6.92 (d, 2H) , 4.58 (s, 2H) , 4.47 (q, 2H) , 4.19 (t, 2H) , 3.82 (s, 3H) , 3.41-3.38 (m, 5H) , 2.12 (s, 3H) , 1.44 (t, 3H) ppm.
Part F: Preparation of 6- [4- (2- { [Acetyl (methyl) amino]methyl} -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-oxo-4,5, 6,7-tetrahydro-lff-pyrazolo[3,4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
Product from Part E (115 mg, 0.21 mmol) was dissolved in dioxane (20 mL) and treated with NH40H (20 mL) . The flask was stoppered and the mixture stirred at room temperature for 54 hours. The solvents were removed in vacuo and the residue purified away from remaining starting material by flash chromatography using MeOH:CHCl3 :NH4OH (20:1000:2 to 10:100:1). It was then was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 113 mg of the final product as the TFA salt. MS (ES+) : 514.4, (M+H)+. iHNMR (CD3OD) δ 7.69 (d, 2H) , 7.65-7.57 (m, 5H) , 7.47 (d,
2H) , 6.95 (d, 2H) , 4.68 (s, 2H) , 4.16 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 2.96 (s, 3H) , 2.01 (s, 3H) ppm.
Example 7
6- [4- (2-{ [ethylcarbonyl (methyl) amino]methyl} -Iff-imidazol- l-yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro- lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000198_0001
Part A: Preparation of 1- (4-methoxyphenyl) -6- (4-{2- [ (methylamino)methyl] -Iff-imidazol-1-yl}phenyl) -7-oxo- 4, 5, 6, 7-tetrahydro-Iff-pyrazolo [3, 4-c]pyridine-3-carboxamide
Ethyl 1- (4-methoxyphenyl) -6- (4-{2- [ (methylamino) methyl] - Iff-imidazol-1-yl}phenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxylate from Part D of Example 6 (500 mg, 1 mmol) was dissolved in 8% NH3 in ethylene glycol (10 mL) in a 50 mL pressure tube. The mixture was heated at 85°C for 18 hours. Water was added and the precipitate filtered. This solid was dissolved in EtOAc, washed with water, dried over MgS04, and concentrated in vacuo . The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give the final product as the bis-TFA salt. MS (ES+) : 472.5, (M+H) + . iHNMR (CD3OD) δ 7.55 (d, 2H) , 7.49-7.43 (m, 4H) , 7.38 (d,
IH) , 7.17 (d, IH) , 6.95 (d, 2H) , 4.24 (s, 2H) , 4.14 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 2.70 (s, 3H) ppm.
Part B: Preparation of 6- [4- (2-{ [ethylcarbonyl (methyl) amino]methy } -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-OXO-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
Product from Part A (250 mg, 0.53 mmol), propionic acid (111 mg, 1.5 mmol), and triethylamine (500 mg, 5 mmol) in EtOAc (20 L) were treated with O-benzotriazol-1-yl- N,N,N' ,N'-tetramethyluronium hexafluorophosphate (569 mg, 1.5 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with
0.05% TFA) to give 183 mg of the final product as the TFA salt. MS (ES+) : 528.5, (M+H)+. 3-HNMR (CD30D) δ 7.72 (d, IH) , 7.65-7.63 (m, 5H) , 7.51 (d, 2H) , 7.00 (d, 2H) , 4.73 (s, 2H) , 4.20 (t, 2H) , 3.84 (s, 3H) , 3.36-3.34 ( , 2H) , 2.97 (s, 3H) , 2.34 (q, 2H) , 1.03 (s, 3H) ppm.
Example 8 6- [4-(2-{ [n-propylcarbonyl (methyl) amino]methyl}-lff- imidazol-1-yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6,7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000199_0001
This compound was prepared by the same methods described in Example 7. MS (ES+) : 542.5, (M+H) + . XHNMR (CD30D) δ 7.68 (d, IH) , 7.64-7.56 (m, 5H) , 7.47 (d, 2H) , 6.96 (d, 2H) , 4.84 (s, 2H) , 4.16 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 2.94 (s, 3H) , 2.25 (t, 2H) , 1.50 (q, 2H) , 0.88 (t, 3H) ppm. Example 9
6-[4-(2-{[i-propylcarbonyl (methyl) amino]methyl} -lff- imidazol-1-yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6,7- tetrahydro-lff-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000200_0001
This compound was prepared by the same methods described in Example 6. MS (ES+) : 486.5, (M+H) + . ^-HNMR (CD30D) δ 7.68 (d, IH) , 7.65-7.60 (m, 5H) , 7.49-7.46 (m, 2H) , 6.97-6.94
(m, 2H) , 4.67 (s, 2H) , 4.16 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 3.00 (s, 3H) , 2.82-2.78 (m, IH) , 0.98 (d, 6H) ppm.
Example 10 6- [4- (2-{ [i-butylcarbonyl (methyl) amino]methyl}-lff- imidazol-1-yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6,7- tetrahydro-lff-pyrazolo[3,4-σ]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000200_0002
This compound was prepared by the same methods described in Example 7. MS (ES+) : 556.5, (M+H) + . iHNMR (CD3OD) δ 7.70 (d, IH) , 7.66-7.59 (m, 5H) , 7.51-7.48 (m, 2H) , 6.99-6.96 (m, 2H) , 4.70 (s, 2H) , 4.18 (t, 2H) , 3.82 (s, 3H) , 3.34 (t, 2H) , 2.97 (s, 3H) , 2.18 (d, 2H) , 2.12-1.95 (m, IH) , 0.89 (d, 6H) ppm.
Example 11
1- (4-Methoxyphenyl) -6-{4- [2- ( {methyl [
(methylamino) carbonyl] -amino}methyl) -Iff-imidazol-1- yl] phenyl} -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000201_0001
Part A: Preparation of ethyl 1- (4-methoxyphenyl) -6- {4- [2- ( {methyl [ (methylamino) carbonyl] amino}methyl) -Iff-imidazol- 1-yl]phenyl} -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- σ]pyridine-3-carboxylate
The product from Part D of Example 6 (200 mg, 0.40 mmol) was dissolved in CH2C12 (10 mL) . Methyl isocyanate (228 mg, 4.0 mmol) was added and the mixture was stirred at room temperature under N2 for 18 h. It was diluted with CH2C12 and washed with H0 and brine. The organic solution was then dried over MgS04 and concentrated in vacuo. The crude product was purified by flash chromatography using MeOH:CHCl3 (1% to 3%) to give 86 mg of the final product. MS (ES+) : 558.5, (M+H)+. iHNMR (CDC13) δ 7.56-7.45 (m,
8H) , 6.94-6.90 (m, 2H) , 4.62 (s, 2H) , 4.47 (q, 2H) , 4.19 ( t , 2H) , 3 . 82 ( s , 3H) , 3 . 42 -3 . 38 (m, 2H) , 3 . 22 ( s , 3H) , 2 . 74 ( s , 3H) , 1 . 44 ( t , 3H) ppm .
Part B: Preparation of 1- (4-methoxyphenyl) -6- {4- [2- ( {methyl [ (methylamino) carbonyl] -amino}methyl) -lff-imidazol- 1-yl]phenyl} -7-oxo-4,5,6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
This compound was prepared using the same methods as described in Part F of Example 6 using the product from Part A as the starting material. MS (ES+) : 529.4, (M+H)+. XHNMR (CD30D) δ 7.69 (d, IH) , 7.65-7.61 (m, 5H) , 7.49 (d,
2H) , 6.98 (d, 2H) , 4.65 (s, 2H) , 4.18 (t, 2H) , 3.82 (s, 3H) , 3.34 (t, 2H) , 2.78 (s, 3H) , 2.65 (s, 3H) ppm.
Example 12
Methyl (l-{4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -7-oxo- 1, 4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl]phenyl} - Iff-imidazol-2-yl)methyl (methyl) carbamate, trifluoroacetic acid salt
Figure imgf000202_0001
Part A: Preparation of ethyl 6-[4-(2-{[ (methoxycarbonyl) (methyl) amino]methyl}-Iff-imidazol-1-yl)phenyl] -1- (4- ethoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- σ]pyridine-3-carboxylate
Ethyl 1- (4-methoxyphenyl) -6- (4-{2- [ (methylamino) methyl ] - lff-imidazol-l-yl}phenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxylate from Part D of Example 6 (200 mg, 0.4 mmol) was dissolved in CH2C1 (10 mL) . Triethylamine (191 mg, 1.9 mmol) was added, followed by methyl chloroformate (159 mg, 1.68 mmol) . The mixture was stirred at room temperature under N2 for 18 h. It was diluted with CH2C12 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by flash chromatography using MeOH:CHCl3 (1% to 3%) as elutent to give 84 mg of the final product. MS (ES+) : 559.5, (M+H)+. 1ENMR (CD30D) δ 7.51-7.38 (m, 8H) , 6.86 (d, 2H) , 4.67 (bs, 2H) , 4.41 (q, 2H) , 4.13 (t, 2H) , 3.76 (s, 3H) , 3.53 (bs, 3H) , 3.32 (t, 2H) , 3.08 (bs, 3H) , 1.38 (t, 3H) ppm.
Part B: Preparation of Methyl (1- {4- [3- (aminocarbonyl) -1-
(4-methoxyphenyl) -7-oxo-1, 4,5, 7-tetrahydro-6ff-pyrazolo [3,4- c]pyridin-6-y1]phenyl}-Iff-imidazol-2-y1)methyl (methyl) carbamate, trifluoroacetic acid salt
This compound was prepared using the same methods as described in Part F of Example 6 using the product from
Part A as the starting material. MS (ES+) : 530.4, (M+H) + . !HNMR (CD3OD) δ 7.70 (d, IH) , 7.65-7.61 (m, 5H) , 7.49 (d,
2H) , 6.98 (d, 2H) , 4.75-4.68 (m, 2H) , 4.18 (t, 2H) , 3.82 (s, 3H) , 3.68-3.13 (m, 3H) , 3.34 (t, 2H) , 2.84 (s, 3H) ppm.
Example 13
Ethyl (l-{4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -7-oxo-
1,4, 5, 7-tetrahydro-6ff-pyrazolo[3, 4-c]pyridin-6-yl]phenyl}-
Iff-imidazol-2-yl)methyl (methyl) carbamate, trifluoroacetic acid salt
Figure imgf000204_0001
1- (4-Methoxyphenyl) -6- (4-{2- [ (methylamino) methyl] -lff- imidazol-1-yl}phenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxamide from Part A of
Example 7 (25 mg, 0.036 mmol) was suspended in CHC1 (5 mL) . Triethylamine (36 mg, 0.36 mmol) was added, followed by ethyl chloroformate (4.3 mg, 0.04 mmol). The mixture was stirred at room temperature under N for 18 h. The solvent was removed in vacuo . The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 18 mg of the final product as the TFA salt. MS (ES+) : 544.5, (M+H)+. !HNMR (CD3OD) δ 7.72-7.59 (m, 6H) , 7.48 (d, 2H) , 6.96 (d, 2H) , 4.75-4.63 (m, 2H) , 4.16 (t, 2H) , 4.10-4.00 (m, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 2.83 (s, 3H) , 1.22- 1.02 (m, 3H) ppm.
Example 14 1- (4-Methoxyphenyl) -6- [4- (2- { [methyl
(methylsulfonyl) amino] -methyl}-lff-imidazol-l-yl)phenyl] -7- oxo-4, 5,6,7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt
Figure imgf000205_0001
Part A: Preparation of ethyl 1- (4-methoxyphenyl) -6- [4- (2- { [methyl (methylsulfonyl)amino]methyl} -Iff-imidazol-1- yl)phenyl] -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxylate
Ethyl 1- (4-methoxyphenyl) -6- (4-{2- [ (methylamino) methyl ] - lff-imidazol-l-yl}phenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxylate from Part D of Example 6 (200 mg, 0.40 mmol) was dissolved in CH2C12 (10 mL) . Triethylamine (170 mg, 1.68 mmol) was added, followed by methanesulfonyl chloride (96 mg, 0.84 mmol) . The mixture was stirred at room temperature under N2 for 18 h.
It was diluted with CH2C12 and washed with H 0 and brine. The organic solution was then dried over MgS04 and concentrated in vacuo . The residue was purified by flash chromatography using MeOH:CHCl3 (1% to 3%) to 82 mg of the final product. MS (ES+) : 579.5, (M+H) + . 1mMR (CDC13) δ
7.58-7.42 (m, 8H) , 6.93 (d, 2H) , 4.77 (s, 2H) , 4.47 (q, 2H) , 4.19 (t, 2H) , 3.82 (s, 3H) , 3.38 (t, 2H) , 2.96 (s, 3H) , 2.91 (s, 3H) , 1.44 (t, 3H) ppm.
Part B: Preparation of l-(4-Methoxyphenyl) -6- [4- (2-{ [methyl (methylsulfonyl) amino] -methyl} -Iff-imidazol-1-yl)phenyl] -7- oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt This compound was prepared using the same methods as described in Part F of Example 6 using the product from Part A as the starting material. MS (ES+) : 550.4, (M+H)+. !HNMR (CD30D) δ 7.78 (d, IH) , 7.70-7.61 (m, 5H) , 7.52 (d, 2H) , 7.09 (d, 2H) , 4.62 (s, 2H) , 4.19 (t, 2H) , 3.84 (s, 3H) , 3.36 (t, 2H) , 2.89 (s, 3H) , 2.84 (s, 3H) ppm.
Example 15
1- (4-Methoxyphenyl)-6-[4-(2-{ [methyl (n- propylsulfonyl) amino] -methyl} -Iff-imidazol-l-yl)phenyl] -7- oxo-4,5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt
Figure imgf000206_0001
1- (4-Methoxyphenyl) -6- (4- {2- [ (methylamino) methyl] -lff- imidazol-1-yl}phenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxamide from Part A of Example 7 (25 mg, 0.03 mmol) was suspended in CH2C12 (5 mL) . Triethylamine (36 mg, 0.36 mmol) was added, followed by propanesulfonyl chloride (16.8 mg, 0.12 mmol). The mixture was stirred at room temperature under N2 for 18 h.
The solvent was removed in vacuo . The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 14 mg of the final product as the TFA salt. MS (ES+) :
578.4(M+H)+. iHNMR (CD3OD) δ 7.72-7.56 (m, 6H) , 7.47 (d, 2H) , 6.95 (d, 2H) , 4.61 (s, 2H) , 4.15 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 3.00-2.95 (m, 2H) , 2.79 (s, 3H) , 1.74- 1.67 (m, 2H) , 0.97 (t, 2H) ppm.
Example 16 6-[4-(2-{ [ [ (3, 5-dimethyl-4-isoxazolyl) sulfonyl] (methylamino]methyl} -Iff-imidazol-1-yl)phenyl] -1- (4-methoxyphenyl) ■ 7-oxo-4,5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt
Figure imgf000207_0001
This compound was prepared using the same methods as described in Example 14. MS (ES+) : 631.4, (M+H) + . iHNMR (CD30D) δ 7.81 (d, IH) , 7.73 (d, IH) , 7.66-7.58 (m, 4H) , 7.50 (d, 2H) , 6.99 (d, 2H) , 4.59 (s, 2H) , 4.18 (t, 2H) , 3.82 (s, 3H) , 3.35 (t, 2H) , 2.80 (s, 3H) , 2.50 (s, 3H) , 2.25 (s, 3H) ppm.
Example 17 1- (4-Methoxyphenyl) -6- [4- (2-{ [methyl (phenylsulfonyl) amino] - methyl} -Iff-imidazol-1-yl)phenyl] -7-oxo-4, 5, 6, 7-tetrahydro- lff-pyrazolo [3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000208_0001
This compound was prepared using the same methods as described in Example 14. MS (ES+) : 612.4, (M+H) + . iHNMR (CD3OD) δ 7.82 (d, IH) , 7.75 (d, IH) , 7.69-7.57 (m, 9H) ,
7.53 (d, 2H) , 7.00 (d, 2H) , 4.40 (s, 2H) , 4.21 (t, 2H) , 3.85 (s, 3H) , 3.37 (t, 2H) , 2.72 (s, 3H) ppm.
Example 18 6-[4-(2-{[Acetyl(ethyl)amino]methyl}-lff-imidazol-l- yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4,5, 6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000208_0002
Part A: Preparation of N- [2- (ethylaminomethyl) ] -lff- imidazole
2-Imidazolecarboxyaldehyde (2.5 g, 26 mmol) was suspended in 100 mL of methanol. Ethylamine (2.0 M in THF) was added. After stirring for 30 minutes at room temperature, NaBH (1.98 g, 52 mmol) was added portion-wise. The reaction mixture was then heated at 50°C for 2 h under N . The solvent was removed. The solid was washed with CH2C12 and filtered. The CH2C1 solution was dried over MgS04, concentrated, and dried under vacuum to afford 3.4g of final product as a yellow oil. 1 NKR (CDC13) δ 7.04 (s, 2H) , 3.91 (s, 2H) , 2.69 (q, 2H) , 1.12 (t, 3H) ppm.
Part B: Preparation of 6- (4-iodophenyl) -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- c] yridine-3-carboxamide
Ethyl 6- (4-iodophenyl) -1- (4-methoxyphenyl) -7-oxo-4 ,5,6,7- tetrahydro-lff-pyrazolo[3 , 4-c]pyridine-3-carboxylate from Part B of example 6 (3.0 g, 5.8 mmol) was suspended in 8% NH3 in ethylene glycol (30 mL) in a 100 mL pressure tube.
The mixture was heated at 85°C for 18 hours. Water was added, and the precipitate was filtered and washed with water. The crude product was dried under vacuum to afford 3.2 g of final product. MS (ES+) : 489.2 (M+H) + . iHNMR (DMSO-d6) δ 7.72-7.68 (m, 3H) , 7.49-7.41 (m, 3H) , 7.15 (d, 2H) , 6.97 (d, 2H) , 4.00 (t, 2H) , 3.77 (s, 3H) , 3.16 (t, 2H) ppm.
Part C: Preparation of 6- (4- {2- [ (ethylamino)methyl] -Iff-imidazol- l-yl}phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide, bis (trifluoroacetic acid) salt
2- (Ethylaminomethyl) imidazole (250 mg, 2 mmol), 6- (4- iodophenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro- lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide from Part B (488 mg, 1.02 mmol), Cul (190 mg, 1 mmol), K2C03 (552 mg, 4 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130°C under N2 for 4 h. The mixture was cooled and aqueous NH 0H (1 mL) was added.
The mixture was filtered through Celite® and washed with EtOAc . The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgS0 , concentrated in vacuo, and chromatographed with MeOH:CHCl3 :NH40H (20:1000:2 to
70:1000:7) to give the desired product. The product was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 170 mg of the final product as the TFA salt. MS (ES+) : 486.5, (M+H) + . iHNMR (CD3OD) δ 7.56 (d, 2H) , 7.49-
7.44 (m, 4H) , 7.38 (d, IH) , 7.18 (d, IH) , 6.96 (d, 2H) , 4.25 (s, 2H) , 4.14 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 3.08 (q, 2H) , 1.25 (t, 2H) ppm.
Part D: Preparation of 6- [4- (2-
{ [Acetyl (ethyl) amino]methyl} -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxamide, trifluoroacetic acid salt
This compound was prepared by the same methods described in Example 7 using the product from Part A as the starting material. MS (ES+) : 528.5, (M+H)+. iHNMR (CD30D) δ 7.68
(d, IH) , 7.63-7.59 (m, 5H) , 7.48 (d, 2H) , 6.96 (d, 2H) , 4.64 (s, 2H) , 4.16 (t, 2H) , 3.80 (s, 3H) , 3.36-3.28 (t, 4H) , 2.05 (s, 3H) , 1.10 (t, 3H) ppm.
Example 19 6-[4-(2-{ [Acetyl (n-propyl) amino]methyl}-Iff-imidazol-1- yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000211_0001
Part A: Preparation of N- [2- (n-propylaminomethyl) ] -lff- imidazole 2-Imidazolecarboxyaldehyde (2.5 g, 26.0 mmol) was suspended in 100 mL of methanol. N-Propylamine (1.53 g, 26 mmol) was added. After stirring for 30 minutes, NaBH (1.97 g, 52 mmol) was added portion-wise. The reaction mixture was then heated at 50°C for 2 h under N2. The solvent was removed. The solid was washed with CH C12 and filtered.
The CH2C12 solution was dried over MgS04, concentrated, and dried under vacuum to give 3.39 g of final product as a yellow oil. MS (AP+) : 140.1, (M+H)+. iHNMR (CDC13 w/CD30D) δ 6.95 (s, 2H) , 3.82 (s, 2H) , 2.56 (t, 2H) , 1.56-1.47 (m, 2H) , 0.93 (t, 3H) ppm.
Part B: Preparation of 1- (4-methoxyphenyl) -7-oxo-6- (4-{2- [ (propylamino)methyl] -Iff-imidazol-1-yl}phenyl) -4, 5, 6,7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, bis (trifluoroacetic acid) salt
2- (Propylaminomethyl) imidazole (562 mg, 4.1 mmol), the product from Part B of Example 18 (1.0 g, 2.05 mmol), Cul (390 mg, 2.65 mmol), K2C03 (1.13 g, 8.2 mmol) were added together with 12 mL of DMSO. The mixture was degassed and then heated at 130°C under N2 for 4 h. The mixture was cooled and aqueous NH 0H was added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgS0 , concentrated in vacuo, and chromatographed with MeOH: CHC13:NH40H (20:1000:2 to 70:1000:7) to give the desired product. The product was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 342 mg of the final product as the TFA salt. MS
(ES+) : 500.5, (M+H)+. iHNMR (CD3OD) δ 7.56 (d, 2H) , 7.49- 7.44 (m, 4H) , 7.41 (d, IH) , 7.22 (d, IH) , 6.95 (d, 2H) , 4.27 (s, 2H) , 4.14 (t, 2H) , 3.80 (s, 3H) , 3.32 (t, 2H) , 3.01-2.95 (m, 2H) , 1.75-1.60 (m, 2H) , 0.95 (t, 3H) ppm.
Part C: Preparation of 6- [4- (2- { [Acetyl (n- propyl) amino]methyl} -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxamide, trifluoroacetic acid salt This compound was prepared by the same methods described in Example 7 using the product from Part B as the starting material. MS (ES+) : 542.4, (M+H)+. iHNMR (CD3OD) δ 7.69
(d, IH) , 7.65-7.57 (m, 5H) , 7.48 (d, 2H) , 6.96 (d, 2H) ,
4.64 (s, 2H) , 4.17 (t, 2H) , 3.80 (s, 3H) , 3.33 (t, 2H) , 3.23-3.18 (m, 2H) , 2.04 (s, 3H) , 1.58-1.43 (m, 2H) , 0.84 (t, 3H) ppm.
Example 20 6- [4-(2-{ [Acetyl (n-propyl) amino]methyl} -Iff-imidazol-1- yl)phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000213_0001
Part A: Preparation of N- [2- (i-propylaminomethyl) ] -lff- imidazole 2-Imidazolecarboxyaldehyde (2.5 g, 26.0 mmol) was suspended in 100 mL of methanol. Isopropylamine (1.54 g, 26 mmol) was added. After stirring for 30 minutes, NaBH4 (1.97 g,
52 mmol) was added portion-wise. The reaction mixture was then heated at 50°C for 2 h under N2. The solvent was removed. The solid was washed with CH2C12 and filtered.
The CH C12 solution was dried over MgS04, concentrated, and dried under vacuum to give 3.7 g of final product as a yellow oil. MS (AP+) : 140.1, (M+H)+. 1H MR (CDC13 w/CD3OD) δ 6.82 (s, 2H) , 3.69 (s, 2H) , 2.73-2.65 (m, IH) , 0.97 (s, 6H) ppm.
Part B: Preparation of 6- (4-{2- [ (isopropylamino)methyl] -lff- imidazol-1-yl}phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5, 6,7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, bis (trifluoroacetic acid) salt
2- (Isopropylaminomethyl) imidazole (562 mg, 4.1 mmol), the product from Part B of Example 18 (1.0 g, 2.05 mmol), Cul (390 mg, 2.65 mmol), K2C03 (1.13 g, 8.2 mmol) were added together with 12 mL of DMSO. The mixture was degassed and then heated at 130°C under N2 for 4 h. The mixture was cooled and aqueous NH40H was added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed with MeOH:CHCl3 :NH40H (20:1000:2 to 70:1000:7) to elute desired product. The product was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 359 mg of the final product as the TFA salt. MS (ES+) : 500.4, (M+H)+ 1HNMR (CD3OD) δ 7.56 (d, 2H) , 7.49-
7.44 (m, 4H) , 7.38 (s, IH) , 7.18 (s, IH) , 6.96 (d, 2H) , 4.24 (s, 2H) , 4.15 (t, 2H) , 3.80 (s, 3H) , 3.42-3.38 (m, IH) , 3.32 (t, 2H) , 1.26 (d, 6H) ppm.
Part C: Preparation of 6- [4- (2- { [Acetyl (n- propyl) amino]methyl} -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- c] yridine-3-carboxamide, trifluoroacetic acid salt
This compound was prepared by the same methods described in Example 7. MS (ES+) : 542.5, (M+H) + . l-HNMR (CD3OD) δ 7.70-
7.60 (m, 6H) , 7.48 (d, 2H) , 6.96 (d, 2H) , 4.51 (s, 2H) , 4.28-4.21 (m, IH) 4.17 (t, 2H) , 3.80 (s, 3H) , 3.33 (t, 2H) , 2.17 (s, 3H) , 1.16 (d, 6H) ppm.
Example 21
6- [4- (2-{ [ethylcarbonylamino]methyl}-lff-imidazol-l- yDphenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluoroacetic acid salt
Figure imgf000215_0001
Part A: Preparation of N- [2- (aminomethyl) ] -lff-imidazole bis (hydrochloric acid) salt Imidazole (6.8 g, 100 mmol) and benzoyl chloride were added together in acetonitrile (200 mL) . Triethylamine (40.4 g, 400 mmol) was added dropwise and the mixture stirred at room temperature for 18 hours . The precipitate was filtered off and washed with water and then dried under vacuum to afford 12.3 g of white solid. This solid was suspended in MeOH (150 mL) . Iso-propanol saturated with HCI (30 mL) was then added and the mixture stirred at reflux for 18 hours. The solvents were, removed in vacuo and the solid washed with acetone and dried under vacuum to afford 2.81 g of off-white solid as final product. -HNMR (CD30D) δ 7.66 (s, 2H) , 4.89 (bs, 2H) ppm.
Part B: Preparation of 6- {4- [2- (aminomethyl) -Iff-imidazol-1- yl]phenyl} -1- (4-methoxyphenyl) -7-oxo-4,5,6, 7-tetrahydro-lff- pyrazolo [3, 4-c]pyridine-3-carboxamide
N- [2- (aminomethyl) ] -lff-imidazole bis (hydrochloric acid) salt (333 mg, 1.96 mmol), the product from Part B of Example 18 (500 mg, 1.2 mmol), Cul (186 mg, 0.98 mmol), K2C03 (1.082 g, 7.84 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130°C under N2 for 4 h. The mixture was cooled and aqueous NH40H was added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgS04, concentrated in vacuo, and chromatographed with MeOH:CHCl3:NH4OH (20:1000:2 to 20:100:2) to give 30 mg of desired product. MS (ES+) : 458.4, (M+H)+. XHNMR (CD30D) δ
7.56 (d, IH) , 7.49-7.43 (m, 4H) , 7.37 (d, IH) , 7.16 (d,
IH) , 6.96 (d, 2H) , 4.15 (s, 2H) , 3.80 (s, 3H) , 3.28 (t, 2H) ppm.
Part C: Preparation of 6- [4- (2-
{ [ethylcarbonylamino]methyl} -Iff-imidazol-1-yl)phenyl] -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxamide, trifluoroacetic acid salt This compound was prepared by the same methods described in Example 7 using the product from Part B as the starting material. MS (ES+) : 514, (M+H) + . iHNMR (CD3OD) δ 7.69 (d, IH) , 7.65-7.52 (m, 5H) , 7.49 (d, 2H) , 6.97 (d, 2H) , 4.52 (s, 2H) , 4.17 (t, 2H) , 3.81 (s, 3H) , 3.33 (t, 2H) , 2.16 (q, 2H) , 1.02 (t, 2H) ppm.
Example 22 N- I (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1, 4, 5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl]phenyl} - Iff-imidazol-2-yl)methyl] -JV-methylacetamide trifluoroacetic acid salt
Figure imgf000217_0001
Part A: Preparation of (1Z) -1- [chloro
(methylsulfonyl)methylene] -2- (4-methoxyphenyl)hydrazine To a solution of p-anisidine (4.39 g, 3.6 mmol) in con. HCI (9.2 mL) and water (20 mL) at 0°C was slowly added sodium nitrite (2.58 g, 3.7 mmol) in water (20 mL) . The reaction mixture was stirred at 0°C for 0.5 h. The above mixture was poured into a mixture of 3-chloromethanesulphonyl acetone (Grossert, JS, et al . , Can. J. Chem. Vol 62, 1984, 798) (6.1 g, 3.5 mmol), acetone (50 mL) , sodium acetate (6.7 g, 8.2 mmol), and water (100 mL) . The resulting mixture was stirred for 4 h at rt . The precipitate was filtered-off and dried to afford the hydrazone as a red solid (5.28 g, 57%); XHNMR (CDC13) δ 8.05 (s, IH) , 7.12 (d, 2H) , 6.91 (d, 2H) , 3.80 (s, 3H) , 3.23 (s, 3H) ppm.
Part B: Preparation of 6- (4-iodophenyl) -1- (4- methoxyphenyl) -3- (methylsulfonyl) -1, 4, 5, 6-tetrahydro-7ff- pyrazolo [3, 4-c]pyridin-7-one
The product of Part A (2.60 g, 10 mol) was stirred with 1- (4-iodophenyl) -3- (4-morpholinyl) -5, 6-dihydro-2 (lff)- pyridinone (3.80 g, 10 mol) prepared in Part B of Example 1 and triethylamine (2.76 mL, 20 mol) in EtOAc (30 mL) . The mixture was heated at 70aC under N for 12 h. The reaction mixture was cooled to 5SC, aqueous HCI (12.4 mL of 4N) was added deropwise. The cooling bath was removed and the mixture was stirred at RT for 4 h. A small amount of hexane (5 mL) and water (10 mL) were added. The precipitate formed was filtered, washed with water and hexane, and dried to afford 4.15 g (80%) of the desired product. iHNMR (CDC13) δ 7.66 (d, 2H) , 7.44 (d, 2H) , 7.05
(d, 2H) , 6.90 (d, 2H) , 4.08 (t, 2H) , 3.80 (s, 3H),3.35(t, 2H) , 3.28 (s, 3H) ppm.
Part C: Preparation of. 1- (4-methoxyphenyl) -6- (4-{2- [ (methylamino)methyl] -Iff-imidazol-1-yl}phenyl) -3-
(methylsulfonyl)-l,4,5,6-tetrahydro-7ff-pyrazolo[3,4- c]pyridin-7-one
The product from Part B (4.15 g, 7.94 mmol), 2- (methylaminmethyl) imidazole from Part C of Example 6.(1.93 g, 16.67 mmol), K2C03 (4.39 g, 31.76 mmol), Cul (1.51 g, 7.94 mmol) were added together with 50 mL of DMSO. The mixture was degassed and then heated at 130aC under N for
4 h. The mixture was cooled, EtOAc and 8% aqueous NH OH were added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The aqueous layer was extracted with CHC13 again. The EtOAc and CHC13 extratcts were washed with water and brine and dried over MgS04 separately. They were then combined, concentrated, and chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH to give 2.79 g of the desired product. This material was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with
0.05% TFA) to give 2.5 g of the bis-TFA salt. MS (ES+) : 507.4, (M+H) + . l-HNMR (DMSO-d6) δ 7.60-7.02 (m, 10H) , 4.28
(s, 2H) , 4.16 (t, 2H) , 3.82 (s, 3H) , 3.38 (s, 3H) , 3.25 (t, 2H) , 2.65 (s, 3H) ppm. Part D: Preparation of JV-[(l-{4-[l-(4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-1,4,5, 7-tetrahydro-6ff-pyrazolo [3,4- c] pyridin-6-yl] phenyl} -Iff-imidazol-2-yl) ethyl] - N- methylacetamide trifluoroacetic acid salt
Product from Part C (119.0 mg, 0.16 mmol), acetic acid (9.26 μL, 0.16 mmol), triethylamine (79.4 μL, 0.57 mmol), and HBTU (61.5 mg, 0.16 mmol) were added together with DMF (5 mL) . The mixture was stirred at RT under N2 for 12 h. Water was added, followed by aqueous NaOH to adjust the pH to 8-9. It was then extracted with EtOAc. The organic layer was washed with water and brine, concentrated, and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give the final product as the TFA salt (84 mg) . MS (ES+) :
549.4(M+H) + . iHNMR (CD3OD) . δ 7.71-7.60 (m, 6H) , 7.49 (d,
2H) , 6.98 (d, 2H) , 4.72 (s, 2H) , 4.22(t, 2H) , 3.83 (s, 3H) , 3.33 (t, 2H) , 3.30 (s, 3H) 3.00 (s, 3H) , 2.04 (s, 3H) ppm.
Example 23
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-
1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c] pyridin-6-yl]phenyl} -
Iff-imidazol-2-yl)methyl] -JV-methylpropanamide trifluoroacetic acid salt
Figure imgf000219_0001
This compound was prepared by the same methods described in Example 22. MS (ES+) : 563.5(M+H)+. !HNMR (CD3OD) δ 7.71- 7.60 (m, 6H) , 7.52 (d, 2H) , 7.02 (d, 2H) , 4.72 (s, 2H) , 4.23 (t, 2H) , 3.85 (s, 3H) , 3.31 (t, 2H) , 3.30 (s, 3H) 2.97 (s, 3H) , 2.34 (q, 2H) , 1.02 (t, 3H) ppm.
Example 24 N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5,7-tetrahydro-6ff-pyrazolo [3, 4-c] pyridin-6-yl]phenyl}- Iff-imidazol-2-yl)methyl] -iV-methylbutanamidetrifluoroacetic acid salt
Figure imgf000220_0001
This compound was prepared by the same methods described in Example 22. MS (ES+) : 577.3 (M+H) + . 1ΗNMR (CD30D) δ 7.67-
7.57 (m, 6H) , 7.48 (d, 2H) , 6.96 (d, 2H) , 4.68 (s, 2H) , 4.19 (t, 2H) , 3.81 (s, 3H) , 3.27 (t, 2H) , 3.26 (s, 3H) 2.93 (s, 3H) , 2.24 (t, 2H) , 1.50 (m, 2H) , 0.87 (t, 3H) ppm.
Example 25 iV- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-
1, 4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl]phenyl} -
Iff-imidazol-2-yl)methyl] -JV, 2-dixnethylpropanamide trifluoroacetic acid salt
Figure imgf000221_0001
This compound was prepared by the same methods described in Example 22. MS (ES+) : 577.3 (M+H)+. !HN R (CD3OD) δ 7.71-
7.62 (m, 6H), 7.51 (d, 2H) , 7.00 (d, 2H) , 4.70 (s, 2H) , 4.23 (t, 2H) , 3.85 (s, 3H) , 3.34 (t, 2H) , 3.29 (s, 3H) 3.04 (s, 3H) , 2.84 (m, IH) , 1.01 (d, 6H) ppm.
Example 26
ΛT- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-
1, 4,5,7-tetrahydro-6ff-pyrazolo[3, 4-c]pyridin-6-yl]phenyl} - lff-imidazol-2-yl)methyl] -JY-methylcyclopropanecarboxamide trifluoroacetic acid salt
Figure imgf000221_0002
This compound was prepared by the same methods described in Example 22. MS (ES+) : 575.5 (M+H)+. 1-HNMR (CD3OD) δ 7.67- 7.59 (m, 6H) , 7.47 (d, 2H) , 6.97 (d, 2H) , 4.70 (s, 2H) , 4.19 (t, 2H) , 3.81 (s, 3H) , 3.31 (t, 2H) , 3.26 (s, 3H) , 3.11 (s, 3H) , 1.82 (m, IH) , 0.79 (m, 4H) ppm. Example 27
Methyl (1- {4-[l-(4-methoxyphenyl) -3- (methylsulfonyl) -7■ oxo-l,4,5,7-tetrahydro-6ff-pyrazolo[3,4-c]pyridin-6- yl ] phenyl } - lff-imidazol-2 -yl ) methyl (methyl ) carbamate trifluoroacetic acid salt
Figure imgf000222_0001
The product from Part C of Example 22 (100 mg, 0.14 mmol) was dissolved in CH2C12 (5 mL) . Triethylamine (0.76 μL,
0.54 mmol) was added, followed by methyl chloroformate (11.6 μL, 0.15 mmol). The mixture was stirred at room temperature under N2 for 1/2 h. It was diluted with CHC12 and washed with H0 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 74 mg of the desired product as the TFA salt. MS (ES+) : 565.4, (M+H) + . -HNMR (CD30H) δ 7.81-7.50 (m, 6H) , 7.48 (d, 2H) , 6.97 (d, 2H) , 4.60 (s, 2H) , 4.11 (t, 2H) ,
3.76 (s, 3H) , 3.50-3.36 (d, 3H) , 3.32 (s, 3H) 3.19 (t, 2H) , 2.71 (s, 3H) ppm.
Example 28 tf-ethyl-N- [ ( l- {4- [l- (4-methoxyphenyl) -3- (methylsulfonyl) - 7 -oxo- 1, 4, 5, 7 -tetrahydro- 6ff-pyrazolo [ 3 , 4 - c] pyridin- 6 - yl]phenyl} -Iff-imidazol-2-yl) ethyl] acetamide trifluoroacetic acid salt
Figure imgf000223_0001
Part A: Preparation of. 6- (4-{2- [ (ethylamino)methyl] -lff- imidazol-1-yl}phenyl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1,4, 5, 6-tetrahydro-7ff-pyrazolo[3,4- c]pyridin-7-one
The product from Part B of Example 22 (0.52 g, 1.00 mmol), 2- (ethylaminmethyl) imidazole from Part A of Example
18.(0.26 g, 2.10 mmol), K2C03 (0.55 g, 4.00 mmol), Cul (0.19 g, 1.00 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 1302C under N for 4 h. The mixture was cooled, CHC13 and 8% aqueous NH40H were added. The mixture was filtered through Celite® and washed with CHC13. The two layers were separated and the aqueous layer was extracted with CHCI3. The organic extratct was washed with water and brin, dried over MgS0 , and concentrated.. The crude product was chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH, then further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 351 mg of the bis-TFA salt. MS (ES+) : 521.3, (M+H)+. iHNMR (DMS0-d6) δ 7.60-7.02 (m, 10H) , 4.28 (s, 2H) , 4.16 ( t , 2H) , 3 . 82 ( s , 3H) , 3 . 38 ( s , 3H) , 3 . 25 ( t , 2H) , 3 . 04 (q, 2H) , 1 . 18 ( t , 3H) ppm .
Part B: Preparation of JV-ethyl-iV- [ (l-{4- [1- (4- methoxyphenyl) -3- (methylsulfonyl) -7-oxo-l, 4, 5,7- tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl]phenyl}-lff- imidazol-2-yl)methyl]acetamide trifluoroacetic acid salt
Product from Part A (150 mg, 0.20 mmol), acetic acid (11.5 μL, 0.20 mmol), triethylamine (118.0 μL, 0.40 mmol), and HBTU (76.0 mg, 0.20 mmol) were added together with DMF (5 mL) . The mixture was stirred at RT under N2 for 30 h.
Water was added, followed by aqueous NaOH to adjust the pH to 8-9. It was then extracted with EtOAc. The organic layer was washed with water and brine, concentrated, and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give the final product as the TFA salt (126 mg) . MS (ES+) : 563.4 (M+H)+. !HNMR (CD3OD) δ 7.69-7.58 (m, 6H) , 7.47 (d, 2H) , 6.98 (d, 2H) , 4.64 (s, 2H) , 4.20 (t, 2H) , 3.81 (s, 3H) , 3.38-3.25 (m, 7H) , 3.28 (s, 3H) , 2.05 (s, 3H) , 1.10 (t, 3H) ppm.
Example 29 iV-isopropyl-IV- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-l, 4,5, 7-tetrahydro-6ff-pyrazolo [3, 4- c]pyridin-6-yl]phenyl} -Iff-imidazol-2-yl)methyl] acetamide trifluoroacetic acid salt
Figure imgf000225_0001
Part A: Preparation of. 6- (4-{2- [ (isopropylamino)methyl] - Iff-imidazol-1-yl}phenyl) -1- (4-methoxyphenyl) -3- (methylsulfonyl)-l,4,5, 6-tetrahydro-7ff-pyrazolo [3,4- σ]pyridin-7-one
The product from Part B of Example 22 (0.52 g, 1.00 mmol), 2- (I-propylaminmethyl) imidazole from Part A of Example 20.(0.29 g, 2.10 mmol), K2C03 (0.55 g, 4.00 mmol), Cul (0.19 g, 1.00 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130aC under N2 for 4 h. The mixture was cooled, CHC13 and 8% aqueous
NH 0H were added. The mixture was filtered through Celite® and washed with CHCI3. The two layers were separated and the aqueous layer was extracted with CHC13. The organic extratct was washed with water and brin, dried over MgS0 , and concentrated. The crude product was chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH, then further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 270 mg of the bis-TFA salt. MS (ES+) : 535.5, (M+H)+.
1ΗNMR (DMSO-d6) δ 7.60-7.02 (m, 10H) , 4.26 (s, 2H) , 4.16
(t, 2H) , 3.82 (s, 3H) , 3.39 (m, IH) , 3.38 (s, 3H) , 3.25 (t, 2H) , 1.22 (d, 6H) ppm. Part B: Preparation of JV-isopropyl-iV- [ (l-{4- [l-(4- methoxyphenyl) -3- (methylsulfonyl) -7-oxo-l, 4, 5, 7- tetrahydro-6ff-pyrazolo [3, 4-c] yridin-6-yl]phenyl}-lff- imidazol-2-yl)methy1] acetamide trifluoroacetic acid salt Product from Part A (130 mg, 0.17 mmol), acetic acid (9.8 μL, 0.17 mmol), triethylamine (95 μL, 0.34 mmol), and HBTU (64.6 mg, 0.17 mmol) were added together with DMF (5 mL) . The mixture was stirred at RT under N2 for 30 h. Water was added, followed by aqueous NaOH to adjust the pH to 8-9. It was then extracted with EtOAc. The organic layer was washed with water and brine, concentrated, and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give the final product as the TFA salt (90 mg) . MS (ES+) : 577.6 (M+H)+. iHNMR (CD30D) δ 7.65-7.60 (m, 6H) , 7.48 (d, 2H) , 6.97 (d, 2H) , 4.51 (s, 2H) , 4.20 (t, 2H) , 3.81 (s, 3H) , 3.28-3.25 (m, 6H) , 2.17 (s, 3H) , 1.15 (d, 6H) ppm.
Example 30 N- [(1- {4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6-yl]phenyl}- lff-imidazol-2-yl)methyl] -N-propylacetamide trifluoroacetic acid salt
Figure imgf000226_0001
Part A: Preparation of. 1- (4-methoxyphenyl) -3-
(methylsulfonyl) -6- (4- {2- [ (propylamino)methyl] -Iff-imidazol- l-yl}phenyl)-l,4,5,6-tetrahydro-7ff-pyrazolo[3,4-c]pyridin-
7-one The product from Part B of Example 22 (0.52 g, 1.00 mmol), 2- (ethylaminmethyl) imidazole from Part A of Example 19.(0.29 g, 2.10 mmol), K2C03 (0.55 g, 4.00 mmol), Cul (0.19 g, 1.00 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130SC under N2 for 4 h. The mixture was cooled, CHC13 and 8% aqueous
NH40H were added. The mixture was filtered through Celite® and washed with CHC13. The two layers were separated and the aqueous layer was extracted with CHC13. The organic extratct was washed with water and brin, dried over MgS04, and concentrated. The crude product was chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH, then further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 300 mg of the bis-TFA salt. MS (ES+) : 535.4, (M+H)+. XHNMR (DMSO-d6) δ 7.60-7.02 (m, 10H) , 4.28 (s, 2H) , 4.16
(t, 2H) , 3.82 (s, 3H) , 3.38 (s, 3H) , 3.25 (t, 2H) , 2.95 (t, 2H) , 1.60 (m, 2H) , 0.87 (t, 3H) ppm.
Part B: Preparation of iV-[(l-{4-[l-(4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-1,4,5,7-tetrahydro-6ff-pyrazolo [3,4- c]pyridin-6-yl] phenyl} -Iff-imidazol-2-yl)methyl] -N- propylacetamide trifluoroacetic acid salt
Product from Part A (150 mg, 0.20 mmol), acetic acid (11.6 μL, 0.20 mmol), triethylamine (110 μL, 0.40 mmol), and HBTU (76.0 mg, 0.20 mmol) were added together with DMF (5 mL) .
The mixture was stirred at RT under N for 12 h. Water was added, followed by aqueous NaOH to adjust the pH to 8-9. It was then extracted with EtOAc. The organic layer was washed with water and brine, concentrated, and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give the final product as the TFA salt (110 mg) . MS (ES+) : 577.6 (M+H)+. iHNMR (CD30D) δ 7.69-7.60 (m, 6H) , 7.47 (d, 2H) , 6.97 (d, 2H) , 4.64 (s, 2H) , 4.20 (t, 2H) , 3.81 (s, 3H) , 3.31-3.21 (m, 7H) , 2.04 (s, 3H) , 1.50 (m, 2H),0.84 (t, 3H) ppm.
Example 31 1- (4-methoxyphenyl) -6- [2 ' - ( {methyl [ (methylamino)carbonyl] - amino}methyl) -1,1" -biphenyl-4-yl] -7-oxo-4,5, 6, 7-tetrahydro- lff-pyrazolo [3, 4-c]pyridine-3-carboxamide trifluoroacetic acid salt
Figure imgf000228_0001
Part A: Preparation of ethyl 6- (2 ' -formyl-1,1' -biphenyl-4- yl) -1- (4-methoxyphenyl) -7-OXO-4, 5, 6, 7-tetrahydro-lff- pyrazolo [3, 4-σ]pyridine-3-carboxylate Ethyl 6- (4-iodophenyl) -1- (4-methoxyphenyl) -7-OXO-4, 5, 6, 7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxylate (1.0 g, 1.93 mmol), K3P04 (1.63 g, 7.72 mmol), 2-
Formylbenzeneboronic acid (579 mg, 3.86 mmol), and Pd(PPh3) (116 mg, 0.1 mmol) were added together with 20 L of 1,4-dioxane. The mixture was degassed and then refluxed for 18 hours. The mixture was cooled and the solvent was removed. The residue was partitioned between EtOAc and H20. The EtOAc layer was washed with brine, dried over MgS0 , concentrated, and chromatographed with 1:1 EtOAc :hexane to afford 490 mg of the desired product (51.3%). MS (ES+) : 496.4, (M+H) + . XHNMR (CDCl3) δ 10.00 (s, IH) , 8.04-8.01 (m, IH) , 7.64-7.61 (m, IH) , 7.53-7.38 (m, 8H) , 6.93 (d, 2H) , 4.48 (q, 2H) , 4.21 (t, 2H) , 3.82 (s, 3H) , 3.38 (t, 2H) , 1.45 (t, 3H) ppm.
Part B: Preparation of ethyl 1- (4-methoxyphenyl) -6- {2 *- [ (methylamino)methyl] -1, 1' -biphenyl-4-yl}-7-oxo-4,5, 6,7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxylate
Ethyl 6- (2 ' -formyl-1, 1' -biphenyl-4-yl) -1- (4-methoxyphenyl) - 7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3- carboxylate (485 mg, 0.98 mmol) and methylamine hydrochloride (135 mg, 2 mmol) were added together in 10 mL of 1:1 MeOH:THF and stirred at room temperature for 15 minutes. Zinc chloride (0.5 M in THF, 1 mL, 0.5 mmol) and Sodium cyanoborohydride (63 mg, 1 mmol) were then added and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc and washed with H20, brine, dried over MgS04, and concentrated to afford 511 mg of desired product (100%). MS (ES+) : 511.4, (M+H) + . -HNMR (CDC13) δ 7.50-7.41 (m, 3H) , 7.39-7.22 (m, 7H) , 6.92 (d, 2H) , 4.47 (q, 2H) , 4.20(t, 2H) , 3.86 (s, 2H) , 3.80 (s, 3H) 3.37 (t, 2H) , 1.44 (t, 3H) ppm.
Part C: Preparation of ethyl 1- (4-methoxyphenyl) -6- [2 ' - ( {methyl [ (methylamino) carbonyl] amino} ethyl) -1, 1 ' - biphenyl-4-yl] -7-oxo-4, 5, 6,7-tetrahydro-lff-pyrazolo[3,4- c]pyridine-3-carboxylate
Ethyl 1- (4-methoxyphenyl) -6- {2 '- [ (methylamino) methyl] - 1, 1 ' -biphenyl-4-yl}-7-oxo-4, 5, 6 , 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxylate (150 mg, 0.29 mmol) and methyl isocyanate (165 mg, 2.9 mmol) were added together in 10 mL of CH2C12 and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with CH2C1 and washed with water, brine, dried over MgS0 , concentrated, and chromatographed with 1:1 EtOAc : hexane and then 5% MeOH:CHCl3 to afford 173 mg of desired product
(100%). MS (ES+) : 568.4, (M+H)+. 1-HNMR (CDC13) δ 7.49 (d, 2H) , 7.40-7.19 (m, 8H) , 6.93 (d, 2H) , 4.51-4.44 ( , 4H) , 4.19(t, 2H) , 3.82 (s, 3H) 3.36 (t, 2H) , 2.77 (d, 3H) , 2.72 (s, 3H) , 1.44 (t, 3H) ppm.
Part D: Preparation of 1- (4-methoxyphenyl) -6- [2 '-( {methyl [ (methylamino)carbonyl] amino}methyl) -1, 1 • -biphenyl-4-yl] -7- oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide
Ethyl 1- (4-methoxyphenyl) -6- [2 ' - ( {methyl [
(methylamino) carbonyl] amino}methyl) -1,1' -biphenyl-4-yl] -7- oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3- carboxylate (130 mg, 0.2 mmol) was dissolved in 7.5 mL of 1,4-dioxane. Concentrated NH4OH (7.5 mL) was added. The reaction vessel was sealed and the mixture was stirred at room temperature for 4 days. The mixture was stripped and chromatographed using 3% MeOH:CHCl3 with 0.1% concentrated NH OH. The fractions containing desired product were combined and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 71 mg of desired product (48% yield) . MS (ES+) : 539.4, (M+H)+. 1HNMR (CDC13) δ 7.48 (t, 2H) , 7.39- 7.19 (m, 9H) , 6.95 (m, 3H) , 6.00 (bs, IH) , 4.47 (s, 2H) ,
4.189(t, 2H) , 3.83 (s, 3H) 3.41 (t, 2H) , 2.77 (s, 3H) , 2.72 (s, 3H) ppm. Example 32 1- (4-methoxyphenyl) -6- (2 ■ - { [methyl (methylsulfonyl) amino] - methyl} -1, 1 ■ -biphenyl-4-yl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pyrazolo[3,4-c]pyridine-3-carboxamide trifluoroacetic acid salt
Figure imgf000231_0001
This compound was prepared using similar procedures described in Example 31. MS (ES+) : 560.3, (M+H)+. 1HNMR (CDC13) δ 7.61 (d, IH) , 7.49-7.03 (m, 11H) , 6.96 (d, 2H) ,
4.29 (s, 2H) , 4.18(t, 2H) , 3.83 (s, 3H) 3.40 (t, 2H) , 2.77 (d, 3H) , 2.60 (s, 3H) ppm.
Example 33 IV- [4- (2- {[Acetyl (methyl) amino]methyl} -Iff-imidazol-1-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -lff-pyrazole-5-carboxamide, bis (trifluoroacetic acid) salt
Figure imgf000231_0002
Part A: Preparation benzyl lff-imidazol-2-ylmethyl (methyl) - carbamate
2-Imidazolecarboxyaldehyde (5.0 g, 52.0 mmol) was suspended in 200 mL of methanol. Methylamine (20 mL of 33% solution in methanol) was added. After stirred for 15 minutes, NaBH (3.95 g, 0.10 mol) was added portion-wise. The reaction mixture was then heated at 50°C for 2 h under N2.
The solvent was removed. The solid was washed with CH2C12 and filtered. The CH2C12 solution was dried over MgS04, concentrated, and dried under vacuum to give the methylamine as a yellow oil. This oil was dissolved in a 1:1 solution of CH2C12 and THF. To it was added Et3N (7.94 mL, 57.0 mmol) and benzylchloroformate (7.4 mL, 52.0 mmol). The mixture was stirred at room temperature under N for 1 h. The solvent was removed and the residue was partitioned between EtOAc and H20. The EtOAc layer was washed with brine, dried over MgS04, and concentrated. The mixture was refluxed with 15 mL of TFA for 30 minutes to convert most of the bis-acylated byproduct to the desired product. The TFA was removed. It was dissolved in EtOAc and washed with Saturated aqueous NaHC03 and brine . The mixture was dried over MgS04, concentrated, and chromatographed with 1:1 EtOAc/hexane to give 6.56 g off-white solid (51.4% yield). MS (AP+) : 246.3, (M+H)+. 1UNMR (CDCl3 ) : δ 7.35 (s, 6H) , 6.90 (s, IH) , 5.14 (s, 2H) , 4.48 (s, 2H) , 3.00 (s, 3H) .
Part B: Preparation of benzyl {1- [4- ( { [1- (3-cyano-4- fluorophenyl) -3- (trifluoromethyl) -lff-pyrazol-5- yl] carbonyl}amino) -3-fluorophenyl] -lff-imidazol-2-yl}methyl (methyl)carbamate Benzyl lff-imidazol-2-ylmethyl (methyl) carbamate from Part A (3.60 g, 14.69 mmol), 2-fluoro-4-iodoaniline (3.50 g, 14.69 mmol), K2C03 (2.23 g, 16.16 mmol), 1, 10-phenanthroline (0.13 g, 0.73 mmol), Cul (0.14 g, 0.73 mmol), and DMSO (60 mL) wetre added together and degassed. The mixture was then heated at 130°C under N2 for 12 h. The mixrure was cooled, 14% aqueous NH4OH (200 mL) and EtOAC (200 mL) were added. The mixture was filtered through Celite® and washed with EtOAc. The filtrate was extracted with EtOAc, the combined organic solution was washed with brine, and dried over MgS04. It was concentrated and purified by chromatography on silica gel with 50-100% hexane in EtOAc to give 3.46 g of the desired product (67%). MS (ES+) : 355.2, (M+H)+.
Part C: Preparation of benzyl {1- [4- ( { [1- (3-cyano-4- fluorophenyl) -3- (trifluoromethyl) -lff-pyrazol-5- yl] carbonyl}amino) -3-fluorophenyl] -lff-imidazol-2-yl}methyl
(methyl)carbamate 1- (3-cyano-4-fluorophenyl) -3- (trifluoromethyl) -lff-pyrazole- 5-carboxylic acid prepared as described in WO 98/57951 (1.00 g, 3.34 mmol) was stirred in 20 mL of CH2C12 at room temperature under N2. Oxalyl chloride (0.43 mL, 5.01 mmol) was added, followed by a few drops of DMF. The mixture was stirred for 2 h. The solvent was removed and the resulting solid was dried under vacuum. This solid was then dissolved in 50 mL of CH2C12, benzyl {1- [4- ( { [1- (3-cyano-4- fluorophenyl) -3- (trifluoromethyl) -lff-pyrazol-5- yl] carbonyl}amino) -3-fluorophenyl] -Iff-imidazol-2-yl}methyl (methyl) carbamate from Part B (1.32 g, 3.34 mmol) was added, followed by DMAP (1.02 g, 8.35 mmol). The mixture was stirred at room temperature under N for 12 h. It was diluted with CH C1 , washed with water and brine, dried over MgS04, and concentrated. The crude product was purified by chromatography on silica gel with 50-100% hexane in EtOAc to give 1.10 g of the desired product (52%). MS (ES+) : 636.1, (M+H)+.
Part D: Preparation of JV-[4-(2-{[ (methy1) amino]methyl}-lff- imidazol-1-yl) -2-fluorophenyl] -1- (3-amino-l, 2-benzisoxazol- 5-yl) -3- (trifluoromethyl) -lff-pyrazole-5-carboxamide Acetohydroxamic acid (0.40 g, 5.34 mmol) was dissolved in 10 mL of DMF. K2C03 (0.98 g, 7.12 mmol) was added, followed by 1 mL of water. The mixture was stirred at room temperature under N for 30 minutes and a solution of benzyl {1- [4- ( { [1- ( 3-cyano-4-fluorophenyl) -3- (trifluoromethyl) -lff-pyrazol-5-yl] carbonyl}amino) -3- fluorophenyl] -lff-imidazol-2-yl}methyl (methyl) carbamate from Part C (1.13 g, 1.78 mmol) in 10 mL of DMF was added. The resulting mixture was stirred at room temperature under N2 for 12 h. Water was added to the reaction mixture. The precipitate formed was filtered and dried. MS (ES+) : 647.1, (M-H)".
The above solid was refluxed with 20 mL of TFA under N2 for
30 minute. The TFA was removed. The residue was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 0.61 g of the desired product as the TFA salt. MS (ES+) : 515.0, (M+H)+.
Part E: Preparation of JV- [4- (2-{ [acetyl
(methyl) amino] ethyl} -Iff-imidazol-1-yl) -2-fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -lff- pyrazole-5-carboxamide
N- [4- (2-{ [ (methyl) amino]methyl} -Iff-imidazol-1-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -lff-pyrazole-5-carboxamide from Part D was acylated with acetyl chloride in CH2C12 and triethylamine.
The product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CΝ gradient with 0.05%
TFA) to give the title compounds as the bis-TFA salt. MS (ES+) : 557.4 (M+H)+. XHNMR (CD30D) δ 8.07 (t, IH) , 7.95 (d, IH) , 7.69-7.38 (m, 7H) , 4.68 (s, 2H) , 2.98 (s, 3H) , 2.00 (s, 3H) ppm.
Example 34 iV-[4-(2-{ [Acetyl (methyl) amino]methyl}-Iff-imidazol-1-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3-
(methylsulfonyl) -lff-pyrazole-5-carboxamide, bis (trifluoroacetic acid) salt
Figure imgf000235_0001
Part A: Preparation of 5-{ (2Z) -2- [chloro
(methylsulfonyl)methylene]hydrazino} -2-fluorobenzonitrile
This compound was prepared using the same methods as described in Part A of Example 22. MS (ES") : 274.1, 276.1, (M-H)". Part B: Preparation of ethyl 1- (3-cyano-4-fluorophenyl) -3- (methylsulfonyl) -4, 5-dihydro-lff-pyrazole-5-carboxylate
The product from Part A (3.8 g, 13.8 mmol) was suspended in toluene (50 mL) and cooled in an ice bath. Triethylamine (3.14 g, 31.1 mmol) was added, followed by ethyl acrylate (4.14 g, 41.4 mmol) dropwise. The mixture was stirred at room temperature under N for 24 h. The mixture was refluxed for 4 h. The mixture was diluted with EtOAc and washed with H 0 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by flash chromatography using EtOAc:Hexane (2:3 to 1:1) to afford 3.79 g of the desired product. MS (ES") : 374.2, (M+Cl)".
Part C: Preparation of ethyl 1- (3-cyano-4-fluorophenyl) -3- (methylsulfonyl) -lff-pyrazole-5-carboxylate
The product from Part B (3.79 g, 11.2 mmol) was dissolved in THF (50 mL) and cooled in an ice bath. N- Chlorosuccinimide (1.64g, 12.3 mmol) was added and the mixture was stirred at room temperature under N for 1 h.
The mixture was diluted with Et20 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated in vacuo to afford 3.92 g of the desired product. MS (ES+) : 360.2, (M+Na)+.
Part D: Preparation of 1- (3-cyano-4-fluorophenyl) -3- (methylsulfonyl) -lff-pyrazole-5-carboxylic acid The product from Part C (3.79 g, 11.2 mmol) was dissolved in THF (30 mL) and then diluted with MeOH (10 mL) and H20 (10 mL) . Lithium hyroxide monohyrate (706 mg, 16.8 mmol) • was added and the mixture was stirred at room temperature for 2h. The mixture was quenched with 1.0 N hyrochloric acid (17 mL) and extracted with EtOAc (3 x 100 mL) . The organic layers were combined and washed with H20 and brine. The organic solution was then dried over MgS0 and concentrated in vacuo to afford 3.35 g of the desired product. MS (ES") : 308.2, (M-H)".
Part E: Preparation of benzyl {1- [4-( { [1- (3-cyano-4- fluorophenyl) -3- (methylsulfonyl) -lff-pyrazol-5- yl] carbonyl}amino)phenyl] -lff-imidazol-2-yl}methyl (methyl) carbamate The product from Part D and the product from Part A of
Example 33 were coupled using the same methods described in Part C of Example 33 (78% yield). MS (ES+) : 526.5 (M+H) + .
Part F: Preparation of 1- (3-amino-l, 2-benzisoxazol-5-yl) -JV- (4-{2-[ (methylamino)methyl] -Iff-imidazol-1-yl}phenyl) -3- (methylsulfonyl) -lff-pyrazole-5-carboxamide
This compound was prepared using the same methods as described in Part D of Example 33 using the product from Part E as the starting material (yield 12%) . MS (ES+) : 659.5 (M+H)+, MS (ES+) : 525.4 (M+H)+.
Part G: Preparation of JV- [4- (2-{ [Acetyl
(methyl) amino]methyl} -Iff-imidazol-1-yl) -2-fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (methylsulfonyl) -lff- pyrazole-5-carboxamide, bis (trifluoroacetic acid) salt
This compound was prepared using the same methods described in Example 7 using the product from Part F as the starting material (yield 18%). MS (ES+) : 567.4 (M+H)+. 1ΗNMR (CD3OD) δ 8.06 (t, IH) , 7.97- (d, IH) , 7.69-7.37 (m, 7H) , 4.67 (s, 2H) , 3.29 (s, 3H) , 2.98 (s, 3H) , 2.00 (s, 3H) ppm. Example 35
N- [4- (2-{ [methylsulfonylamino]methyl} -Iff-imidazol-1-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lff- pyrazole-5-carboxamide, trifluoroacetic acid salt
Figure imgf000238_0001
Part A: Preparation of ethyl 1- (4-methoxyphenyl) -3-
(methylsulfonyl) -4, 5-dihydro-lH-pyrazole-5-carboxylate
The product from Part A of example 22 (5 g, 19.1 mmol) was suspended in toluene (50 mL) and cooled in an ice bath. Triethylamine (2.9 g, 28.7 mmol) was added, followed by ethyl acrylate (4.14 mL, 38.2 mmol) dropwise. The mixture was stirred at room temperature under N2 for 24 h. The mixture was diluted with EtOAc and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated. The crude product was purified by flash chromatography using EtOAc:Hexane (1:2 to 2:3) to afford 5.21 g of the desired product. MS (ES") : 325.3, (M-H)".
Part B: Preparation of ethyl 1- (4-methoxyphenyl) -3- (methylsulfonyl) -lff-pyrazole-5-carboxylate
The product from Part A (5.2 g, 16 mmol) was dissolved in THF (50 mL) and cooled in a 0 C ice bath. N- Chlorosuccinimide (2.34 g, 17.5 mmol) was added and the mixture was stirred at room temperature under N for 1 h. The mixture was diluted with Et20 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated in vacuo to afford 5.32 g of the desired product. MS (ES+) : 325.3, (M+H) + .
Part C: Preparation of 1- (4-methoxyphenyl) -3- (methylsulfonyl) -lff-pyrazole-5-carboxylic acid
The product from Part B (5.3 g, 16.0 mmol) was dissolved in THF (30 mL) and then diluted with MeOH (10 mL) and H20 (10 mL) . Lithium hyroxide monohyrate (1.03 g, 24.5 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was quenched with 1.000 N hyrochloric acid (25 mL) and extracted with EtOAc (3 x 100 mL) . The organic layers were combined and washed with H0 and brine. The organic solution was then dried over MgS04 and concentrated in vacuo to afford 4.76 g of the desired product. MS (ES" ) : 295.2, (M-H)".
Part D: Preparation of benzyl {1- [4- ({ [1- (4-methoxyphenyl) - 3- (methylsulfonyl) -lff-pyrazol-5-yl] carbonyl}amino)phenyl] - lff-imidazol-2-yl}methyl (methyl)carbamate
The product from Part C (696 mg, 2.35 mmol) was suspended in CH2C12 (10 mL) . Oxalyl chloride (0.41 mL, 4.7 mmol) was added followed by a drop of DMF and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo. The residue was dissolved in CH2C1 (10 mL) and treated with 4-dimethylaminopyridine (1.73 g, 14.1 mmol) and Part B of Example 33 (1.05 g, 4.23 mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with CHC1 and washed with H20 and brine. The organic solution was then dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc :EtOH:Hexane (10:2:10 to 10:3:10) to elute 949 mg of the desired product. MS (ES+) : 633.5, (M+H)+. Part E: Preparation of 1- (4-methoxyphenyl) -JV- (4- {2- [ (methylamino)methyl] -lff-imidazol-l-yl}phenyl) -3- (methylsulfonyl) -Iff-pyrazole-5-carboxamide The product from Part D (940 mg, 1.49 mmol) was dissolved in EtOH (30 mL) and trifluoroacetic acid (0.5 mL) added. 20% Palladium Hydroxide was then added under N and the mixture shaken under 55 psi H2 for 18 h. The mixture was filtered through Celite® under a N purge and was concentrated in vacuo. The residue was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 76 mg of the desired product as the TFA salt. MS (ES+) : 499.4, (M+H) + .
Part F: Preparation of JV-[4-(2-
{ [methylsulfonylamino]methyl} -Iff-imidazol-1-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lff- pyrazole-5-carboxamide, trifluoroacetic acid salt
AN1315-29 (100 mg, 0.16 mmol) was dissolved in CH2C12 (5 mL) . Triethylamine (160 mg, 1.6 mmol) was added, followed by methanesulfonyl chloride (37 mg, 0.32 mmol). The mixture was stirred at room temperature under N2 for 18 h. The mixture was diluted with CH2C12 and washed with H0 and brine and dried over MgS04 and the solvent was removed in vacuo. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H20/CH3CN gradient with 0.05% TFA) to give 62 mg of the final product as the TFA salt. MS (ES+) : 577.3 (M+H)+, iHNMR (DMSO-d6) δ 10.82
(s, IH) , 7.85 (t, IH) , 7.76 (bs, IH) , 7.70-7.42 (m, 6H) , 7.07 (d, 2H) , 4.52 (s, 2H) , 3.82 (s, 3H) 3.38 (s, 3H) , 2.93 (s, 3H) , 2.73 (s, 3H) ppm. Example 36
N- [4-(2-{ [methylsulfonylamino]methyl}-lff-imidazol-l-yl)-2- fluorophenyl] -1- (4-methoxyphenyl) -3- (aminocarbonyl) -lff- pyrazole-5-carboxamide, trifluoroacetic acid salt
Figure imgf000241_0001
Part A: Preparation of methyl 4- (2-furyl) -2,4-dioxobutanoate
Sodium Methoxide (25% in methanol, 11.9 g, 55 mmol) was treated dropwise (over 30 minutes) with a solution of 2- acetylfuran (5.01 mL, 50 mmol) and dimethyloxalate (5.14 mL, 50 mmol) in THF. The resulting suspension was stirred at room temperature for 18 h. The solid was filtered, washed with ether, dissolved in EtOAc/H20, and acidified to pH 2-3 with 10% HCI. The mixture was then extracted with more EtOAc. The organic layers was combined, dried over MgS04, filtered, concentrated, and dried under vacuum to afford desired product (10.2 g, 95%).
Part B: Preparation of methyl 5- (2-furyl) -1- (4- methoxyphenyl) -lff-pyrazole-3-carboxylate
The product from Part A (1.96 g, 10 mmol), p-anisidine (1.23g 10 mmol), and p-Toluenesulfonic acid (1.90 g, 10 mmol) were dissolved in methanol and the resulting solution refluxed for 3 h. The solvents were removed in vacuo and the residue filtered through a silica gel bed with ethyl acetate . The solvents were removed in vacuo and the residue crystallized from ether/hexane to afford desired product (>85% yield) .
Part C: Preparation of 3- (methoxycarbonyl) -1- (4- methoxyphenyl) -lff-pyrazole-5-carboxylic acid
The compound from Part B (1.0 g, 3.4 mmol) was dissolved in acetonitrile (10 mL) and cooled in a 0 C ice bath. NaH P04
(2.32 g, 16.8 mmol) in H0 (4 mL) was then added followed by NaCl02 in H0 (12 mL) and the mixture stirred at room temperature for 2 h. The mixture was quenched with sat. sodium bisulfite and extracted with EtOAc (2 x 50 mL) . The organic extracts were combined, dried over MgS04 and concentrated in vacuo. The residue was triturated with Et20 and the solid collected and dried under vacuum to afford 190 mg of desired product. iHNMR (DMS0-d6) δ 7.40 (m, 3H) , 7.05 (d, 2H) , 3.83 (s, 3H) , 3.82 (s, 3H) .
Part D: Preparation of methyl 5- ({[4- (2-
{ [ [ (benzyloxy) carbonyl] (methyl) amino]methyl}-Iff-imidazol- 1-y1)phenyl] amino}carbonyl) -1- (4-methoxyphenyl) -lff- pyrazole-3-carboxylate
The product from Part C and the product from Part B of Example 33 were coupled using the same methods as described in Part D of Example 35. MS (ES+) : 613.5 (M+H) + .
Part E: Preparation of methyl 1- (4-methoxyphenyl) -5- {[ (4- {2- [ (methylamino)methyl] -Iff-imidazol-1- yl}phenyl) amino] carbonyl}-lff-pyrazole-3-carboxylate The product from Part D was hydrogenated using the same methods as described in Part E of Example 35. MS (ES+) : 479.5 (M+H)+. Part F: Preparation of methyl 1- (4-methoxyphenyl) -5- ({ [4- (2-{ [methyl (methylsulfonyl) amino]methyl}-Iff-imidazol-1- yl)phenyl] amino}carbonyl) -lff-pyrazole-3-carboxylate
Product from Part E (100 mg, 0.17 mmol) was dissolved in CH2C12 (10 mL) . Triethylamine (170 mg, 1.7 mmol) was added, followed by methanesulfonyl chloride (39 mg, 0.34 mmol) . The mixture was stirred at room temperature under N for 18 h. The mixture was diluted with CH2C12 and washed with H20 and brine and the solvent was removed in vacuo. The crude product was purified by flash chromatography using MeOH:CHCl3 (2%) to elute 58 mg of the final product.
MS (ES+) : 557.4 (M+H)+.
Part G: Preparation of N-[4-(2- { [methylsulfonylamino]methyl} -Iff-imidazol-1-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (aminocarbonyl) -lff- pyrazole-5-carboxamide, trifluoroacetic acid salt (DPC-
AN3174-17)
This compound was prepared using the same methods as described in Part G of Example 6. MS (ES+) : 542.5 (M+H)+,
!HNMR (CDC13) δ 8.07 (t, IH) , 7.69-7.68 (m, IH) , 7.58-7.37
(m, 6H) 6.99 (d, 2H) , 4.56 (s, 2H) , 3.81 (s, 3H) , 2.85 (s,
3H) , 2.80 (s, 3H) ppm.
Example 37
5-{[5-(2-{ [acetyl (methyl) amino]methyl} -Iff-imidazol-1-yl) -
2, 3-dihydro-lff-indol-1-yl] carbonyl} -1- (3-amino-l, 2- benzisoxazol-5-yl) -lff-pyrazole-3-carboxamide trifluoroacetate
Figure imgf000244_0001
Part A. Preparation of lithium l-tβrt-butoxy-4- (2-furyl) - l,4-dioxo-2-buten-2-olate A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to -78°C and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 min, di- tert-butyl oxalate was added dropwise over 1 h as a solution in 100 mL of ether. The resulting mixture was warmed to 23°C over a period of 3 h and was maintained at room temperature for 20 h. The mixture was then filtered, and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was dried in a vacuum oven for 1 h to afford lithium l-tert-butoxy-4- (2-furyl) -1, 4-dioxo-2- buten-2-olate (25 g, 83%) as a cream colored solid. 1HNMR (DMSO-d6) δ 7.75(t, IH) , 6.96 (m, IH) , 6.56 (m, IH) , 3.34 (s, 2H) , 1.46 (s, 9H) .
Part B. Preparation of tert-butyl 1- (3-cyano-4- fluorophenyl) -5- (2-furyl) -lff-pyrazole-3-carboxylate
To the product (13 g, 54 mmol) from Part A was added 2- fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250 mL of glacial acetic acid. The resulting orange mixture was maintained at room temperature for 20 h and then concentrated to dryness. The resulting residue was taken up in 30% chloroform in hexanes and filtered to afford tert-butyl 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) - lff-pyrazole-3-carboxylate (18 g, 95%) as a light brown solid. LC/MS (ESI+) : 354.2 (M+H)+. XHNMR (CDCl3) δ 7.64-7.78
(m, 3H) , 7.42 (s, IH) , 7.05 (s, IH) , 6.45 (s, IH) , 6.30 (s, IH) , 1.61 (s, 9H) .
Part C. Preparation of 1- (3-cyano-4-fluorophenyl) -5- (2- furyl) -lff-pyrazole-3-carboxylate
To the product from Part B (10 g, 28 mmol) was added 125 mL of dichloromethane and 125 mL of trifluoroacetic acid. The resulting black solution was maintained at room temperature under nitrogen for 2 h and was then concentrated to dryness. The resulting solid was dried in a vacuum oven for 4 h to afford 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) - lff-pyrazole-3-carboxylate (8.4 g, 99%) as a brown solid. LC/MS (ESI+) : 298.1 (M+H)+. 1ΗNMR (CD3OD) δ 7.90 (m, IH) ,
7.75 (m, IH) , 7.51 (s, IH) , 7.46 (t, IH) , 6.98 (s, IH) , 6.47 (m, IH) , 6.35 (m, IH) .
Part D. Preparation of 1- (3-cyano-4-fluorophenyl) -5- (2- furyl) -lff-pyrazole-3-carboxamide
To the product (4.1 g, 14 mmol) from Part C was added 23 mL of dichloromethane and 2.0 M oxalyl chloride (10 mL, 21 mmol) in dichloromethane. After dropwise addition of N, N- dimethylformamide (10 drops) to the brown mixture, the mixture became clear over a period of 30 min. When no more gas evolved, the brown solution was concentrated. The resulting residue was redissolved in 100 mL of dichloromethane and 0.5 M ammonia in dioxane (110 mL, 55 mmol) was added via cannula. After 30 min, the resulting suspension was concentrated and poured into water. The aqueous layer was washed with ethyl acetate (3X70 mL) , and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The resulting residue was dissolved in 10 mL of dichloromethane and 50 mL of hexanes were added. The resulting suspension was filtered, and the filter cake was washed with 50 mL of hexanes. The filter cake was dried in a vacuum oven to afford 1- (3-cyano-4- fluorophenyl) -5- (2-furyl) -lff-pyrazole-3-carboxamide (2.5 g, 62%) as a brown solid. LC/MS (ESI+) : 297.1 (M+H)+. iHNMR (CDC13) δ 7.75 (m, IH) , 7.64 (m, IH) , 7.42 (s, IH) , 7.33 (t, IH) , 7.16 (s, IH) , 6.79 (br s, IH) , 6.46 (m, IH) , 6.36 (m, IH) , 5.50 (br s, IH) .
Part E. Preparation of 3- (aminocarbonyl) -1- (3-cyano-4- fluorophenyl) -lff-pyrazole-5-carboxylic acid To the product (2.5 g, 8.3 mmol) from Part D was added water (51 mL) , 5% aqueous sodium dihydrogenphosphate (35 mL) , and terfc-butanol (51 mL) . The resulting mixture was warmed to 60°C, and potassium permanganate (8.0 g, 51 mmol) was added over a period of 10 min. After an additional 10 min, the resulting purple slurry was cooled to 0SC, and the reaction was quenched by the addition of 200 mL of saturated aqueous sodium bisulfite. The resulting mixture was filtered, washed with 300 mL of water, and the filtrate was acidified with concentrated hydrogen chloride. The aqueous layer was extracted with ethyl acetate (6X100 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. Concentration afforded 3- (aminocarbonyl) -1- (3- cyano-4-fluorophenyl) -lff-pyrazole-5-carboxylic acid (1.6 g, 71%) as a yellow solid. LC/MS (ESI+) : 275.1 (M+H)+. l-HNMR (CD3OD) δ 8.03 (m, IH) , 7.90 (m, IH) , 7.5 (t, IH) , 7.44 (s, IH) . Part F. Preparation of JV- (Iff-imidazol-2-ylmethyl)-JV- methylamine
To a flame-dried 500- mL flask was added methanol (200 mL) , 2-imidazolecarboxaldehyde (5-.0 g, 52 mmol), and 8.0 M methylamine (20 mL, 160 mmol) . The reaction was stirred for 45 min, at which time, all carboxaldehyde dissolved. Sodium borohydride (4.0 g, 104 mmol) was added in four equal portions over a period of 2 min, resulting in a vigorous exotherm and a reaction temperature of 45°C. The reaction temperature was increased to 50°C and maintained at this temperature for 2 h. The reaction was then cooled, concentrated, and dichloromethane (200 mL) was added. The mixture was concentrated, and dichloromethane (200 mL) was again added. The resulting mixture was filtered, the filter cake was washed with dichloromethane (2D50 mL) , and the filtrate was concentrated. The resulting viscous yellow oil solidified upon standing to afford N- ( lff- imidazol-2-ylmethyl) -N-methylamine as a yellow solid (5.5 g, 95%) which was used without further purification. 1HΝMR (CDC13) δ 6.99 (s, 2H) , 3.87 (s, 2H) , 2.46 (s, 3H) .
Part G. Preparation of tert-butyl 5-iodo-1- indolinecarboxylate
Sodium cyanoborohydride (1.54 g, 25 mmol) was added in one portion to a stirring orange solution of 5-iodo-lff-indole
(6.0 g, 25 mmol) in glacial acetic acid (350 mL) . After 24 h, the orange solution was concentrated. To the resulting red residue was added tetrahydrofuran (250 mL) and di- tert- butyl dicarbonate (16 g, 74 mmol) followed by saturated aqueous sodium bicarbonate (20 mL) . The resulting mixture was stirred for 24 h and was then poured into aqueous IN hydrogen chloride (70 mL) . The layers were separated, and the aqueous layer was washed with ethyl acetate (3x50 mL) . The combined organic layers were washed with saturated aqueous sodium chloride (50 mL) , dried over sodium sulfate and concentrated. The resulting residue was dissolved in THF (100 mL) , and benzyl amine (6 mL, 55 mol) was added. The resulting solution was stirred for 1.5 h and was then poured into IN hydrogen chloride (70 mL) . The layers were separated and the aqueous layer was washed with ethyl acetate (3X50 L) . The combined organic layers were washed with saturated aqueous sodium chloride (50 mL) , dried over sodium sulfate, and concentrated. Purification of the resulting residue by flash column chromatography (5% ethyl acetate in hexanes) affored tert-butyl 5-iodo-l- indolinecarboxylate (3.9 g, 45%) as a white solid. LC/MS (ESI+) : 346.1 (M+H)+.
Part H. Preparation of tert-butyl 5-{2-[
(methylamino)methyl] -lff-imidazol-l-yl}-l- indolinecarboxylate
A flame-dried flask was charged with methyl sulfoxide (46 mL) , anhydrous potassium carbonate (1.28 g, 9.3 mmol), and N- (Iff-imidazol-2-ylmethyl) -N-methylamine (520 mg, 4.6 mmol). The product (0.80 g, 2.3 mmol) from Part G was added, and the mixture was degassed by alternating treatment with vacuum and nitrogen (x3) . Copper (I) iodide (440 mg, 2.3 mmol) was added, and the reaction mixture was again degassed. The green mixture was maintained at 130°C for 2.5 h and was then cooled to room temperature. The mixture was poured into saturated aqueous ammonium hydroxide (100 mL) and the aqueous layer was washed with ethyl acetate (150 mL) . The organic layer was washed with saturated aqueous ammonium hydroxide (50 mL) , water (2X50 mL) , and saturated aqueous sodium chloride (50 mL) . The organic layer was then dried over sodium sulfate, concentrated, and the resulting green-black residue was purified by radial chromatography (5% methanol in dichloromethane) to afford tert-butyl 5-{2-[ (methylamino) methyl] -Iff-imidazol-l-yl}-l- indolinecarboxylate (0.40 g, 52%) as a brown oil. LC/MS (ESI+) : 329.3 (M+H)+.
Part I. Preparation of tert-butyl 5- (2- { [acetyl (methyl) - amino]methyl} -Iff-imidazol-1-yl) indolinecarboxylate
To the product from Part H (0.20 g, 0.61 mmol) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Acetyl chloride (0.048 L, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous IN hydrogen chloride (10 mL) . The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL) , dried over sodium sulfate, and concentrated to give tert-butyl 5- (2-{ [acetyl (methyl) -amino] methyl}-lff- imidazol-1-yl) indolinecarboxylate (230 mg, 100%) as a brown oil). LC/MS (ESI+) : 371.3 (M+H) + .
Part J. Preparation of JV-{ [1- (2,3-dihydro-lff-indol-5-yl) - Iff-imidazol-2-yl}methyl} -N-methylacetamide
To the product from Part I (0.23 mg, 0.62 mmol) was added 50% triflouoroacetic acid in dichloromethane (6 mL) . The resulting brown solution was stirred for 2 h and was then concentrated. The resulting residue was poured into saturated aqueous sodium bicarbonate (30 mL) , and the aqueous layer was washed with ethyl acetate (4D50 mL) . The combined organic layers were washed with saturated aqueous sodium chloride (50 mL) , dried over sodium sulfate, and concentrated to give N- { [1- (2 , 3-dihydro-lff-indol-5-yl) -lff- imidazol-2-yl}methyl}-i\7-methylacetamide (96 mg, 57%) as a brown oil. LC/MS (ESI+) : 271.3 (M+H) + .
Part K. Preparation of 5-{ [5- (2-{ [acetyl (methyl) - amino]methyl}-lff-imidazol-l-yl) -2, 3-dihydro-lff-indol-l- yl]carbonyl}-1- (3-amino-1,2-benzisoxazol-5-yl) -lff-pyrazole- 3-carboxamide trifluoroacetate
To the product from Part J (96 mg, 0.36 mmol) was added 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -lff-pyrazole-5- carboxylic acid (107 mg, 0.39 mmol), followed by pyridine (3.2 mL) and N, N-dimethylformamide (0.80 mL) . 1,3- Diisopropylcarbodiimide (0.067 mL, 0.43 mmol) was added, and the resulting solution was stirred for 14 h. The red mixture was then poured into IN aqueous hydrogen chloride (70 mL) and washed with ethyl acetate (3D50 mL) . The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA in CH3CΝ/H20) to give partially pure 5- { [5- (2- { [acetyl
(methyl) amino] methyl} -Iff-imdazol-1-yl) -2 , 3-dihydro-lff- indol-1-yl] carbonyl}-l- (3-cyano-4-fluorophenyl) -lff- pyrazole-3-carboxamide (187 mg) as a red residue (LC/MS (ESI+) : 527.3 (M+H)+). This material was dissolved in N, N- dimethylformamide (2.8 mL) , and potassium carbonate (250 mg, 1.8 mmol) and water (0.70 L) were added. Acetohydroxamic acid (30 mg, 0.39 mmol) was added in one portion, and the resulting yellow mixture was warmed to 50°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate (40 L) . The organic layer was washed with water (2X50 mL) , saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated. The resulting brown oily residue was purified by radial chromatography (5% methanol in dichloromethane) and preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA in CH3CN/H20) to give 5-{[5-
(2-{ [acetyl (methyl) -amino]methyl}-lff-imidazol-l-yl) -2 , 3- dihydro-Iff-indol-1-yl] carbonyl} -1- (3-amino-l, 2- benzisoxazol-5-yl) -lff-pyrazole-3-carboxamide trifluoroacetate (13 mg, 5.6%). LC/MS (ESI+) : 540.3
(M+H) + . iHNMR (CD3OD) δ 8.29 (br s, IH) , 7.95 (br s, IH) ,
7.77 (br s, IH) , 7.65 (d, 2H) , 7.30-7.51 (br m, 3H) , 7.32 (s, IH) , 4.69 (br s, 2H) , 4.21 (t, 2H) , 3.22 (br s, 2H) , 3.00 (s, 3H) , 2.07 (s, 3H) .
Example 38 1- (3-amino-l, 2-benzisoxazol-5-yl) -5-{ [5- (2-{ [methyl (methylsulfonyl) amino]methyl} -Iff-imidazol-1-yl) -2,3- dihydro-Iff-indol-1-yl] carbonyl} -lff-pyrazole-3-carboxamide trifluoroacetate
Figure imgf000251_0001
Part A. Preparation of tert-butyl 5- (2- { [methyl
(methylsulfonyl) amino]methyl}-Iff-imidazol-1-yl) -1- indolinecarboxylate
To tert-butyl 5-{2-[ (methylamino) methyl] -lff-imidazol-1- yl}-l-indolinecarboxylate (0.20 g, 0.61 mmol; from Part H of Example 37) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Methanesulfonyl chloride (0.052, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous IN hydrogen chloride (10 mL) . The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL) , dried over sodium sulfate, and concentrated to give tert-butyl 5- (2-{ [methyl (methylsulfonyl) amino]methyl}-lff-imidazol-l- yl) -1-indolinecarboxylate (250 mg, 100%) as a brown oil). LC/MS (ESI+) : 407.3 (M+H) + .
Part B. Preparation of JV- [ {1- (2, 3-dihydro-Iff-indol-5-yl) - Iff-imidazol-2-yl]methyl} -N-methyl methanesulfonamide To the product from Part A (0.25 mg, 0.61 mmol) was added 50% triflouoroacetic acid in dichloromethane (6 L) . The resulting brown solution was stirred for 2 h and was then concentrated. The resulting residue was poured into saturated aqueous sodium bicarbonate (30 mL) , and the aqueous layer was washed with ethyl acetate (4x50 mL) . The combined organic layers were washed with saturated aqueous sodium chloride (50 mL) , dried over sodium sulfate, and concentrated to give N- [ {1- (2 , 3-dihydro-Iff-indol-5-yl) -lff- imidazol-2-yl ] methyl } -N-methyl methanesulfonamide (150 mg, 78%) as a brown oil. LC/MS (ESI+) : 307.3 (M+H)+.
Part C. Preparation of 1- (3-amino-l,2-benzisoxazol-5-yl) -5- { [5-(2-{ [methyl (methylsulfonyl)amino]methyl}-Iff-imidazol- l-yl)-2,3-dihydro-lff-indol-l-yl]carbonyl}-lff-pyrazole-3- carboxamide trifluoroacetate
To the product from Part B (150 mg, 0.48 mmol) was added 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -lff-pyrazole-5- carboxylic acid (140 mg, 0.52 mmol) followed by pyridine (3.2 mL) and N, N-dimethylformamide (0.80 mL) . 1,3- Diisopropylcarbodiimide (0.090 mL, 0.57 mmol) was added, and the resulting solution was stirred for 14 h. The red mixture was then poured into water (70 mL) and washed with EtOAc (3D50 mL) . The combined organic layers were washed with aqueous IN hydrogen chloride (50 mL) , and the combined aqueous layers were made basic with saturated aqueous sodium hydrogencarbonate . The aqueous layers were then concentrated. The resulting residue was treated with dichloromethane (3X50 mL) and filtered to afford crude 1- (3-cyano-4-fluorophenyl) -5-{[5-(2-{ [methyl (methylsulfonyl) -amino] methyl} -Iff-imidazol-1-yl) -2 , 3- dihydro-Iff-indol-1-yl] carbonyl} -lff-pyrazole-3-carboxamide (180 mg) as a pink residue (LC/MS (ESI+) : 563.3 (M+H)+). This material was dissolved in N, N-dimethylformamide (2.5 mL) , and potassium carbonate (221 mg, 1.6 mmol) and water (0.64 mL) were added. Acetohydroxamic acid (26 mg, 0.35 mmol) was added in one portion, and the resulting yellow mixture was warmed to 50°C. After 2 h, the reaction was cooled to room temperature and half of the reaction mixture was purified by preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA in CH3CΝ/H20) to give 1- (3-amino-l, 2- benzisoxazol-5-yl) -5-{ [5- (2-{ [methyl (methylsulfonyl) amino] methyl} -Iff-imidazol-1-yl) -2,3- dihydro-Iff-indol-1-yl] carbonyl} -lff-pyrazole-3-carboxamide trifluoroacetate (27 mg, 25%). LC/MS (ESI+) : 576.3 (M+H) + . iHNMR (CD3OD) δ 8.25(br s, IH) , 7.95 (br s, IH) , 7.60-7.72
(m, 3H) , 7.30-7.51 (br m, 3H) , 7.32 (s, IH) , 4.56 (br s, 2H) , 4.21 (t, 2H) , 3.22 (br s, 2H) , 3.89 (s, 3H) , 2.81 (s, 3H) . Example 39
2- (3-Aminobenzo[d]isoxazol-5-yl) -5-trifluoromethyl-2H- pyrazole-3-carboxylic acid (l-{2- [ (acetylmethylamino) - methyl] henyl} -piperidin-4-yl) amide
Figure imgf000254_0001
Part A. Preparation of [1- (2-Formylphenyl) -piperidin-4- yl] carbamic acid t-butyl ester
A mixture of 4-t-butoxycarbonylaminopiperidine (1 g, 4.99 mmol) 2-fluorobenzaldehyde (0.8 mL, 7.59 mmol) and potassium carbonate (1.38 g, 10 mmol) in DMSO (10 mL) was stirred overnight in an 85-90°C oil bath under N2. After cooling to room temperature, the reaction mixture was poured into 10 volumes of water, and the product extracted 3X with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous Na2S04, filtered, and evaporated. Purification by flash silica gel chromatography (hexane/ethyl acetate 3:1) provided the product as an off-white solid (0.74 g, 49%). MS (ESI+) m/z 305.1 (M+H) + , 205.1 (M+H-BOC) + . -HNMR (CDC13) δ 10.24 (lH,s), 7.80 (lH,d, J=12 Hz), 7.52 (lH,t, J=12 Hz), 7.16, (IH, m) , 3.65 (lH,m), 3.30 (lH,m), 3.04 (lH,m) , 2.09 (2H, m) , 1.80-1.48 (4H,m) , 1.44 (9H,s).
Part B. Preparation of [l-(2- Methylaminomethylphenyl)piperidin-4-yl] -carbamic acid t- butyl ester A mixture of the product from Part A (0.5 g, 1.64 mmol) and methylamine hydrochloride (0.22g, 3.28 mmol) in 1,2- dichloroethane (10 mL) was stirred 5-10 min followed by addition of sodium triacetoxyborohydride (0.52 g, 2.46 mmol) . The resulting mixture was stirred for 72 h under N2. The reaction was quenched by addition of 2N NaOH and extracted into Et20. Purification of the resulting residue by rotary prep TLC (silica gel, CH2Cl2-MeOH-NH4OH 95:5:0.5- 90:10:1) to remove some alcohol by-product provided the desired N-methylamine product (0.31 g, 58%). MS (ESI+) m/z 320.4 (M+H)+.
Part C. Preparation of (l-{2-
[ ( cetylmethylamino)methyl]phenyl}piperidin-4-yl)carbamic acid t-butyl ester
A solution of the product from Part B (0.1 g, 0.313 mmol) in CHC12 (1 mL) was cooled in an ice bath under N with stirring while acetyl chloride (25-30 μl) was added. The whole was stirred overnight at room temperature. The mixture was diluted with additional CH2C12 and washed with 5% citric acid solution, saturated NaHC03 and brine, then dried over anhydrous Na2S04, filtered, and evaporated. Purification on 5 g silica gel cartridge eluted with hexane-ethyl acetate (1:1) provided the acetamide as a white foam. This was used without purification in Part D below.
Part D. Preparation of N- [2- (4-Aminopiperidin-l-yl)benzyl] - N-methylacetamide, bis (trifluoroacetate) The product from Part C was dissolved in a mixture of
CHC1 (4 mL) and TFA (1 mL) and stirred overnight at room temperature. Mixture was evaporated in vacuo and the residue triturated with Et 0 to provide the amine salt as a sticky solid (32 mg, 39% over two steps) . MS (ESI+) m/z 262.3 (M+H)+.
Part E. Preparation of 2- (3-Cyano-4-fluorophenyl) -5- trifluoromethyl-2H-pyrazole-3-carboxylic acid (l-{2- [ (acetylmethylamino) -methy1] henyl} iperidin-4-yl)amide
A mixture of 2- (3-cyano-4-fluorophenyl) -5-trifluoromethyl- 2H-pyrazole-3-carboxylic acid (25 mg, 0.084 mmol), the product from Part D (32 mg, 0.065 mmol), Castro's reagent (43 mg, 0.098 mmol) and N-methylmorpholine (50 μ mL, 0.455 mmol) in DMF (1 mL) was stirred overnight at room temperature under N . The resulting mixture was poured into water and extracted 3X into ethyl acetate. The combined extracts were washed with water, saturated NaHC03, and brine, then dried over anh. Na2S0 , filtered and evaporated to provide the product (41 mg, 90% crude yield) that was used without purification in Part F below.
Part F. Preparation of 2- (3-Aminobenzo [d] isoxazol-5-yl) -5- trifluoromethyl-2H-pyrazole-3-carboxylic acid (l-{2- [ (acetyl-methyl-amino)methyl]phenyl}piperidin-4-yl)amide
A mixture of acetoxyhydroxamic acid (38 mg, 0.5 mmol) and K2C03 (95 mg., 0.7 mmol) in DMF (0.5 mL) was treated with 5 drops of water and stirred for 30 min at room temperature. To the resulting mixture was added a solution of the compound from Part E (41 mg, 0.07 mmol) in DMF (0.5-1.0 mL) and the whole was stirred at room temperature under N2 for 72 h. The mixture was diluted with water and extracted 3X with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous Na2C03, filtered and evaporated. Purification by C18 reverse phase HPLC provided the target compound (20 mg, 43%) . MS (ESI+) m/z 556.5 (M+H)+. XHNMR (DMSO-d6) δ 8.05 (lH,s), 7.59 (2H,m) , 7.48 (lH,m), 7.32-7.00 (4H,m), 4.55 (2H,m) 2.95 (2H,m) 2.77 (3H,s), 2.70 (2H,m), 2.10 (3H,s), 1.85 (2H,m), 1.63 (2H,m) .
Example 40
2- (3-Aminobenzo[d]isoxazol-5-yl) -5-trifluoromethyl-2H- pyrazole-3-carboxylic acid (l-{2-[ (methanesulfonylmethyl- amino)methyl]phenyl}piperidin-4-yl) amide
Figure imgf000257_0001
This compound was prepared in analogous fashion to Example 39 above by substituting methanesulfonyl chloride for the acetyl chloride in Part C of Example 39. MS (ESI+) m/z 592.5 (M+H) + . XHNMR (CD3CN) δ 7.83 (IH, s), 7.60 (IH, d, J=8Hz), 7.49 (IH, d, J=8Hz) , 7.44-7.26 (5H, m) , 7.17 (2H, m) , 4.42 (2H, s) , 4.03 (IH, m) , 3.22 (4H, m) , 2.95 (3H, s) , 2.69(3H, s) , 2.06 (2H, m) , 1.92 (2H, m) .
Example 41 2- (4-Methoxyphenyl) -5-trifluoromethyl-2H-pyrazole-3- carboxylic acid [1- (2- {[ (2-hydroxyethyl)methylamino] methyl}phenyl)piperidin-4-yl] amide
Figure imgf000258_0001
Part A. Preparation of 2- [2- (4-Aminopiperidin-l- yl)benzyl]methyl-aminoethanol
The compound from Part A of Example 39 (0.20 g, 0.66 mmol) was charged to a 25 mL reaction vessel, and sodium triacetoxyborohydride (0.21 g, 1.0 mmol), and 5 mL of 1,2- dichloroethane were added. While stirring under N 2- aminoethanol (0.04 g, 0.77 mmol) was added. The reaction mixture was stirred for an additional 14 h at room temperature. The mixture was concentrated in vacuo . The crude product was redissolved in 5 mL dioxane and treated with 5 mL of 4N solution of HCI in dioxane. The reaction was stirred under N2 for 2 h and then filtered. The resulting white solid was dried under high vacuum for 14 h to provide the desired product (0.210 g, 95% yield). -HNMR (DMS0-d6) δ 8.59-8.42 (bs, 2H) , 7.59-7.56 (d, IH) , 7.50-
7.47 (t, IH) , 7.35-7.32 (d, IH) , 7.29-7.21 (t, IH) , 4.66- 4.34 (m, 4H) , 3.77 (bs, IH) , 3.24-3.15 (m, 2H) , 2.44 (m,
4H) , 2.00 (m, 4H) ; MS (ESI+) m/z 264.3 (M+H)+.
Part B. Preparation of 2- (4-Methoxyphenyl) -5- trifluoromethyl-2H-pyrazole-3-carboxylic acid [l-(2-{[(2- hydroxyethyl)methylamino] -methyl}phenyl)piperidin-4- yl] amide A small reaction vessel was charged with the compound of from Part A (0.053g, 0.20 mmol), 2- (4-Methoxyphenyl) -5- trifluoromethyl-2H-pyrazole-3-carboxylic acid (0.037 g, 0.13 mmol), 4-methylmorpholine (36 ul, 0.33 mmol) and DMF (3 mL) . While stirring under N2 , Castro's Reagent (0.089 g, 0.20 mmol) was added and the reaction mixture was allowed to stir at room temperature for 48 h. The reaction was concentrated and purified by prep LC/MS to obtain the target compound. (0.016 g, 23% yield). 1HNMR (DMS0-d6) δ 8.72 (d, IH) , 7.50-7.41 (m, 7H) , 7.34-7.23 (t, IH) , 7.08- 7.03 (d, 2H) , 4.49-4.45 (m, 2H) , 3.81 (s, 3H) , 3.77 (m, 2H) , 3.14 (m, 2H) , 2.98 (m, 2H) , 2.80 (bs, 4H) , 1.89 (m, 2H) , 1.71 (m, 2H) ; MS (ESI+) m/z 532.5, (M+H)+.
Examples 42 and 43 N- (2- {4- [3-cyano-l- (4-methoxyphenyl) -7-oxo-l, 4,5,7- tetrahydro-6ff-pyrazolo[3, 4-c]pyridin-6-yl] -1- piperidinyl}benzyl) -N-methylacetamide, trifluoroacetic acid salt and6- [1- (2- { [acetyl (methyl) amino]methyl}phenyl) -4- piperidinyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro- lff-pyrazolo [3, 4-c]pyridine-3-carboxamide, trifluroacetic acid salt
Figure imgf000259_0001
Part A. Preparation of 1' -benzyl-1,4' -bipiperidin-2-one l-Benzyl-4-aminopiperidine (16.97 g, 89.0 mmol) was stirred in EtOAc (400 mL) . Aqueous K2C03 (20%w/w, 13.56 g in 54 mL H20, 1.1 eq) was added, followed by dropwise addition of 5- bromovaleryl chloride (19.53 g, 1.1 eq) during a half-hour period at room temperature under N2. The resulting mixture was stirred at room temperature for lh. LC-MS showed completion of the reaction. The layers were separated. The aqueous layer was extracted with EtOAc (2x) . The combined organic layers were washed with H20 (2x) , brine (2x) , dried over MgS04, filtered, and concentrated to dryness to yield off-white solids (17.57 g) . This compound was stirred in THF (200 mL) at 0eC under N2. KO-tBu (7.26 g, 1.3 eq) was added portionwise over 10-min period. The mixture was stirred at 0aC for 0.5 h. LC-MS showed completion of the reaction. Sat'd NH4C1 was added, and the mixture was extracted with EtOAc (2x) . The organic layer was washed with H 0 (2 x) , brine (2x) , dried over MgS04, filtered, and concentrated to dryness to yield the desire product, 1 ' -benzyl-1, 4 ' -bipiperidin-2-one, as off-white floatable solids (13.38 g, yield: 99%). iHNMR (CDC13) δ 7.30 (m, 5H) , 4.54 (m, IH) , 3.50 (s, 2H) , 3.19 (m, 2H) , 2.92 (m, 2H) , 2.39 (t, J = 5.8 Hz, 2H) , 2.11 (td, J = 11.7, 2.5 Hz, 2H) , 1.76 (m, 4H) , 1.58 (m, 2H) .
Part B. Preparation of 1 ' -benzyl-3, 3-diσhloro-1,4 ' - bipiperidin-2-one
The product from Part A (9.94 g, 36.54 mmol) and PC15 (22.80 g, 109.6 mmol) were refluxed in CHC13 (100 mL) for 3 h under N2. LC-MS showed completion of the reaction. The mixture was cooled in an ice bath, and H0 was added. The product was extracted with CHC13, washed with sat'd NaHC03, H20, brine, dried over MgS04, filtered, and concentrated to dryness. The desired product (10.56 g, 85%) was essentially pure 1 ' -benzyl-3 , 3-dichloro-l, 4 ' -bipiperidin-2- one, and used directly in the next step. LC/MS (ESI+) , 341.4 (M+H) . !HNMR (CDCI3) δ 7.32 (m, 5H) , 4.46 (m, IH) , 3 . 55 ( s , 2H) , 3 . 31 ( t , J = 6 . 0 Hz , 2H) , 2 . 99 (m, 2H) , 2 . 76 (m, 2H) , 2 . 16-1 . 64 (m, 8H) .
Part C. Preparation of l-(l-benzyl-4-piperidinyl)-3- (4- morpholinyl) -5, 6-dihydro-2 (Iff) -pyridinone
The product from Part B (10.56 g, 31.06 mmol) was refluxed in morpholine (50 mL) overnight under N . LC-MS showed completion of the reaction. Solvent was evaporated. The residue was diluted with EtOAc, washed with H0 (2x) , brine (2x) , dried over MgS04, and concentrated to yield light tan foam of 1- (l-benzyl-4-piperidinyl) -3- (4-morpholinyl) -5, 6- dihydro-2 (Iff) -pyridinone (9.85 g, 86%). LC/MS (ESI+) , 356.2 (M+H) .
Part D. Preparation of ethyl 6- (l-benzyl-4-piperidinyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7-tetrahydro-lff-pyrazolo[3,4- c]pyridine-3-carboxylate
The product from Part C (9.75 g, 27.46 mmol) and ethyl 2- chloro[ (4-methoxyphenyl)hydrazono] ethanoate (7.03 g, 27.46 mmol) were stirred in toluene (100 mL) room temperature under N2. Et3N (7.65 mL, 55.11 mmol) was added. The mixture was stirred overnight at 85°C. It was cooled to room temperature and concentrated. The residue was dissolved in CH2C12 (100 mL) . 4N HCI (35 mL) was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 7h. LC-MS showed completion of the reaction. After cooling, the reaction was basified with IN NaOH, and extracted with CHC12 (3x) .
The organic layers were washed with H20 (2x) , brine (2x) , dried over MgS04, filtered, and concentrated to dryness.
The residue was purified by Flash column chromatography (silica gel, CH2C12, then EtOAc, then EtOAc :MeOH:Et3N = 10:1:0.5) to produce the desired compounds of ethyl 6-(l- benzyl-4-piperidinyl) -1- (4-methoxyphenyl) -7-oxo-4, 5, 6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxylate as light-tan solids (5.5 g, yield: 41%). 1HNMR (CDC13) δ 7.45 (d, J = 8.7 Hz, 2H) , 7.30 (m, 5H) , 6.94 (d, J = 8.9 Hz,
2H) , 4.54 (m, IH) , 4.43 (q, J = 7.2 Hz, 2H) , 3.83 (s, 3H) , 3.58 (t, J = 6.7 Hz, 2H) , 3.49 (s, 3H) , 3.11 (t, J = 6.8 Hz, 2H) , 2.95 (m, 2H) , 2.76 (m, 2H) , 2.16-1.64 (m, 8H) , 1.40 (t, J = 7.2 Hz, 3H) . LC/MS (ESI+) , 489.6 (M+H) .
Part E. Preparation of ethyl 1- (4-methoxyphenyl) -7-oxo-6-
(4-piperidinyl)-4,5,6, 7-tetrahydro-lff-pyrazolo [3,4- c]pyridine-3-carboxylate
CH3COOH (0.1 mL) was added to a mixture of the product from Part D (600 mg, 1.2 mmol), 10% Pd-C (600 mg) , and MeOH (10 mL) under an H2 atmosphere (balloon) . The suspension was stirred at room temperature for 3h and then filtered through a bed of Celite®. The filter cake was washed with methanol and concentrated in vacuo to give ethyl l-(4- methoxyphenyl) -7-oxo-6- (4-piperidinyl) -4,5,6, 7-tetrahydro- lff-pyrazolo [3 , 4-c] pyridine-3-carboxylate (460 mg, 94%). LC/MS (ESI+) 399.6 (M+H). λHNMR (CDCI3) δ 7.42, 6.92
(AA'BB', J = 8.9 Hz, 4H) , 4.50 (m, IH) , 4.40 (q, J = 6.9 Hz, 2H) , 3.80 (s, 3H) , 3.55 (t, J" = 6.6 Hz, 2H) , 3.08 (m, 4H) , 2.03 (m, 2H) , 1.71 (m, 2H) , 1.60 (m, 2H) , 1.35 (t, J = 6.9 Hz, 3H) .
Part F. Preparation of 1- (4-methoxyphenyl) -7-oxo-6- (4- piperidinyl) -4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine- 3-carboxamide
The product from Part E (400 mg, 1.5 mmol) was heated in 8% NH3(g) solution in ethylene glycol (10 mL) in a sealed tube at 85°C for 2h. The reaction mixture was then purified by Reverse phase HPLC (20-98% CH3CN/H20 30 min) to obtain the desire product 1- (4-methoxyphenyl) -7-oxo-6- (4-piperidinyl) - 4,5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide (350 mg, 80%). LC/MS (ESI+) 370.6 (M+H). ^-HNMR (CDC13) D
7.20 (AA'BB', J = 9.0 Hz, 4H) , 4.76 (m, IH) , 4.40 (m, IH) , 3.81 (s, 3H) , 3.52 (m, 4H) , 3.08 (m, 2H) , 2.92 (m, 2H) , 2.12 (m, 2H) , 1.81 (m, 2H) . 13C NMR (CDC13) δ 164.2,
160.0, 157.4, 133.2, 132.3, 126.7, 125.2, 113.7, 55.6, 47.1, 43.8, 41.8, 26.0, 21.2.
Part G. Preparation of 6- [1- (2-formylphenyl) -4- piperidinyl] -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro- lff-pyrazolo [3, 4-c]pyridine-3-carboxamide The product from Part F (350 mg, 0.95 mmol), o- fluorobenzaldehyde (0.15 mL, 1.4 mmol), and K2C0 (262 mg,
1.9 mmol) were heated in anhydrous DMSO (2 mL) at 85°C for 16h. The reaction mixture was then partitioned between water and ethyl acetate . The organic layer was washed by sat'd NaHC03, brine, dried (Na2S04) , filtered, and concentrated in vacuo. The residue was purified by FCC (80% ethyl acetate/Hexane) to produce 6-[l-(2- formylphenyl ) -4-piperidinyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide (160 mg, 78% based on recovered starting material) . LC/MS (ESI+) 474.4 (M+H). ^-HNMR (CDC13) δ 10.3 (s, IH) , 7.78 (dd, J = 1 . 1 , 1.4 Hz, IH) , 7.48 (dd, J = 8.0, 1.9 Hz, IH) , 7.44, 6.97 (AA'BB', J= 9.0 Hz, 4H) , 7.08 (t, J = 8.0 Hz, 2H) , 4.71 (m, IH) , 3.84 (s, 3H) , 3.63 (t, J = 6.8 Hz, 2H) , 3.35 (m, 2H) , 3.21 (t, J" = 6.8 Hz, 2H) , 2.96 (td, J = 10.8, 1.8 Hz, 2H) , 2.02 (m, 2H) , 1.78 (m, 2H) . 13C NMR (CDC13) δ 191.2, 163.8, 159.9, 157.4, 155.4, 140.5, 135.0, 133.8, 132.6, 130.3, 128.5, 127.0, 126.9, 124.9, 122.6, 119.2,
113.7, 55.5, 53.9, 49.5, 42.0, 29.6, 21.2.
Part H. Preparation of 1- (4-methoxyphenyl) -6- (l-{2- [ (methylamino)methyl]phenyl} -4-piperidinyl) -7-oxo-4,5, 6, 7- tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3-carboxamide
A solution of the product from Part G (100 mg, 0.2 mmol), methyl amine (0.1 mL) , NaBH(0Ac)3 (100 mg, 1.2 mmol), and
HOAc (0.02 mL) were stirred in anhydrous MeOH/CH2Cl2 (3:1, 4 mL) at room temperature for 2h under N2. The mixture was then concentrated in vacuo. The residue was purified by prep LC-MS (5-98% CH3CN/H20 in a 10-min run) to obtain the product 1- (4-methoxyphenyl) -6-(l-{2-[ (methylamino) methyl] phenyl} -4-piperidinyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide (85 mg, 86%). LC/MS (ESI+) 489.6 (M+H). iH MR δ 9.83 (br, s, NH2 , 2H) , 7.45 (dd, J = 7.9, 2.2 Hz, 2H) , 7.39 (dd, J = 1.1, 1.4 Hz, IH) , 7.32 (dd, J = 1.1. , 1.8 Hz, IH) , 7.19 (t, J = 7.4 Hz, 2H) , 6.99 (d, J" = 7.9, 2.2 Hz, 2H) , 4.67 (m, IH) , 4.21 (br s, 2H) , 4.64 (m, IH) , 3.80 (s, 3H) , 3.62 (t, J = 3.6
Hz, 2H) , 3.12 (m, 4H) , 2.86 (t, J = 11.1 Hz, 2H) , 2.58 (m, 3H) , 2.03 (m, 2H) , 1.77 (m, 2H) .
Part I. Preparations of 6- [1- (2- { [acetyl (methyl) amino]methyl}phenyl) -4-piperidinyl] -1- (4- methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff-pyrazolo [3, 4- c]pyridine-3-carboxamide and , JV- (2-{4- [3-cyano-l- (4- methoxyphenyl) -7-oxo-l, 4, 5, 7-tetrahydro-6ff-pyrazolo [3, 4- c]pyridin-6-yl] -1-piperidinyl}benzyl) -N-methylacetamide A solution of the product from Part H (17 mg, 0.02 mmol), acetyl chloride (0.05 mL) , and pyridine (0.05 mL) in anhydrous CH2C12 (1 mL) was stirred at room temperature for 2h under N2. Two products (1:5) were detected by LC/MS
(ESI+) : 531.6 (M+H) and 513.6 (M+H) for the amide (I-l) and the nitrile (1-2), respectively. The mixture was then concentrated in vacuo, and the residue was purified by prep LC-MS (5-98% CH3CN/H20 in a 10-min run) to obtain the product I-l, 6- [1- (2-{ [acetyl (methyl) amino]methyl}phenyl) - 4-piperidinyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide (1.6 mg, 10%). LC/MS (ESI+) , 531.6 (M+H). And product 1-2, N- (2-{4- [3-cyano-l- (4-methoxyphenyl) -7-oxo-l, 4 , 5, 7- tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6-yl] -1- piperidinyl}benzyl) -N-methylacetamide (8 mg, 50%). LC/MS (ESI+) , 513.6 (M+H) .
Example 44
1- (4-methoxyphenyl) -6-[l-(2-{ [methyl
(methylsulfonyl)amino]methyl}phenyl) -4-piperidinyl] -7-oxo-
4,5, 6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide, trifluoroacetic acid salt
Figure imgf000265_0001
A solution of the product from Part G of Example 42 (12 mg, 0.01 mmol), methanesulfonyl chloride (0.02 mL) , and pyridine (0.02 mL) in anhydrous CHC12 (1 mL) was stirred at room temperature for 2h under N2. The mixture was then concentrated. The residue was purified by prep LC/MS (5- 98% acetonitrile/H0 in a 10-min run) to give l-(4- methoxyphenyl) -6- [1- (2- { [methyl (methylsulfonyl) amino] methyl}phenyl) -4-piperidinyl] -7-oxo-4, 5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3 -carboxamide (10 mg, 85%). LC/MS (ESI+) 567.6 (M+H); !HNMR ((CD3)2CO) δ 7.50 (dd, J = 6.6, 1.8 Hz, 2H) 7.27 (m, 2H) , 7.12 (m, 2H) , 6.99 (dd, J" = 7.0, 2.0 Hz, 2H) , 4.82 (m, 2H) , 4.58 (m, IH) , 3.80 (s, 3H) , 3.78 (t, J = 5.6 Hz, 2H) , 3.20-2.80 (m, 9H) , 1.71 (m, 2H) .
Example 45 6-(4-{2-[ (dimethylnitroryl)methyl] -Iff-imidazol-1- yl}phenyl) -1- (4-methoxyphenyl) -3- (trifluoromethyl) -1,4, 5, 6- tetrahydro-7ff-pyrazolo [3, 4-c]pyridin-7-one
Figure imgf000266_0001
Part A: Preparation of 1- [4-methoxyphenyl] -3- trifluoromethyl-6- [4-iodophenyl]-l, 4,5,6- tetrahydropyrazolo- [3, 4-c] -pyridin-7-one
3-Hydroxy-l- (4-iodophenyl) -4- (trifluoroacetyl) -5 , 6-dihydro- 2(1 ff) -pyridinone (10.0 g, 24.3 mmol) and 4- methoxyhydrazme hydrochloride (4.28 g, 24.3 mmol) were dissolved in HCI (IN, 200 mL) and methanol (400 mL) and refluxed overnight. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with brine, and dried (Na2S04) . Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent afforded the desired trimethylpyrazole intermediate 9.28 g (74%); 1HNMR (CDC13) δ 7.69 (d, j=9.4Hz, 2H) , 7.45 (d, j=8.8Hz, 2H) , 7.06 (d, j=8.8Hz, 2H) , 6.92 (d, j=9.2Hz, 2H) , 4.11(t, j=6.8Hz, 2H) , 3.81 (s, 3H) , 3.15 (t, j=6.5Hz, 2H) ppm; Mass Spec (M+H)+ 514.3.
Part B: Preparation of 6-(4-{2-[ (dimethylamino)methyl] -lff- imidazol-l-yl}phenyl) -1- (4-methoxyphenyl) -3- (trifluoromethyl) -1,4, 5, 6-tetrahydro-7ff-pyrazolo[3,4- c]pyridin-7-one
The product from part A (500 mg, 0.97 mmol), 2- dimethylammomethyl imidazole (146 mg, 1.17 mmol), cesium carbonate (348 mg, 1.07 mmol), and copper iodide (37 mg, 0.20 mmol) were charged to a flask and flushed with N .
DMSO (6 mL) was syringed into the flask and the reaction was heated to 120°C overnight. The reaction was cooled to room temperature, quenched with water and ammonium hydroxide to pH 12, extracted with ethylacetate, washed with brine, and dried (Na2S04) . Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane followed by 0%-10% methanol/ethyl acetate as eluents, prep. HPLC and freeze-dying afforded the desired product 268.6 mg (54%). iHNMR (CDC13) δ 7.53-7.43 ( , 4H) , 7.37 (d, j=8.5Hz, 3H) , 7.27 (s, IH) , 6.94 (d, j=9.2Hz, 2H) , 4.49 (s, 2H) , 4.24 (t, j=6.6Hz, 2H) , 3.82 (s, 3H) , 3.22(t, j=6.4Hz, 2H) , 2.83 (s, 6H) ppm; Mass Spec (M+H)+ 511.5.
Part C: Preparation of 6-(4-{2-[ (dimethylnitroryl)methyl] - lff-imidazol-l-yl}phenyl) -1- (4-methoxyphenyl) -3- (trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pyrazolo [3,4- c]pyridin-7-one The product from part B (100 mg) was dissolved in dichloromethane (20 mL) . To this solution was added 3 equivalents of MCPBA and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate and the organic layer separated and concentrated. The title compound was obtained as colorless crystals by purification va reverse phase HPLC and lyophylization. ESI mass spectrum 527 (M+H); HNMR (CDCI3) δ 7.54 (m, 6H) , 7.38 (d, 2H) , 6.95 (d, 2H) , 5.40 (s) , 4.20(t, 2H) , 3.82 (s, 3H) , 3.50 (s, 6H) , 3.20(t, 2H) ppm.
Example 46
1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2 ' - { [bis (2- hydroxyethyl) amino]methyl}-l, 1' -biphenyl-4-yl) -3-
(trifluoromethyl) -1,4, 5, 6-tetrahydro-7ff-pryazolo[3,4- c]pyridin-7-one Trifluoroacetic acid salt
Figure imgf000268_0001
Part A: Preparation of 1- [3-cyano-4-fluorophenyl] -3- trifluoromethyl-6- [4-iodophenyl] -1,4,5,6- tetrahydropyrazolo- [3, 4-c] -pyridin-7-one
To 1- (4-iodophenyl) -3- (4-morpholinyl) -4- (trifluoroacetyl) - 5, 6-dihydro-2 (Iff) -pyridinone (2.2g,4.6 mmol) was added 2- fluoro-5-hydrazinobenzonitrile hydrochloride (l.llg,6 mmol) and 50% con. HCI (10 mL) , acetic acid (25 mL) and MeOH (30 mL) . The reaction was heated to reflux for 24h, then cooled and concentrated. The residue was extracted with ethyl acetate, washed with water, brine, and sat'd NaHC0 , and dried (Na2S0 ) . Purification by chromatography on silica gel using 3:1 Hexanes/ethyl acetate as eluent afforded 0.68g(28%) of a yellow foam. Mass Spec (M-H)" 524.9.
Part B: Preparation of 1- [3-cyano-4-fluorophenyl] -3- trifluoromethyl-6- [2 '-formyl-1, 1' -biphenyl] -1,4, 5,6- tetrahydropyrazolo- [3,4-σ] -pyridin-7-one
To the iodo compound from Part A (0.67 g, 1.27 mmol) was added 2-formylbenzeneboronic acid (0.29 g, 1.9 mmol), K3P04
(0.95 g, 4.5 mmol) and dioxane (25 mL) and the mixture was degassed with N for 15 min. Tetrakistriphenylphosphine
Palladium (73 mg) was added and the reaction was heated to reflux 1.5h. The reaction was stripped and purification by chromatography on silica gel using 2:1 Hexanes/ethyl acetate as eluent afforded 0.37g(58%) of a brown foam. MS (M+H20)" 522.1.
Part C. Preparation of 1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2'-bromomethyl}-l, 1' -biphenyl-4-yl) -3- (trifluoromethyl) - l,4,5,6-tetrahydro-7ff-pryazolo[3,4-c]pyridin-7-one To the aldehyde from Part B (2 g, 0.3.8 mmol) in 2:1
THF/MeOH (50 mL) at 0 °C was added NaBH4 (0.17 g, 0.46 mmol) and the reaction was stirred 30 min. The reaction was concentrated and partitioned between CH2C12/H20. The organic layer was washed with brine and dried (MgS04) to afford crude alcohol. To acetohydroxamic acid (0.89 g, 11.9 mmol) in DMF (5 mL) was added K2C03 (2.139 g, 15.9 mmol) and several drops of water. After 30min the above alcohol in DMF (15 mL) was added and the reaction was stirred 24h. The reaction was concentrated, diluted with water and extracted with ethyl acetate, washed with water and brine and dried (MgS04) to afford the crude aminobenzisoxazole . To the above compound in CH2C12 (25 L) was added PBr3(0.52 mL,5 mmol) and the reaction was stirred 30min. The reaction was quenched with water, extracted with CH2C12 and dried (Na S04) . Purification by chromatography on silica gel using 1:1 hexanes/ethyl acetate then 1:1 ethyl acetate/CHCl2 as eluent afforded 1.5g(75%) of a orange foam. iHNMR (CDC13) δ 7.79 (s, IH) , 7.74 (dd,j=9.2, 1.8Hz ,
IH) , 7.53-7.45 (m, 4H) , 7.40 (d,j=8.4Hz, 2H) , 7.35 (m, 2H) , 7.22 (dd,j=8.4, 1.8Hz, IH) , 4.43 (s,4H), 4.26 ( t, j=6.6Hz, 2H) , 3.25(t, j=6.6Hz, 2H) ppm.
Part D. Preparation of 1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2'-{ [bis (2-hydroxyethyl) amino]methyl}-l, 1' -biphenyl-4-yl) - 3- (trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pryazolo[3,4- c] pyridin-7-one Trifluoroacetic acid salt
The bromide from Part C (0.2 g, 0.344 mmol) was combined with excess diethanolamine (0.5 mL) in 10:1 CH3CN/CHCI3 (20 mL) and the reaction was stirred 24h. TFA was added and the solvents removed. The residue was purified by HPLC and freeze-dried to afford 70 mg(29%); ^-HNMR (DMSO-d6) D 8.79 (m, IH) , 8.11 (d,j=1.8Hz, IH) , 7.81 (dd, j=8.8, 2.2Hz , IH) ,
7.76 (m, IH) , 7.58 (d,j=8.8Hz, 2H) , 7.54 (m, IH) , 7.51 (d,j=8.8Hz, 2H) , 7.40 (d,j=8.4Hz, 2H) , 7.36 (m, 2H) , 6.57 (s, 2H) , 4.47 (s, 2H) , 4.23 (t,j=6.6Hz, 2H) , 3.55 (m, 4H) ,
3 . 21 ( t , j =6 . 2Hz , 2H) , 3 . 03 (m, 4H) ppm; HRMS for C31H30F3O4N6
(M+H) + 607 . 2268 .
Example 47 1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2'-{ [ (3-aminopropyl)
(methyl) amino]methyl}-1, 1' -biphenyl-4-yl) -3- (trifluoromethyl) -1, 4, 5, 6-tetrahydro-7ff-pryazolo [3,4- c]pyridin-7-one Trifluoroacetic acid salt
Figure imgf000271_0001
Part A. Preparation of benzyl 3- ( ethylamino)propylcarbamate
To benzyl chloroformate (1 g, 5.8 mmol) in CH2C12 (25 mL) at 0°C was added dropwise imidazole (0.79g, 11.7 mmol) in CH2C12 (20 mL) . After the additon was complete the reaction was stirred at room temperature for 15 min. , then washed with 10% citric acid, brine, and dried (MgS04) . The product obtained was combined with N-methyl-1, 3-propane diamine (0.6 mL, 5.8 mmol) and DMAP (15 mg) in CH2C12 (30 mL) and stirred for 24h. The reaction was stripped, diluted with ethyl acetate, washed with 5% citric acid and brine and dried (MgS04) . Mass Spec (M+H)+ 223.3
Part B. Preparation of 1- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2 ' -{ [ (3-aminopropyl) (methyl) amino]methyl}-1, 1' -biphenyl- 4-yl) -3- (trifluoromethyl) -1,4, 5, 6-tetrahydro-7ff- pryazolo[3,4-c]pyridin-7-one trifluoroacetic acid salt
To the product of Part A (0.12 g, 0.54 mmol) was added the bromide (0.157 g, 0.27 mmol) from Part C of Example 46 in CH3CN and the reaction was stirred 72h. The solvent was removed and the residue dissolved in ethyl acetate, washed with water and dried (MgS04) . TFA (5 mL) was added and the reaction was heated to reflux lh. The TFA was removed and the crude product was purified by HPLC and freeze-dried to afford 65 mg(29%). l-HNMR (DMSO-d6) δ 8.11 (d,j=1.9Hz, IH) , 7.81 (dd, j=2.2,8.8Hz, IH) , 7.74 (brd s, 4H) , 7.58 (d,j=9.2Hz, 2H) , 7.50 (m, IH) , 7.51 (d,j=8.5Hz, 2H) , 7.42 (d,j=9Hz, IH) , 7.39 (m, IH) , 6.58 (s, 2H) , 4.31 (m, IH) , 4.24 (m, IH) , 4.23 ( t , j=6.6Hz, 2H) , 3.21 ( t, j=6.6Hz, 2H) , 3.10 (m, IH) , 2.89 (m, IH) , 2.72 (m, 2H) , 2.50 (s, 3H) , 1.75 (m, 2H)ppm; HRMS (M+H) + for C31H31F3N702 590.2498
Example 48 6- (2 • - { [ (2-hydroxyethyl) (methyl) amino]methyl}-1, 1' - biphenyl-4-yl) -1- (4-methoxyphenyl) -7-oxo-4,5,6,7- tetrahydro-lff-pryazolo [3, 4-c]pyridine-3-carboxamide trifluoroacetic acid salt
Figure imgf000272_0001
To ethyl 6- (2 ' -formyl-1, 1 ' -biphenyl-4-yl) -1- (4- methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c] pyridine-3-carboxylate from Part A of Example 31 (0.46 g, 0.93 mmol) in THF (15 mL) and ethanol (25 mL) was added 2- methylaminoethanol (0.1 5 mL, 1.8 mmol) and the reaction was stirred 15min. A 0.5M solution of ZnCl2 in THF (0.93 mL, 0.4 mmol) followed by NaBH3CN (58 mg, 0.9 mmol) were added.
The reaction was stirred 24 h. The reaction was concentrated and partitioned with ethyl acetate and water. Extraction with ethyl acetate and drying (Na2S0 ) afforded crude ester. The ester was treated with excess NHOH in methanol (20 mL) for 24h. The solvents were removed and purification by silica gel chromatography using 1 to 9% methanol/CH2Cl2 (w/l%NH3) as eluent afforded 0.24g of free base. The free base was treated with TFA (0.1 mL) in water and CH3CN and freeze-dried to afford 0.29g(49%); XHNMR
(DMS0-d6) δ 7.76 (s, IH) , 7.75 (m, IH) , 7.55 (m, 3H) , 7.50 (d, j=8.8Hz,4H) ,7.38 (d,j=8.8Hz, 2H) , 7.35 (m, IH) , 7.02 (d,j=8.8, 2H) , 4.39 (m, 3H) , 4.13 (t,j=6.6Hz, 2H) , 3.81 (s, 3H) , 3.58 (m, 2H) , 3.26 (t,j=6.5Hz, 2H) , 3.05 (m, IH) , 2.90 (m, IH) , 2.59 (s, 3H) ppm; HRMS (M+H) + for C30H32N5O4
526.2470.
Example 49 6- (2 ' - { [bis (2-hydroxyethyl) amino]methyl} -1, 1' -biphenyl-4- yl) -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-lff- pryazolo [3, 4-c]pyridine-3-carboxamide Trifluoroacetic acid salt
Figure imgf000273_0001
To ethyl 6- (2 ' -formyl-1, 1 ' -biphenyl-4-yl) -1- (4- methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c] pyridine-3-carboxylate from Part A of Example 31 (0.4 g, 0.81 mmol) in THF (15 mL) and methanol (25 mL) was added diethanolamine (0.18 mL, 1.8 mmol) and the reaction was stirred 15 min. A 0.5M solution of ZnCl2 in THF (0.8 mL, 0.4 mmol) followed by NaBH3CN (50 mg, 0.79 mmol) were added. The reaction was stirred 24h. The reaction was concentrated and partitioned with ethyl acetate and water. Extraction with ethyl acetate and drying (Na2S0 ) afforded crude ester. The ester was treated with excess NH OH and NH4C1 in methanol (20 mL) for 72h. The solvents were removed and purification by silica gel chromatography using 1 to 9% methanol/CH2C12 (w/l%NH3) as eluent afforded 0.37g of free base. The free base was treated with TFA (0.1 mL) in water and CHCN and freeze-dried to afford 0.41g(66%); l-HNMR (DMSO-d6) δ 7.7 (m, 2H) , 7.55 (m, 4H) , 7.50 (d, j=9.2Hz,4H) ,7.39 (d,j=8.4Hz, 2H),7.35 (m, 1H),7.03 (d,j=8.8, 2H) , 4.49 (s, 2H) , 4.10 (m, IH) , 4.15 (t, j=6.6Hz , 2H) , 3.81 (s, 3H) , 3.57 (m, 4H) , 3.26 ( t , j=6.5Hz, 2H) , 3.04 (m, 4H)ppm; HRMS (M+H)+ for C31H34N5θ5 556.2574.
Example 50 6-(2'-{[ (3-aminopropyl) (methyl) amino]methyl}-l, 1'- biphenyl-4-yl) -1- (4-methoxyphenyl) -7-oxo-4,5, 6,7- tetrahydro-lff-pryazolo [3, 4-c]pyridine-3-carboxamide
Trifluoroacetic acid salt
Figure imgf000274_0001
To ethyl 6- (2 ' -formyl-1, 1 ' -biphenyl-4-yl) -1- (4- methoxyphenyl ) -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c] pyridine-3-carboxylate from Part A of Example 31 (0.4 g, 0.81 mmol) in THF (15 mL) and ethanol (25 mL) was added the carbobenzyloxy protected amine from Part A of Example 47 (0.54 g, 2.4 mmol). The reaction was stirred for 15 min. A 0.5M solution of ZnCl2 in THF (0.8 mL, 0.4 mmol) followed by NaBH3CN (50 mg, 0.79 mmol) were added. The reaction was stirred 24h. The reaction was concentrated and partitioned with ethyl acetate and water. Extraction with ethyl acetate and drying (Na2S0 ) afforded crude ester. The ester was treated with excess NH OH and NHC1 in methanol (20 mL) for 72h. The solvents were removed and purification by silica gel chromatography using 0 to 10% methanol/CH2C1
(w/l%NH3) as eluent afforded carbobenzyloxy protected product. The protected product was treated with TFA at reflux for lh and purified by HPLC and freeze-dried to afford 0.1g(16%); !HNMR (DMS0-d6) δ 7.77 (m, 4H) , 7.53 (m, 5H) , 7.50 (d,j=8.7Hz, 2H) , 7.41 (d,j=8.8Hz, 2H) , 7.30 (m, IH) , 7.03 (d,j=8.8, 2H) , 4.45 (m, IH) , 4.25 (m, IH) , 4.15(t, j=6.6Hz, 2H) , 3.81 (s, 3H) , 3.27 ( t , j=6.2Hz, 2H) ,
3 . 05 (m, IH) , 2 . 95 (m, IH) , 2 . 72 (m, 2H) , 2 . 50 ( s , 3H) , 1 . 85 (m, 2H) ppm; HRMS (M+H) + for C31H35N603 539 . 2767 .
Example 51 6- (2' -{[(2-hydroxyethyl) (methyl) amino]methyl}-l, 1'- biphenyl-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -
1,4,5, 6-tetrahydro-lff-pryazolo [3, 4-c]pyridin-7-one trifluoroacetic acid salt
Figure imgf000275_0001
Part A. Praparation of 6- (2'-formyl-l, 1' -biphenyl) -1- (4- methoxyphenyl) -3- (methylsulfonyl) -1,4, 5, 6-tetrahydro-7ff- pyrazolo[3,4-c]pyridin-7-one
6- (4-Iodophenyl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) - 1, 4, 5, 6-tetrahydro-7ff-pyrazolo [3, 4-c]pyridin-7-one from Part B of Example 22 (0.41 g, 0.7 mmol) and 2-formyl phenylboronic acid (0.18 g, 1.1 mmol) was added 2M Na2C03
(1 mL) , ethanol (20 L) and toluene (30 mL) and the mixture was degassed with N for 15 min. Tetrakistriphenylphosphine Palladium (0) (50 mg) was added and the reaction was heated to reflux 24h. The reaction was cooled, concentrated and the residue extracted with ethyl acetate, washed with water and dried (MgS04) . Purification by silica gel chromatography using 1:1 hexane/ethyl acetate as eluent afforded 0.28g(71.8%) of an grey solid; Mass Spec (M+Na)+ 524.
Part B. Preparation of 6- (2' -{[ (2-hydroxyethyl) (methyl) amino]methyl}-l, 1' -biphenyl-4-yl) -1- (4- methoxyphenyl) -3- (methylsulfonyl) -1,4,5, 6-tetrahydro-lff- pryazolo[3,4-c]pyridin-7-one Trifluoroacetic acid salt
To the product of Part A (0.06 g, 0.11 mmol) in THF (10 mL) and methanol (10 mL) was added N-methylethanolamine (27 mg, 0.3 mmol) and the reaction was stirred 15min. A 0.5M solution of ZnCl2 in THF (0.119 mL, 0.059 mmol) followed by NaBH3CN (7.5 mg, 0.11 mmol) were added. The reaction was stirred 24h. The reaction was concentrated and partitioned with ethyl acetate and water. Extraction with ethyl acetate and drying (Na2S04) afforded crude amine. Purification by HPLC and freeze-drying afforded 54 mg(66%); XHNMR (DMS0-d6) δ 7.75 (m, IH) , 7.54 (d,j=8.8Hz, 2H) , 7.53 (m, 2H) , 7.48 (d,j=8.8Hz, 2H) , 7.38 (d,j=8.5Hz, 2H) , 7.34 (m, IH) , 7.03 (d,j=9.2Hz, 2H) , 4.35 (m, 2H) , 4.17(t, j=6.6Hz, 2H) , 3.80 (s, 3H) , 3.56 (m, 2H) , 3.36 (s, 3H) , 3.24(t, j=6.6Hz, 2H) , 3.0 (m, 1H),2.95 (m, 1H),2.56 (s, 3H)ppm; HRMS (M+H) + for C30H33 4O5S 561.2164.
The following nomenclature is intended for group A in the following tables.
Figure imgf000277_0001
phenyl 2-pyridyl 3-pyridyl
^"B -C -χ}~B ~ "B
2-pyrimidyl 2-Cl-phenyl 2-F-phenyl piperidinyl
Table 1
Figure imgf000278_0001
,4a. CH2N(Me)20 , a. CH2N(Me)20 =CH2NHC02Me =CH2NHC02Me =CH2N(Et)C02Me =CH2N(Et)C02Me =CH2NHC(θ)NHMe =CH2NHC(0)NHMe =CH2N(Me)Cθ2Et =CH2N(Me)C02Et =CH2N(Me)Cθ2Me =CH2N(Me)C02Me =CH2N(Me)C(0) HMe =CH2N(Me)C(θ)NHMe =CH2NHS02Me =CH2NHS02Me =CH2NHS02Et =CH2NHS02Et =CH2N(Me)S02Me =CH2N(Me)S02Me =CH2N(Me)Sθ2Et =CH2N(Me)S02Et =CH2N(Me)Sθ2Pr =CH2N(Me)S02Pr =CH2NHC(0)Me =CH2 HC(0)Me =CH2NHC(θ)Et =CH2NHC(0)Et =CH2NHC(θ)Pr =CH2NHC(0)Pr =CH2NHC(θ)Bu =CH2NHC(0)Bu =CH2N(Me)C(θ)Me =CH2N(Me)C(0)Me =CH2N(Me)C(θ)Et =CH2N(Me)C(0)Et =CH2N(Me)C(θ)Pr =CH2N(Me)C(θ)Pr =CH2N(Me)C(θ)Bu =CH2N(Me)C(0)Bu =CH2N(Et)C(θ)Me =CH2N(Et)C(θ)Me =CH2N(Et)C(0)Et =CH2N(Et)C(0)Et =CH2N(Et)C(0)Pr =CH2N(Et)C(0)Pr =CH2N(Et)C(0)Bu =CH2N(Et)C(0)Bu =CH2N(Pr)C(0)Me =CH2N(Pr)C(θ)Me =CH2N(Pr)C(θ)Et =CH2N(Pr)C(0)Et =CH2N(Pr)C(θ)Pr =CH2N(Pr)C(0)Pr =CH2N(Pr)C(θ)Bu =CH2N(Pr)C(0)Bu =CH2NHC (0) cyclopropyl =CH2NHC (0) cyclopropyl =CH2N (Me) C(θ) cyclopropyl =CH2N(Me) C (O) cyclopropyl =CH2NHC (0) CH2 eye lopropyl =CH2NHC (O) CH2cyclopropyl =CH2N (cyclopropyl ) C (0) Me =CH2N(eye1opropy1) C (0)Me = CH2N ( CH2 eye 1 opr opy 1 ) C ( 0 ) Me =CH2N(CH2cyclopropyl) C (O)Me =CH2N (Me ) C ( 0 ) CH2cyclopropyl =CH2N (Me) C (0) CH2cyclopropyl =CH2 ( eye lopropyl ) C ( 0 ) Et =CH2N (eyelopropy1) C (0) Et =CH2N (CH2 eye lopropyl) C (0) Et =CH2N (CH2eyelopropyl) C (O) Et =CH2N ( eye lobuty 1 ) C ( O ) Me =CH2N(cyclobutyl) C (0)Me =CH2N ( eye lopentyl ) C ( 0 ) Me =CH2N(cyclopentyl)C(0)Me
Figure imgf000279_0001
=CH2NHC02Me =CH2NHC02Me
=CH2N(Et)C02Me =CH2N(Et)C02Me
=CH2NHC(θ)NHMe =CH2NHC(θ)NHMe
=CH2N(Me)C02Et =CH2N(Me)Cθ2Et
=CH2N(Me)C02Me =CH2N(Me)C02Me
=CH2N(Me)C(0)NHMe =CH2N(Me)C(0)NHMe
=CH2NHS02Me =CH2NHS02Me
=CH2NHS02Et =CH2NHS02Et
=CH2N(Me)S02Me =CH2N(Me)S02Me
=CH2N(Me)S02Et =CH2N(Me)S02Et
=CH2N(Me)S02Pr =CH2N(Me)S02Pr
=CH2NHC(θ)Me =CH2NHC(θ)Me
=CH2NHC(θ)Et =CH2NHC(θ)Et
=CH2NHC(θ)Pr =CH2NHC(θ)Pr
=CH2NHC(θ)Bu =CH2NHC(0)Bu
=CH2N(Me)C(θ)Me =CH2N(Me)C(0)Me
=CH2N(Me)C(θ)Et =CH2N(Me)C(0)Et
=CH2N(Me)C(θ)Pr =CH2N(Me)C(0)Pr
=CH2N(Me)C(0)Bu =CH2N(Me)C(0)Bu
=CH2N(Et)C(θ)Me =CH2N(Et)C(0)Me
=CH2N(Et)C(θ)Et =CH2N(Et)C(0)Et
=CH2N(Et)C(θ)Pr =CH2N(Et)C(0)Pr
=CH2N(Et)C(θ)Bu =CH2N(Et)C(0)Bu
=CH2N(Pr)C(θ)Me =CH2N(Pr)C(θ)Me
=CH2N(Pr)C(0)Et =CH2N(Pr)C(0)Et
=CH2N(Pr)C(θ)Pr =CH2N(Pr)C(0)Pr
=CH2N(Pr)C(θ)Bu =CH2N(Pr)C(0)Bu
=CH2NHC (0) cyclopropyl =CH2 HC (O) cyclopropyl
=CH2N(Me) C (0) cyclopropyl =CH2N (Me) C (0) cyclopropyl
=CH2NHC (0) CH2eyelopropyl =CH2NHC (O) CH2cyclopropyl
=CH2N (cyclopropyl) C (0)Me =CH2N (cyclopropyl) C(θ)Me
=CH2N(CH2cyclopropyl)C(θ)Me =CH2N(CH2cyclopropyl)C(0)Me
=CH2N (Me) C (0) CH2cyclopropyl =CH2N (Me) C (0) CH2eyelopropyl
=CH2N (cyclopropyl ) C (O) Et =CH2N (cyclopropyl)C(θ)Et
=CH2N (CH2cyclopropyl) C (0) Et =CH2N (CH2eyelopropyl) C (0) Et
=CH2N (eyelobuty1) C (0) Me =CH2N(eyelobuty1) C (0) Me
=CH2N (eyelopentyl ) C (0)Me =CH2N(eyelopentyl) C (0)Me
Figure imgf000280_0001
,4a. CH2N(Me)2θ ,4a =CH2N(Me)20 =CH2NHC02Me =CH2NHC02Me =CH2N(Et)C02Me =CH2N(Et)C02Me =CH2NHC(0)NHMe =CH2 HC(θ)NHMe =CH2N(Me)C02Et =CH2N(Me)C02Et =CH2N(Me)C02Me =CH2N(Me)C02Me =CH2N(Me)C(0)NHMe =CH2N(Me)C(θ)NHMe =CH2NHS02Me =CH2 HS02Me =CH2NHS02Et =CH2NHS02Et =CH2N(Me)S02Me =CH2N(Me)S02Me =CH2N(Me)S02Et =CH2N(Me)S02Et =CH2N(Me)S02Pr =CH2N(Me)S02Pr =CH2NHC(0)Me =CH2NHC(0)Me =CH2NHC(θ)Et =CH2NHC(θ)Et =CH2NHC(0)Pr =CH2NHC(θ)Pr =CH2NHC(θ)Bu =CH2NHC(θ)Bu =CH2N(Me)C(0)Me =CH2N(Me)C(θ)Me =CH2N(Me)C(θ)Et =CH2N(Me)C(0)Et =CH2N(Me)C(θ)Pr =CH2N(Me)C(0)Pr =CH2N(Me)C(θ)Bu =CH2N(Me)C(θ)Bu =CH2N(Et)C(0)Me =CH2N(Et)C(θ)Me =CH2N(Et)C(θ)Et =CH2N(Et)C(0)Et =CH2N(Et)C(0)Pr =CH2N(Et)C(θ)Pr =CH2N(Et)C(θ)Bu =CH2N(Et)C(0)Bu =CH2N(Pr)C(θ)Me =CH2N(Pr)C(0)Me =CH2N(Pr)C(0)Et =CH2N(Pr)C(θ)Et =CH2N(Pr)C(0)Pr =CH2N(Pr)C(θ)Pr =CH2N(Pr)C(θ)Bu =CH2N(Pr)C(θ)Bu =CH2NHC (0) cyclopropyl =CH2NHC (0) cyclopropyl =CH2N (Me) C (0) cyclopropyl =CH2N (Me) C (0) cyclopropyl =CH2NHC (0) CH2cyclopropyl =CH2NHC (0) CH2 eye lopropyl =CH2N ( eye lopropyl ) C ( O ) Me =CH2N ( eye lopropyl ) C ( 0 ) e =CH2N (CH2cyclopropyl ) C ( 0) Me =CH2N(CH2eyclopropyl)C(0)Me =CH2N (Me) C (0) CH2cyclopropyl =CH2N(Me) C (O) CH2cyclopropyl =CH2N (cyclopropyl ) C (O) Et =CH2N ( eye lopropyl ) C ( 0 ) Et =CH2N (CH2cyclopropyl ) C (0) Et =CH2N(CH2cyclopropyl) C (O) Et =CH2N (eye lobuty 1 ) C (0) Me =CH2N(cyclobutyl)C(θ)Me =CH2N ( eye lopentyl ) C ( 0 ) Me =CH2N(cyclopentyl)C(θ)Me
Figure imgf000280_0002
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Table 2
Figure imgf000285_0001
R4a=CH2N(Me)20 R a l=CH2N(Me)20
=CH2NHC02Me =CH2NHC02Me
=CH2N(Et)Cθ2Me =CH2N(Et)C02Me
=CH2NHC(0)NHMe =CH2NHC(0)NHMe
=CH2N(Me)C02Et =CH2N(Me)C02Et
=CH2N(Me)C02Me =CH2N(Me)C02Me
=CH2N(Me)C(θ)NHMe =CH2N(Me)C(0)NHMe
=CH2NHS02Me =CH2NHS02Me
=CH2 HS02Et =CH2NHS02Et
=CH2N(Me)S02Me =CH2N(Me)Sθ2Me
=CH2N(Me)S02Et =CH2N(Me)S02Et
=CH2N(Me)Sθ2Pr =CH2N(Me)S02Pr
=CH2NHC(0)Me =CH2NHC(0)Me
=CH2NHC(θ)Et =CH2NHC(0)Et
=CH2NHC(0)Pr =CH2NHC(0)Pr
=CH2 HC(0)Bu =CH2NHC(θ)Bu
=CH2N(Me)C(θ)Me =CH2N(Me)C(0)Me
=CH2N(Me)C(θ)Et =CH2N(Me)C(θ)Et
=CH2N(Me)C(θ)Pr =CH2N(Me)C(θ)Pr
=CH2N(Me)C(0)Bu =CH2N(Me)C(θ)Bu
=CH2N(Et)C(θ)Me =CH2N(Et)C(θ)Me
=CH2N(Et)C(θ)Et =CH2N(Et)C(0)Et
=CH2N(Et)C(0)Pr =CH2N(Et)C(0)Pr
=CH2N(Et)C(0)Bu =CH2N(Et)C(θ)Bu
=CH2N(Pr)C(θ)Me =CH2N(Pr)C(0)Me
=CH2N(Pr)C(θ)Et =CH2N(Pr)C(0)Et
=CH2N(Pr)C(θ)Pr =CH2N(Pr)C(θ)Pr
=CH2N(Pr)C(0)Bu =CH2N(Pr)C(θ)Bu
=CH2NHC (0) cyclopropyl =CH2NHC (0) cyclopropyl
=CH2N(Me) C (0) cyclopropyl =CH2N(Me) C (0) cyclopropyl
=CH2NHC (0) CH2cyclopropyl =CH2NHC (0) CH2cyclopropyl
=CH2N ( cyclopropyl ) C ( 0 ) Me =CH2N ( eye lopropyl ) C ( 0 ) Me
=CH2N ( CH2cyclopropyl ) C ( 0 ) Me =CH2N (CH2 eye lopropyl ) C ( 0) Me
=CH2N (Me) C (0) CH2cyclopropyl =CH2N (Me) C (0) CH2cyclopropyl
=CH2N ( cyclopropyl ) C ( 0 ) Et =CH2N (cyclopropyl) C (0) Et
=CH2N(CH2cyclopropyl) C (O) Et =CH2N (CH2cyclopropyl ) C (0) Et
=CH2N ( eye lobuty 1 ) C ( 0 ) Me =CH2N (cyclobutyl) C (0) Me
=CH2N ( eye lopentyl ) C ( 0 ) Me =CH2N (cyclopentyl )C(0) Me
Figure imgf000286_0001
R4a=CH2N(Me)20 ,4a. CH2N(Me)2θ
=CH2NHC02Me =CH2NHC02Me
=CH2N(Et)Cθ2Me =CH2N(Et)Cθ2Me
=CH2NHC(0)NHMe =CH2NHC(0)NHMe
=CH2N(Me)Cθ2Et =CH2N(Me)C02Et
=CH2N(Me)C02Me =CH2N(Me)C02Me
=CH2N(Me)C(θ)NHMe =CH2N(Me)C(θ)NHMe
=CH2 HS02Me =CH2NHS02Me
=CH2NHS02Et =CH2NHS02Et
=CH2N(Me)S02Me =CH2N(Me)S02Me
=CH2N(Me)S02Et =CH2N(Me)S02Et
=CH2N(Me)Sθ2Pr =CH2N(Me)Sθ2Pr
=CH2NHC(0)Me =CH2NHC(θ)Me
=CH2NHC(0)Et =CH2NHC(θ)Et
=CH2NHC(0)Pr =CH2NHC(θ)Pr
=CH2NHC(0)Bu =CH2NHC(θ)Bu
=CH2N(Me)C(θ)Me =CH2N(Me)C(θ)Me
=CH2N(Me)C(θ)Et =CH2N(Me)C(θ)Et
=CH2N(Me)C(θ)Pr =CH2N(Me)C(θ)Pr
=CH2N(Me)C(0)Bu =CH2N(Me)C(0)Bu
=CH2N(Et)C(0)Me =CH2N(Et)C(θ)Me
=CH2N(Et)C(θ)Et =CH2N(Et)C(θ)Et
=CH2N(Et)C(θ)Pr =CH2N(Et)C(θ)Pr
=CH2N(Et)C(θ)Bu =CH2N(Et)C(θ)Bu
=CH2N(Pr)C(θ)Me =CH2N(Pr)C(θ)Me
=CH2N(Pr)C(0)Et =CH2N(Pr)C(0)Et
=CH2N(Pr)C(θ)Pr =CH2N(Pr)C(θ)Pr
=CH2N(Pr)C(θ)Bu =CH2N(Pr)C(θ)Bu
=CH2NHC (0) cyclopropyl =CH2NHC (O) cyclopropyl
=CH2N (Me) C (0) cyclopropyl =CH2N (Me) C (0) cyclopropyl
=CH2 HC (0) CH2cyclopropyl =CH2NHC (O) CH2cyclopropyl
=CH2N (eyelopropyl) C (O)Me =CH2N (eyelopropyl) C (O)Me
=CH2N (CH2cyclopropyl) C (θ)Me =CH2N (CH2eyelopropyl ) C (O)Me
=CH2N (Me) C (0) CH2eyelopropyl =CH2N(Me)C(θ)CH2cyclopropy1
=CH2N (eyelopropyl) C (0) Et =CH2N(eyelopropyl) C (O) Et
=CH2N (CH2cyclopropyl ) C (0) Et =CH2N(CH2eyelopropyl ) C (O) Et
=CH2N (eyelobutyl) C (0) Me =CH2N(eyelobuty1) C (0) Me
=CH2 (eyelopentyl ) C (0)Me =CH2N(eyelopentyl) C (0)Me
Figure imgf000287_0001
,4a. CH2N(Me)20 R4a=CH2N(Me)20 =CH2NHC02Me =CH2NHC02Me =CH2N(Et)C02Me =CH2N(Et)Cθ2Me =CH2 HC(0)NHMe =CH2NHC(0)NHMe =CH2N(Me)C02Et =CH2N(Me)C02Et =CH2N(Me)C02Me =CH2N(Me)Cθ2Me =CH2N(Me)C(0)NHMe =CH2N(Me)C(0)NHMe =CH2NHS02Me =CH2NHS02Me =CH2 HS02Et =CH2NHS02Et =CH2N(Me)S02Me =CH2N(Me)S02Me =CH2N(Me)S02Et =CH2N(Me)S02Et =CH2N(Me)S02Pr =CH2N(Me)S02Pr =CH2NHC(0)Me =CH2NHC(0)Me =CH2NHC(0)Et =CH2NHC(0)Et =CH2NHC(0)Pr =CH2NHC(θ)Pr =CH2NHC(0)Bu =CH2NHC(0)Bu =CH2N(Me)C(0)Me =CH2N(Me)C(0)Me =CH2N(Me)C(0)Et =CH2N(Me)C(0)Et =CH2N(Me)C(0)Pr =CH2N(Me)C(0)Pr =CH2N(Me)C(θ)Bu =CH2N(Me)C(θ)Bu =CH2N(Et)C(θ)Me =CH2N(Et)C(0)Me =CH2N(Et)C(θ)Et =CH2N(Et)C(0)Et =CH2N(Et)C(0)Pr =CH2N(Et)C(θ)Pr =CH2N(Et)C(0)Bu =CH2N(Et)C(θ)Bu =CH2N(Pr)C(0)Me =CH2N(Pr)C(0)Me =CH2N(Pr)C(0)Et =CH2N(Pr)C(0)Et =CH2N(Pr)C(0)Pr =CH2N(Pr)C(θ)Pr =CH2N(Pr)C(0)Bu =CH2N(Pr)C(θ)Bu =CH2 HC (O) cyclopropyl =CH2NHC (O) cyclopropyl =CH2N (Me ) C(θ) cyclopropyl =CH2N (Me )C(0) cyclopropyl =CH2 HC (0) CH2 eye lopropyl =CH2NHC ( 0 ) CH2cyclopr opyl =CH2 ( eye lopropyl ) C ( O ) Me =CH2N ( eye lopropyl ) C ( O ) Me =CH2N (CH2cyclopropyl ) C (0) Me =CH2N(CH2cyclopropyl)C(θ)Me =CH2N (Me) C (0) CH2cyclopropyl =CH2N (Me) C (0) CH2cyclopropyl =CH2N ( eye lopropyl ) C ( O ) Et =CH2N ( eye lopropyl ) C ( O ) Et =CH2N (CH2cyclopropyl) C (0) Et =CH2N (CH2cyclopropyl ) C (O) Et =CH2 ( eye lobuty 1 ) C ( O ) Me =CH2N(cyelobutyl)C(0)Me =CH2 (cyclopentyl )C(0) Me =CH2N ( eye lopentyl ) C ( O ) Me
Rla is CH3,
Figure imgf000287_0002
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Table 3 Examples 3-1-through 3-6090 use the structures from Table 2 and the corresponding A and G groups from Examples 1-203 of Table 2:
Examples 3-1 to 3-203, Rla is CH2CH3 ; Examples 3-204 to 3-406, Rla is CF3 ; Examples 3-407 to 3-609, Rla is SCH3 ; Examples 3-610 to 3-812, Rla is S0CH3 ; Examples 3-813 to 3-1015, Rla is S02CH3;
Examples 3-1016 to 3-1218, Rla is Cl;
Examples 3-1219 to 3-1421, Rla is F;
Examples 3-1422 to 3-1624, Rla is C02CH3 ;
Examples 3-1625 to 3-1827, Rla is CH2OCH3; Examples 3-1828 to 3-2030, Rla is CONH2 ;
Examples 3-2031 to 3-2233, Rla is -CN;
Examples 3-2234 to 3-2436, Rla is CH2NHCH3 ;
Examples 3-2437 to 3-2639, Rla is CH2NHS02CH3 ; Examples 3-2640 to 3-2842, Rla is l-imidazolyl-CH2 ;
Examples 3-2843 to 3-3045, Rla is Br;
Examples 3-3046 to 3-3248, Rla is 5-tetrazolyl;
Examples 3-3249 to 3-3451, Rla is N(CH3)2;
Examples 3-3452 to 3-3654, Rla is NHCH3 ; Examples 3-3655 to 3-3857, Rla is S02NH2;
Examples 3-3858 to 3-4060, Rla is 2-pyridine;
Examples 3-4061 to 3-4263, Rla is 3-pyridine;
Examples 3-4264 to 3-4466, Rla is 4-pyridine;
Examples 3-4467 to 3-4872, Rla is 2-pyridine-N-oxide; Examples 3-4873 to 3-5075, Rla is 3-pyridine-N-oxide;
Examples 3-5076 to 3-5287, Rla is 4-pyridine-N-oxide;
Examples 3-5288 to 3-5481, Rla is 0CH3 ;
Examples 3-5482 to 3-5684, Rla is CH20C (0)NHCH3 ;
Examples 3-5685 to 3-5887, Rla is CH2NHC02CH3 ; Examples 3-5888 to 3-6090, Rla is CH2NHC (0) NHCH3 ; and,
Examples 3-6091 to 3-6293, Rla is H.
Table 4
Figure imgf000294_0001
=CH2NHC02Me =CH2NHC02Me =CH2N(Et)Cθ2Me =CH2N(Et)C02Me =CH2NHC(0)NHMe =CH2NHC(0)NHMe =CH2N(Me)C02Et =CH2N(Me)C02Et =CH2N(Me)Cθ2Me =CH2N(Me)C02Me =CH2N(Me)C(θ)NHMe =CH2N(Me)C(0)NHMe =CH2NHS02Me =CH2NHS02Me =CH2NHS02Et =CH2NHS02Et =CH2N(Me)Sθ2Me =CH2N(Me)S02Me =CH2N(Me)S02Et =CH2N(Me)S02Et =CH2N(Me)Sθ2Pr =CH2N(Me)S02Pr =CH2NHC(0)Me =CH2NHC(θ)Me =CH2NHC(θ)Et =CH2NHC(θ)Et =CH2NHC(θ)Pr =CH2NHC(θ)Pr =CH2NHC(θ)Bu =CH2 HC(θ)Bu =CH2N(Me)C(0)Me =CH2N(Me)C(θ)Me =CH2N(Me)C(0)Et =CH2N(Me)C(θ)Et =CH2N(Me)C(0)Pr =CH2N(Me)C(θ)Pr =CH2N(Me)C(0)Bu =CH2N(Me)C(θ)Bu =CH2N(Et)C(0)Me =CH2N(Et)C(θ)Me =CH2N(Et)C(θ)Et =CH2N(Et)C(θ)Et =CH2N(Et)C(0)Pr =CH2N(Et)C(θ)Pr =CH2N(Et)C(0)Bu =CH2N(Et)C(θ)Bu =CH2N(Pr)C(0)Me =CH2N(Pr)C(θ)Me =CH2N(Pr)C(0)Et =CH2N(Pr)C(θ)Et =CH2N(Pr)C(0)Pr =CH2N(Pr)C(θ)Pr =CH2N(Pr)C(0)Bu =CH2N(Pr)C(θ)Bu =CH2NHC (O) cyclopropyl =CH2NHC (0) cyclopropyl =CH2N (Me) C (0) cyclopropyl =CH2N(Me) C (0) cyclopropyl =CH2NHC (O) CH2cyclopropyl =CH2NHC (0) CH2cyclopropyl =CH2 (eyelopropyl) C (0)Me =CH2N(eyelopropyl) C (O)Me =CH2N (CH2cyclopropyl) C (O)Me =CH2N(CH2cyclopropyl) C (O)Me =CH2N (Me) C (0) CH2cyclopropyl =CH2N(Me) C (0) CH2eyelopropyl =CH2N (cyclopropyl)C(0)Et =CH2N(eyelopropyl) C (O) Et =CH2N (CH2cyclopropyl) C (O) Et =CH2N(CH2cyclopropyl)C(θ)Et =CH2N(cyelobutyl)C(0)Me =CH2N(eyelobutyl) C (O) Me =CH2N(cyelopentyl)C(0)Me =CH2N(eyelopentyl) C (O)Me
Figure imgf000295_0001
R a=CH2N(Me)20 R4a=CH2N(Me)2θ
=CH2NHC02Me =CH2NHC02Me
=CH2N(Et)C02Me =CH2N(Et)C02Me
=CH2NHC(θ)NHMe =CH2NHC(θ)NHMe
=CH2N(Me)C02Et =CH2N(Me)C02Et
=CH2N(Me)C02Me =CH2N(Me)C02Me
=CH2N(Me)C(0)NHMe =CH2N(Me)C(0)NHMe
=CH2NHS02Me =CH2NHS02Me
=CH2NHS02Et =CH2NHS02Et
=CH2N(Me)S02Me =CH2N(Me)S02Me
=CH2N(Me)S02Et =CH2N(Me)S02Et
=CH2N(Me)S02Pr =CH2N(Me)S02Pr
=CH2NHC(θ)Me =CH2NHC(θ)Me
=CH2NHC(θ)Et =CH2NHC(θ)Et
=CH2NHC(θ)Pr =CH2NHC(0)Pr
=CH2 HC(0)Bu =CH2NHC(0)Bu
=CH2N(Me)C(0)Me =CH2N(Me)C(0)Me
=CH2N(Me)C(θ)Et =CH2N(Me)C(0)Et
=CH2N(Me)C(0)Pr =CH2N(Me)C(0)Pr
=CH2N(Me)C(θ)Bu =CH2N(Me)C(0)Bu
=CH2N(Et)C(θ)Me =CH2N(Et)C(0)Me
=CH2N(Et)C(0)Et =CH2N(Et)C(0)Et
=CH2N(Et)C(θ)Pr =CH2N(Et)C(θ)Pr
=CH2N(Et)C(0)Bu =CH2N(Et)C(θ)Bu
=CH2N(Pr)C(0)Me =CH2N(Pr)C(0)Me
=CH2N(Pr)C(0)Et =CH2N(Pr)C(0)Et
=CH2N(Pr)C(0)Pr =CH2N(Pr)C(0)Pr
=CH2N(Pr)C(0)Bu =CH2N(Pr)C(0)Bu
=CH2NHC (O) cyclopropyl =CH2NHC (0) cyclopropyl
=CH2N(Me) C (0) cyclopropyl =CH2N (Me) C (0) cyclopropyl
=CH2NHC (0) CH2cyclopropyl =CH2NHC (0) CH2cyclopropyl
=CH2N (eyelopropyl) C (0) Me =CH2N (eyelopropyl) C (0)Me
=CH2N (CH2cyclopropyl ) C (0)Me =CH2N(CH2cyclopropyl)C(0)Me
=CH2N(Me) C (0) CH2cyclopropyl =CH2N (Me) C (0) CH2eyelopropyl
=CH2N (eyelopropyl) C (0) Et =CH2N (eyelopropyl ) C (0) Et
=CH2N(CH2cyelopropyl)C(0)Et =CH2N (CH2cyclopropyl) C (O) Et
=CH2N (eyelobuty1) C (O) Me =CH2N (cyclobutyl) C (0) Me
=CH2N (eyelopentyl) C (0)Me =CH2N (cyclopentyl ) C (θ)Me
Figure imgf000295_0002
Figure imgf000296_0001
Table 5
Figure imgf000297_0001
,4a. CH2N(Me)20 R4a=CH2N(Me)2θ =CH2NHC02Me =CH2 HC02Me =CH2N(Et)C02Me =CH2N(Et)C02Me =CH2NHC(0)NHMe =CH2NHC(0)NHMe =CH2N(Me)Cθ2Et =CH2N(Me)C02Et =CH2N(Me)Cθ2Me =CH2N(Me)C02Me =CH2N(Me)C(0)NHMe =CH2N(Me)C(0)NHMe =CH2NHS02Me =CH2 HS02Me =CH2NHS02Et =CH2NHS02Et =CH2N(Me)Sθ2Me =CH2N(Me)S02Me =CH2N(Me)Sθ2Et =CH2N(Me)S02Et =CH2N(Me)Sθ2Pr =CH2N(Me)S02Pr =CH2NHC(0)Me =CH2 HC(0)Me =CH2NHC(0)Et =CH2NHC(0)Et =CH2NHC(0)Pr =CH2NHC(0)Pr =CH2NHC(0)Bu =CH2 HC(0)Bu =CH2N(Me)C(θ)Me =CH2N(Me)C(0)Me =CH2N(Me)C(0)Et =CH2N(Me)C(0)Et =CH2N(Me)C(θ)Pr =CH2N(Me)C(0)Pr =CH2N(Me)C(0)Bu =CH2N(Me)C(0)Bu =CH2N(Et)C(θ)Me =CH2N(Et)C(0)Me =CH2N(Et)C(θ)Et =CH2N(Et)C(0)Et =CH2N(Et)C(0)Pr =CH2N(Et)C(0)Pr =CH2N(Et)C(θ)Bu =CH2N(Et)C(0)Bu =CH2N(Pr)C(0)Me =CH2N(Pr)C(0)Me =CH2N(Pr)C(0)Et =CH2N(Pr)C(0)Et =CH2N(Pr)C(θ)Pr =CH2N(Pr)C(0)Pr =CH2N(Pr)C(θ)Bu =CH2N(Pr)C(0)Bu =CH2NHC (O) cyclopropyl =CH2NHC (O) cyclopropyl =CH2N (Me) C (0) cyclopropyl =CH2N(Me)C(0) cyclopropyl =CH2NHC (O) CH2cyclopropyl =CH2NHC (O) CH2cyclopropyl =CH2N (cyclopropyl ) C (0) Me =CH2N(eyelopropyl) C (0)Me =CH2N(CH2cyelopropyl)C(0)Me =CH2N(CH2cyclopropyl) C (θ)Me =CH2N (Me) C (0) CH2cyclopropyl =CH2N(Me) C (O) CH2cyclopropyl =CH2N (cyclopropyl ) C (0) Et =CH2N(eyelopropyl) C (O) Et =CH2N (CH2cyclopropyl) C (0) Et =CH2N(CH2cyclopropyl ) C (0) Et =CH2N ( eye lobutyl ) C ( 0 ) Me =CH2N(eyelobutyl) C (0) Me =CH2N (cyclopentyl ) C (0) Me =CH2N(eyelopentyl) C (0)Me
Figure imgf000297_0002
Figure imgf000298_0001
Examples 5-33 through 5-64, G is 2-aminomethylphenyl and Rla is as shown in Examples 5-1 through 5-32. Examples 5-65 through 5-96, G is 3-aminomethylphenyl and Rla is as shown in Examples 5-1 through 5-32. Examples 5-97 through 5-128, G is 2-amidophenyl and Rla is as shown in Examples 5-1 through 5-32. Examples 5-129 through 5-160, G is 2-amido-4- methoxyphenyl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-161 through 5-192, G is 3-amidophenyl and
Rla is as shown in Examples 5-1 through 5-32. xamples 5-193 through 5-224, G is 3-chlorophenyl and
Rla is as shown in Examples 5-1 through 5-32. xamples 5-225 through 5-256, G is 3-amino-4- chlorophenyl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-257 through 5-288, G is 2- aminosulfonylphenyl and Rla is as shown in Examples 5- 1 through 5-32. xamples 5-289 through 5-320, G is 2-aminosulfonyl-4- methoxyphenyl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-321 through 5-352, G is 3-(l',2',4'- triazolin-5 ' -on-3 ' -yl) phenyl and Rla is as shown in
Examples 5-1 through 5-32. xamples 5-353 through 5-384, G is 1-aminoisoquinolin-
6-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-385 through 5-416, G is 1-aminoisoquinolin- 7-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-417 through 5-448, G is 4-aminoquinazol-6-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-449 through 5-480, G is 4-aminoquinazol-7-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-481 through 5-512, G is 3-aminobenzisoxazol-
5-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-513 through 5-544, G is 3-aminobenzisoxazol-
6-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-545 through 5-576, G is 3-aminoindazol-5-yl and Rla is as shown in Examples 5-1 through 5-32. xamples 5-577 through 5-608, G is 3-aminoindazol-6-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-609 through 5-640, G is indolin-5-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-641 through 5-672, G is indolin-6-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-673 through 5-704, G is 2-naphthyl and Rl is as shown in Examples 5-1 through 5-32. For Examples 5-705 through 5-736, G is 3 -amido-naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-737 through 5-768, G is 3-methylsulfonyl- naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-769 through 5-800, G is 3-aminomethyl- naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-801 through 5-832, G is 3-flouro-naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-833 through 5-864, G is 3 -chloro-naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-865 through 5-896, G is 3-aminosulfonyl- naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32. For Examples 5-897 through 5-928, G is 6-chloro-naphth-2-yl and Rla is as shown in Examples 5-1 through 5-32.
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.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I:
P4-P-M-M4
I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
M is a 3-10 membered carbocycle or a 4-10 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, N, and NZ2 ;
ring M is substituted with 0-3 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
P is fused onto ring M and is a 5, 6, or 7 membered carbocycle or a 5 , 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, and N;
ring P is substituted with 0-3 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
alternatively, ring P is absent and P4 is directly attached to ring M;
one of P4 and M4 is -Z-A-B and the other -Gi-G, provided that P4 and M4 are attached to different rings when ring P is present;
G is a group of formula Ila or lib:
Figure imgf000301_0001
Ila lib ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p;
ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1-2 R;
alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, wherein the 5-6 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and has 0-3 ring double bonds;
R is selected from H, CX-4 alkyl, F, Cl, Br, I, OH, OCH3 , OCH2CH3, OCH(CH3)2, OCH2CH2CH3 , CN, C (=NR8) NR7R9 , NHC(=NR8)NR7R9, ONHC (=NR8) NR7R9 , NR8CH (=NR7 ) , NH2 , NH(Cι_3 alkyl), N(Cι_3 alkyl)2, C(=NH)NH2, CH2NH2 , CH2NH(Cι_3 alkyl), CH2N(Cι_3 alkyl) 2, CH2CH2NH2 , CH2CH2NH(Cι-3 alkyl), CH2CH2N(Cι_3 alkyl) 2, (CR8R9)tC(0)H, (CR8R9)tC(0)R2c, (CR8R9) tNR7R8 , (CR8R9)tC(0)NR7R8, (CR8R9) NR7C(0)R7, (CR8R9)tOR3, (CR8R9)tS(0)pNR7R8, (CR8R9) tNR7S (0) pR7 , (CR8R9)tSR3, (CR8R9)tS(0)R3, (CR8R9)tS(0)2R3, and OCF3;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is selected from:
C3_ιo carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of
N, 0, and S(0)p and substituted with 0-2 R4;
B is Y or X-Y, provided that Z and B are attached to different atoms on A;
X is selected from - (CR2R2a) X-4-, -CR2 (CR2R2b) (CH2) t- ,
-C(0)-, -C(=NRlb)-, -CR2(NRlbR2)-, -CR2(OR2)-, -CR2(SR2)-, -C(0)CR2R2a-, -CR2R2aC(0), -S-, -S(O)-, -S(0)2-, -SCR2R2a-, -S(0)CR2R2a-, -S (0) 2CR2R2a- , -CR2R2aS-, -CR2R2aS(0)-, -CR2R2 S (0) 2- , -S(0)2NR2-,
-NR2S(0)2-, -NR2S(0)2CR2R2a-, -CR2R2aS (0) 2NR2- , -NR2S(0)2NR2-, -C(0)NR2-, -NR2C(0)-, -C (0) NR2CR2R2a- , -NR2C(0)CR2R2a-, -CR2R2 C(0)NR2-, -CR2R2aNR2C (0) - , -NR2C(0)0-, -0C(0)NR2-, -NR2C (0) NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2aO-, and -OCR2R2a- ;
Y is selected from: C3-10 carbocycle substituted with 1 R4a and 0-2 R4, and,
5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 1 R4a and 0-2 R4;
G- is absent or is selected from (CR3R3 )1-5,
CR3R3a) 0-2CR3=CR3 (CR3R3a) 0-2, (CR3R3a) o-2C≡C (CR3R a) 0-2 , CR3R3a)uC(0) (CR3R3a)w, (CR3R a)uC(0)0(CR3R3a)w, CR3R3a)uOC(0) (CR3R3a)w, (CR3R3a)uO(CR3R a)w, CR3R3a) uN3b (CR3R3a) w, (CR3R3a) UC (0) N3b (CR3R a) w, CR3R3a)uN bC(0) (CR3R3a)w, (CR3R3a) U0C (0) N3b (CR3R3a) w, CR3R3a)uN3bC(0)0(CR3R3a)w, (CR3R3a) uN3bC (0)N3b(CR3R3a) w, CR3R3a)uN3bC(S)N3b(CR3R3a)w, (CR3R3a) US (CR3R3 ) w, CR3R3a)uS(0) (CR3R3a)w, (CR3R3a)uS(0)2(CR3R a)w, CR3R3 )uS(0)N3b(CR3R3a)w, (CR3R3 ) uN3bS (0) 2 (CR3R3a) w, CR3R3a)uS(0)2N3b(CR3R3a)w, (CR3R3a) uN3bS (0) 2N3b (CR3R3a) w, CR3R3a)uNR3e(CR3R3a)w, CR3R3a)uC(0) (CR3R3a)uC(0) (CR3R a)w, CR3R3a)uNR3b(CR3R3a)uC(0)NR3b(CR3R3a)W/ CR3R3a)uNR3bC(0) (CR3R3a)uC(0) (CR3R3a)w, CR3R3a)uC(0) (CR3R3a)uC(0)NR3b(CR3R3a)w, CR3R3a)uNR3bC(0) (CR3R3a)uC(0)NR3b(CR3R3 )w, CR3R3a)uS(0)NR3bC(0) (CR3R3a)w, CR3R3 )uC(0)NR3bS(0)2 (CR3R3a)w, and
CR3R3a)uS(0)2NR3bC(0)NR3bCR3R3a)w, wherein u + w total 0, 1, 2, 3, or 4, provided that G- does not form a N- S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached; Z is selected from a bond, - (CR3R3e) 1-4- ,
CR3R3e)qO(CR3R3e)ql, (CR R3e) qNR3b (CR3R3e) ql , CR3R3e)qC(0) (CR3R e)gι, (CR3R3e) qC (0) 0 (CR3R3e) ql , CR R3e ) gOC ( 0 ) ( CR3R3e ) qι , ( CR3R3e ) qC ( 0 ) NR3b ( CR3R3e ) gι , CR3R3e)qNR3bC(0) (CR3R3e)qi, (CR3R3e) qOC (0) O (CR3R3e) qι, CR3R3e) qOC (O) NR3b (CR3R3e) qι , CR3R3e) qNR3bC (0)0 (CR3R3e) qι , CR3R3e)qNR3bC(0)NR3b(CR3R3e)qi, CR3R3e)qC(0) (CR3R3e)qC(0) (CR3R3e)qι, CR3R3e)qNR3b(CR3R3e)qC(0)NR3b(CR3R3e)qi, CR3R3e)qNR3bC(0) (CR3R3e)qC(0) (CR3R3e)qι, CR3R3e) qC (0) (CR3R e) qC (0)NR3b (CR3R3e) qi , CR3R3e)qNR bC(0) (CR3R3e)qC(0)NR3b(CR3R3e)qi, CR R3e)qS(CR3R3e)qι, (CR3R3e)qS(0) (CR3R3e)qι, CR3R3e)qS(0)2(CR3R3e)qι, (CR3R3e)qS02NR3b(CR3R3e)qi, CR R3e) qNR3bS02 (CR3R3e) qι, CR3R3e)qS(0)NR3bC(0) (CR3R3e)qι, CR3R3e) qC (0) NR3bS (0) 2 (CR3R3e) qι, and
CR3R3e)qNR3bS02NR3b(CR3R3e)gι, wherein q + ql total 0, 1, 2, 3, or 4, provided that Z does not form a N-S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
Z2 is selected from H, S(0)2NHR b, C(0)R3b, C(0)NHR3b, C(0)0R3f, S(0)R3f, S(0)2R3f, Cι_6 alkyl substituted with 0-2 Rla, C2-6 alkenyl substituted with 0-2 Rla, C2-6 alkynyl substituted with 0-2 Rla, - (C0-4 alkyl)- cycloalkyl substituted with 0-3 Rl , - (C0-4 alkyl) - heterocycle substituted with 0-3 Rla, -(Co-4 alkyl) - aryl substituted with 0-3 Rla, and, - (C0-4 alkyl) - heteroaryl substituted with 0-3 Rla;
Rla, at each occurrence, is selected from H, - (CR3R3 ) r-Rlb, -(CR3Ra)r-CR3RlbRlb, - (CR3R3a) r-0- (CR3R3a) r-Rlb,
- (CR3R3a) r-NR2- (CR3R3 ) r-Rlb,
- (CR3R3a) r-S (O) p- (CR3R3a) r-Rlb, - (CR3R3a) r-C02- (CR3R3a) r-Rlb,
- (CR3R3a) r-C (O) NR2- (CR3R3a) X-Rlh , -(CR3R3a)r-C(0)-(CR3R3a)r-Rlb, -C2_6 alkenylene-Rlb,
-C2-6 alkynylene-Rlb, and - (CR3R3a) r-C (=NRlb)NR3Rlb, provided that Rla forms other than an N-halo, N-S, 0- 0, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 R4b and comprising: 0-3 double bonds;
Rlb is selected from H, C1-3 alkyl, F, Cl, Br, I, -CN, -N02 , -CHO, (CF2)rCF3, (CR3R3a)rOR2, NR2R2a, C(0)R2b, C02R2b, 0C(0)R2, CH(CH20R2)2, (CF2) rC02R2a, S(0)pR2b,
NR2(CH2)rOR2, C(=NR2c)NR2R2a, NR2C(0)R2b, NR2C (0) NR2R2 , NR2C(0)2R2a, OC(0)NR2R2a, C(0)NR2R2a, C (0) NR2 (CH2 ) r0R2 , Sθ2NR2R2a, NR2S02R2, C (0) NR2Sθ2R2 , C3-6 carbocycle substituted with 0-2 R4b, and 5-10 membered heterocycle substituted with 0-2 Rb and consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond and provided that S(0)pR2 forms other than S(0)2H or S(0)H;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, - (CH2)r-C3_ιo carbocycle substituted with 0-2 Rb, and - (CH2) r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, - (CH2) r _C3-ιo carbocycle substituted with 0-2 R4b, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, Cι_6 alkyl substituted with 0-2 R4b, - (CH2) r-C3-ιo carbocycle substituted with 0-2 R4b, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b; R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, - (CH2) 3--C3-10 carbocycle substituted with 0-2 R4b, and -(CH )r-5-10 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb;
R2d, at each occurrence, is selected from H, R c, Cι_6 alkyl substituted with 0-2 R4c, - (CR3R3a) r-C3-ιo carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S (Op- halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-0, O-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, Cι_6 alkyl substituted with 0-2 Rc, - (CR3R3a) r-C3-ιo carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R3, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl; R3a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R3 and R3a are attached, and 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R3b, at each occurrence, is selected from CF3, C1-.4 alkoxy substituted with 0-2 Rb, Cι_6 alkyl substituted with 0-2 R4b, - (CH2)r-C3_ιo carbocycle substituted with 0-2 Rb, and -(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R3c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C-L-4 alkyl-phenyl , and C(=0)R3c;
R3e, at each occurrence, is selected from H, SO2NHR3, S02NR3R3, C(0)R3, C(0)NHR3, C(0)OR3f, S(0)R3f, S(0)2R3f, C1-6 alkyl substituted with 0-2 Rla, C2-6 alkenyl substituted with 0-2 Rla, C2-6 alkynyl substituted with
0-2 Rla, -(Co-4 alkyl) -5-10 membered carbocycle substituted with 0-3 Rla, and - (C0-4 alkyl) -5-10 membered heterocycle substituted with 0-3 Rla and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p;
R3f, at each occurrence, is selected from: Cι_6 alkyl substituted with 0-2 Rl , C2-6 alkenyl substituted with 0-2 Rla, C2-6 alkynyl substituted with 0-2 Rla, - (C0-4 alkyl) -5-10 membered carbocycle substituted with 0-3 Rla, and -(C0-4 alkyl) -5-10 membered heterocycle substituted with 0-3 Rla and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p;
R39, at each occurrence, is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, - (CH2 ) r-3-6 membered carbocycle, and -(CH2)r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p;
alternatively, when R3 and R39 are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
R4, at each occurrence, is selected from H, =0,
(CR3R3a ) rOR2 , F , Cl , Br , I , Cι_4 alkyl , (CR3R3a ) rCN, (CR3R3a ) rN02 , (CR3R3a) rNR2R2 , (CR3R a) rC (0 ) R2c ,
(CR3R3a) rNR2C (0) R2b, (CR3R3a) rC (0) NR2R2a , (CR3R3a)rNR2C(0)NR2R2a, (CR3R3a) rC (=NR2) NR2R a, (CR3R3 )rC(=NS(0)2R5a)NR2R2a, (CR3R3a) rNHC (=NR2)NR2R2a, (CR3R3a)rC(0)NHC(=NR2)NR2R2a, (CR3R3a) rS02NR2R2a, (CR3R3a)rNR2S02NR2R2a, (CR3R3a) rNR2S02-Cι_4 alkyl, (CR3R3a)rNR2S02R5a, (CR3R3a) rS (0)pR5a,
(CR3R3a)r(CF2)rCF3, NHCH2Rlb, OCH2Rlb, SCH2Rl ,
N(CH2)2(CH2)tRlb, 0(CH2)2(CH2)tRlb, S (CH2 ) 2 (CH2) tRlb, (CRRa) r-5-6 membered carbocycle substituted with 0-1
R5, and a (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R5;
R 4a s selected from (CR3R39) rN(→0) R2dR2d, (CR3R39)v-NR2dC(0)R2e, (CR3R3^) V-C (0)NR2dR2d,
(CR3R39)v-NR2dC(0)NR2dR2d, (CR3R39) v-NR2dC (0) 0R2d, (CR3R39) v-S02NR2dR2d, (CR3R39) v-NR2dS02NR2dR2d, (CR3R39)v-C(0)NR2dS02R2d, (CR3R39) v-NR2dSθ2R2d, and (CR3R39)v-S(0)pR2d, provided that S(0)pR2d forms other than S(0)2H or S(0)H;
alternatively, R4a is selected from (CR3R39) rNR2dR2d,
NR2dC(0)R2e, C(0)NR2dR2d, NR2dC (0) NR2dR2d, NR2dC (0) OR2d, Sθ2NR2dR2d, NR2dS02NR2dR2d, C (0) NR2dS02R2d, NR2dSθ2R2d, and S(0)pR2d, provided that at least one of R2d and R2e is alkyl substituted with at least one Rc that is other than alkyl, provided that S(0)pR2d forms other than S(0)2H or S(0)H;
R4b, at each occurrence, is selected from H, =0, (CH2)rOR3, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, (CH2)rCN, (CH2)rN02, (CH2 ) rNR R3a, (CH2 ) rC (0) R3 , (CH2)rC(0)0R3c, (CH2)rNR3C(0)R3 , (CH2 ) r-C (0) NR3R3a, (CH2 ) rNR3C ( 0 ) NR3R3a , (CH2 ) r~C ( =NR3 ) NR3R3a , (CH2 ) rNR3C ( =NR3 ) NR3R3a, (CH2 ) rS02NR3R3a, (CH2)rNR3S02NR3R3a, (CH2) rNR3S02-Cι_ alkyl,
(CH2)rNR3S02CF3, (CH2 ) rNR3S02 -phenyl , (CH2) rS (0)pCF3, (CH2)rS(0)p-Ci_4 alkyl, (CH2 ) rS (0) p-phenyl , and (CH2)r(CF2)rCF3;
R4c, at each occurrence, is selected from =0, (CR3R3a) rOR2 , (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a) rCF3 , C1-4 alkyl, (CR3R3a)rCN, (CR3R3a) rN02 , (CR3R3a) rNR2R2a, (CR3R3a)rN(→0)R2R2a, (CR3R3a)rC(0)R2c, (CR3R3a) rNR2C (0) R2b, (CR3R3a) rC (0)NR2R2a, (CR3R3a)rN=CHOR3, (CR3R3a) rC (0) NH (CH2 ) 2NR2R2a,
(CR3R3a)rNR2C(0)NR2R2a, (CR3R3a) rC (=NR2 ) NR2R2a, ( CR R3a ) rNHC ( =NR2 ) NR2R2a , ( CR3R3a ) rSθ2NR2R2a , (CR3R3a)rNR2S0 NR2R2a, (CR3R3 ) rC (0) NHS02-Cι_4 alkyl, (CR3R3a)rNR2S02R5a, (CR3R3a)rS(0)pR5a, (CF2)rCF , (CR3R3a)rC3-ιo carbocycle substituted with 0-2 R4b, and
(CR3R3a) r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, Cι_6 alkyl, =0, (CH2)rOR3, F, Cl, Br, I, -CN, N02 , (CH2) rNR3R3a, (CH2)rC(0)R3, (CH2)rC(0)OR3c, (CH2 ) rNR3C (0) R3a, (CH2)rC(0)NR3R3a, (CH2)rNR3C(0)NR3R3a, (CH2 ) rCH (=N0R3d) , (CH2)rC(=NR3)NR3R3a, (CH2 ) rNR3C (=NR3 ) NR3R3a, (CH2 ) rS02NR3R a, (CH2 ) rNR3S02NR3R3a, (CH2)rNR3S02-Ci-4 alkyl, (CH2) rNR3S02CF3, (CH2)rNR3S02-phenyl, (CH2) rS (OpCF3 ,
(CH2)rS(0)p-Cι_4 alkyl, (CH2) rS(0) p-phenyl, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6 ;
R5a, at each occurrence, is selected from Cι_6 alkyl,
(CH2)rOR3, (CH2)rNR3R3a, (CH2 ) rC (0) R3 , (CH2 ) rC (0) OR3c, (CH2)rNR3C(0)R3a, (CH2)rC(0)NR3R3a, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6 , provided that R5a does not form a S-N or S(0)p-C(0) bond;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2' halo, Cι-4 alkyl, CN, N02, (CH2) rNR2R2a, (CH2) rC (O) R2b, NR2C(0)R2b, NR2C(0)NR2R2a, C(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S0 Cι_4 alkyl;
R7, at each occurrence, is selected from H, OH, Cι_6 alkyl, Cι_6 alkyl-C (0)-, Cι_6 alkyl-O-, (CH2)n-phenyl, Cι_ alkyl-OC (0)-, C6_ι0 aryl-0-, C6-ιo aryl-OC(O)-, C6-ιo aryl-CH2-C(0)-, Cι_ alkyl-C (0) O-C1-4 alkyl-OC (0) - , C6-ιo aryl-C(0)0-Ci_4 alkyl-OC (O) - , Cι-6 alkyl-NH2-C(0)-, phenyl-NH2-C (O) - , and phenyl C1-4 alkyl-C (0)-;
R8, at each occurrence, is selected from H, C^ alkyl, and (CH2)n-phenyl; alternatively, R7 and R8, when attached to the same nitrogen, combine to form a 5-10 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R9 , at each occurrence, is selected from H, Cι_6 alkyl, and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;
t, at each occurrence, is selected from 0, 1, 2, and 3;
v, at each occurrence, is selected from 1, 2, 3, 4, 5, and 6 ; and,
provided that when ring M is phenyl and is substituted 1,2 by M4 and P4 and G;L is present, then Z-A is other than
NHC(O) -thienyl, NHCH2-thienyl, NHC (0) -benzothienyl, and NHCH2-benzothienyl;
further provided that when (a) P is absent, (b) ring M is a non-aromatic ring with at least one ring N, (c) G-Gi is attached via a ring N, and (d) Z is at least two atoms in length, then Y is other than phenyl or pyridyl .
2. A compound according to Claim 1, wherein the compound is of Formula II:
Figure imgf000315_0001
II or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M, including P1# P2, M1( and M2, is a 5, 6, or 7 membered carbocycle or a 5 , 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0)p, N, and NZ2 ;
ring M is substituted with 0-2 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
ring P, including P1# P2 , and P3 , is a 5 or 6 membered aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from 0, S(0) , and N;
alternatively, ring P, including Pl t P2, and P3, is a 5 or 6 membered dihydro-aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from O, S(0)p, and N;
ring P is substituted with 0-2 Rla;
one of P4 and M is -Z-A-B and the other -Gi-G;
G is a group of formula Ila or lib:
Figure imgf000316_0001
I la l ib
ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p;
ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
alternatively, ring D is absent, and ring E is selected from phenyl , pyridyl , pyrimidyl , and thienyl , and ring E is substituted with 1-2 R;
alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds ;
R is selected from H, Cχ-4 alkyl, F, Cl, OH, 0CH3 , OCH2CH3 , OCH(CH3)2, CN, C(=NH)NH2, C(=NH)NHOH, C (=NH) H0CH3 , NH2, NH(Ci_3 alkyl), N(Cι_3 alkyl) 2, C(=NH)NH2, CH2NH2 , CH2NH(Cι_3 alkyl), CH2N(Cι_3 alkyl)2, (CR8R9) NR7R8, C ( 0 ) NR7R8 , CH2C ( 0 ) NR7R8 , S ( 0 ) 2R3 , S ( 0 ) pNR7R8 , CH2S (0 ) pNR7R8 , and OCF3 ;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is selected from:
C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4;
X is selected from - (CR2R2a) X-4-, -C(O)-, -C(=NRlb)-, -CR2(NRlbR2)-, -C(0)CR2R2a-, -CR2R2aC(0), -C(0)NR2-, -NR2C(0)-, -C(0)NR2CR2R2a-, -NR2C (0) CR2R2a- , -CR2R2aC(0)NR2-, -CR2R2aNR2C(0)-, -NR2C (0) NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2aO-, and -OCR2R2a-;
Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-2 R : cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl , thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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;
Z is selected from a bond, CH , CH2CH2, CH20, 0CH2, C(0), NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)CH2C(0)NH, S(0)2, CH2S(0)2, S(0)2(CH2), S02NH, and NHSO2, provided that Z does not form a N-S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(0)R3b, S(0)R3f, and S(0)2R3f;
Rla, at each occurrence, is selected from H, -(CH2)r-Rlb -(CH(CH3) )r-Rlb, - (C (CH3) 2 ) r-Rlb, -O- (CR3R3a) r-Rlb,
-NR2-(CR3R3a)r-Rlb, and -S- (CR3R3a) r-Rlb, provided that Rla forms other than an N-halo, N-S, O-O, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 R4b and comprising: 0-3 double ring bonds;
R lb is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, -CN, -CHO, CF3 , OR2, NR2R2a, C(0)R2b, C02R2b, OC(0)R2, C02R2a, S(0)pR2, NR2 (CH2 ) rOR2 ,
NR2C(0)R2b, NR2C(0)NHR2, NR2C(0)2R2a, 0C(0)NR2R2a, C(0)NR2R2a, C(0)NR2(CH2)rOR2, S02NR2R2a, NR2S02R2, C _6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CF3, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, a C5-6 carbocyclic-CH2-group substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2 , at each occurrence, is selected from H, CF3, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2,
CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p; R2b, at each occurrence, is selected from CF3, C1-.4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5_6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-.4 alkoxy, CH3 , CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5_6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, - (CR3R3a) 1-C3-6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S (Op- halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, 0-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R4c, - (CR3R3 ) r-C3_6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R3, at each occurrence, is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
R3a, at each occurrence, is selected from H, CH3 , CHCH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R3 and R3a are attached;
R3c, at each occurrence, is selected from CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
R3d, at each occurrence, is selected from H, CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2-phenyl, CH2CH2-phenyl, and C(=0)R3c;
R39, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclopropyl-methyl, benzyl, and phenyl;
alternatively, when R3 and R39 are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
R4, at each occurrence, is selected from H, =0, OR2,
CH2OR2, (CH2) OR2, F, Cl, Br, I, Cι_4 alkyl, -CN, N02 , NR2R2a, CH2NRR2a, (CH2 ) 2NR2R2a, C(0)R2c, NR2C(0)R2b, C(0)NR2R2a, S02NR2R2a, S(0)pR5 , CF3 , CF2CF3 , 5-6 membered carbocycle substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R5;
R4a is selected from (CR3R39) rN(→0) R2dR2d,
(CR3R39)v-NR2dC(0)R2e, (CR3R39)v-NR2dC(0)NR2dR2d, (CR3R33)v-NR2dC(0)0R2d, (CR3R3^) v-NR2dS02NR2dR2d, and (CR3R39)v-NR2dS02R2d;
alternatively, R4a is selected from (CR3R3S) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) 0R2d, NR2dS02NR2dR2d, and NR2dS0 R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl; Rb, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH (CH3) CH2CH3 , C(CH3)3, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)OR3c, CH2C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH2C(0)NRR3a, NR3C(0)NR3R3a, CH2NR3C (0) NR3R3a, C(=NR3)NR3R3 , CH2C(=NR3)NR3R3a, NR3C (=NR3) NR3R3a, CH2NR3C(=NR3)NR3R3a, S02NR3R3a, CH2S0NR3R3a,
NR3S02NR3R3a, CH2NR3S02NR3R3a, NR3S02-Cι_4 alkyl, CH2NR3S02-Ci-4 alkyl, NR3S02CF , CH2NR3S02CF3 , NR3S02-phenyl, CH2NR3S02-phenyl, S(0)pCF3, CH2S(0)pCF3, S(0)p-Ci-4 alkyl, CH2S (0)p-Cι_4 alkyl, S (0)p-phenyl, CH2S(0) p-phenyl, CF , and CH2-CF3; Rc, at each occurrence, is selected from =0, (CR3R3a) rOR2 (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3 ) rCF3 , C1-4 alkyl, (CR3R3a)rCN, (CR3R3a) rN02, (CR3R3a) rNR2R2a, (CR3R3a) rN (→O) R2R2a, (CR3R3a) rC (0) R2 , (CR3R3a)rNR2C(0)R2b, (CR3R3a) rC (0) NR2R2a,
(CR3R3a) rNR2C (O) NR2R2a, (CR3R3a) rS02NR2R2a, (CR3R3a) rNR2Sθ2NR2R2a, (CR3R3a) rNR2S02R5a, (CR3R3a)rS(0)pR5a, (CF2)rCF3, (CR3R a) rC3-io carbocycle substituted with 0-2 Rb, and (CR3R3a) r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3 , F, Cl, -CN, N02 , NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)0R3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, NR3C (0)NR3R3a, CH(=N0R3d), C(=NR3)NR3R3a, NR3C (=NR3) NR3R3a, S02NR3R3a, NR S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S0 CF3, NR3S02" phenyl, S(0)pCF3, S(0)p-Cι_4 alkyl, S (0) p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 ,
CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, -CN, N02 , NR2R2 ,
CH2NR2R2 , C(0)R2b, CH2C(0)R2 , NR2C(0)R2b,
NR2C(0)NR2R2 , C(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S02Cι_4 alkyl; r, at each occurrence, is selected from 0, 1, and 2; and,
v, at each occurrence, is selected from 1, 2, and 3
3. A compound according to Claim 2, wherein
ring M is substituted with 0-2 Rla and is selected from the group :
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000327_0002
Figure imgf000327_0003
Figure imgf000327_0004
Figure imgf000327_0005
Figure imgf000327_0006
Figure imgf000328_0001
ring P, including P1# P2, P3, and P4 is selected from group :
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
one of P4 and M4 is -Z-A-B and the other -G1-G;
G is selected from the group:
Figure imgf000331_0002
Figure imgf000331_0004
Figure imgf000331_0003
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000333_0002
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
absent or is selected from (CR3R3 )1-3,
(CR3R3a)uC(0) (CR3R3a)w/ (CR3R a)u0(CR3R3a)w, (CR3R3a)uNR b(CR3R3a)w, (CR3R a)uC (0) NR3b (CR3R3a) w, (CR3R3 )uNR C(0) (CR3R3a)w, (CR3R3a)uNR bC(0) (CR3R3a)uC(0)NR (CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(0) (CR3R3a)w,
(CR3R3a)uS(0)2(CR3R a)w, (CR3R a)uS(0)NR3b(CR3R3a)w,
(CR3R3a)u NR3bS(0)2(CR3R3a)w, and
(CR3R3a)uS(0)2NR3b(CR3Ra)w, wherein u + w total 0, 1, or 2, provided that G;L does not form a N-S, NCH2N,
NCH20, or NCH2S bond with either group to which it is attached;
Rla is selected from H, Rlb, CH(CH3)Rlb, C(CH3)2Rlb, CH2Rlb, and CH2CH2Rlb, provided that Rla forms other than an N- halo, N-S, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 Rb and 0-3 ring double bonds;
Rlb is selected from H, CH3, CH2CH3, F, Cl, Br, -CN, -CHO, CF3, OR2, NR2R2a, C(0)R2b, C02R2b, OC(0)R2, C02R2a, S(0)pR2, NR2(CH2)rOR2, NR2C(0)R2b, C(0)NR2R2a, Sθ2NR2R2a, NR2Sθ2R2, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an O-O, N-halo, N-S, or N-CN bond;
A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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, indolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
X is selected from -C(O)-, -C(=NRlb)-, -C(0)NR2-,
-NR2C(0)-, -NR2C(0)CR2R2a-, -NR2C (0) NR2- , and 0;
Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 Ra and 0-1 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3-oxadiazole, 1,2,4- oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2 , 5-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2, 3-triazole, 1, 2 , 4-triazole, 1, 2, 5-triazole, 1, 3 , 4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; R2, at each occurrence, is selected from H, CF3, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with
0-2 R4b, a benzyl substituted with 0-2 R , and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
Rb;
R2a, at each occurrence, is selected from H, CF3 , CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0) and substituted with 0-2 R4b;
alternatively, R2 and R2 , 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 consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, OCH3,
OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R c, Cι-4 alkyl substituted with 0-2 R c, C3-6 carbocycle substituted with 0-2 R4c, - (CR3R3a)-C3_6 carbocycle substituted with 0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-0, O-N, O-S, or 0-0 moiety;
Re, at each occurrence, is selected from H, R c, C1-.4 alkyl substituted with 0-2 R c, C3-.6 carbocycle substituted with 0-2 R c, - (CR3R3a) -C3-6 carbocycle substituted with 0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from H, (CH2)2θR2, CH2OR2, OR2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN, N02, NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, C(0)R2c, NR C(0)R2b, C(0)NR2R2a, S02NR2R2a, CF3 , and CF2CF3;
R a is selected from (CH2) rN(→0)R2dR2d, (CH2) v-NR2dC (0) R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2 ) v-NR2dC (0) OR2d, and (CH2)v-NR2dS02R2d;
alternatively, R a is selected from (CH2) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) OR2d, and
NR2dS0 R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R4c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3,
CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)0R3c, CH2-C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH2-C(0)NR3R3a, S02NR3R3a, CH2S02NR3R3a, NR3S02-Cι_4 alkyl, CH2NR3S02-Cι_ alkyl, NR3S02 -phenyl, CH2NR3S02- phenyl, S(0)pCF3, CH2S(0)pCF3, S(0)p-Cι-4 alkyl, CH2S(0)P-Cι_4 alkyl, S (0) p-phenyl, CH2S (0)p-phenyl, and CF3;
R c, at each occurrence, is selected from =0, OR2, (CR3R3a)OR2, F, (CR3R3a)F, Br, (CR3R3a)Br, Cl, (CR3R3a)Cl, CF3, (CR3R3a)CF3, Cι_ alkyl, -CN,
(CR3R3a)CN, N02, (CR3R3a)N0 , NR2R2a, (CR3R3a)NR2R2a, N(→0)R2R2a, (CR3R3a)N(→0)R R2 , C(0)R2c, (CR3R3a)C(0)R2c, NR2C(0)R2b, (CR3R3a) NR2C (0) R2b,
C(0)NR2R2a, (CR3R3a)C(0)NR2R2a, NR2C (0) NR2R2a, (CR3R3a)NRC(0)NR2R2a, S02NR2R2a, (CR3R3a) S02NR2R2a, NR2S02NR2R2a, (CR3R3a)NR2S02NR2R2a, NR2S02R5a,
(CR3R3a)NR S02R5a, S(0)pR5a, (CR3R3a) S (0) pR5a, CF3 , CF2CF3, C3_ιo carbocycle substituted with 0-2 R4b, (CR3R3a)C3_ιo carbocycle substituted with 0-2 R4b, 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
Rb, and (CR3R3a)5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)OR3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S0 CF3, NR3S02-phenyl , S(0)PCF3, S(0)p-Cι_4 alkyl, S (0)p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, S02NR2R2a, and NR2Sθ2Cι_4 alkyl; and,
v, at each occurrence, is selected from 1 and 2.
A compound according to Claim 3, wherein: ring M is substituted with 0-2 Rla and is selected from the group :
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
ring P, including Pi, P2, P3, and P4 is selected from group :
Figure imgf000345_0002
Figure imgf000346_0001
one of P4 and M4 is -A-B and the other -G;
G is selected from the group:
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
G1 is absent or is selected from CH2 , CH2CH2 , CH20, OCH2, NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O),
CH2S(0)2, S(0)2(CH2), S0NH, and NHΞ02 , provided that Gi does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached;
A is selected from piperidinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4;
B is selected from phenyl, pyridyl, pyrrolidino, N- pyrrolidino-carbonyl, morpholino, N-morpholino- carbonyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a and 0-1 R4;
Rla ig selected from H, Rlb, C(CH3)2Rlb, and CH2Rlb, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
Rlb ig selected from CH3, CH2CH3, F, Cl, Br, -CN, CF , OR2, NR2R2a, C(0)R2b, C02R2b, C02R2a, S(0)pR2, C(0)NR2R2a, Sθ2NR2R2a, NR2Sθ2R2, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb, provided that Rlb forms other than an O-O, N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3, CHCH3 ,
CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3, CHCH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with
0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 Rb;
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 0-1 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from 0CH3 , OCHCH3 ,
OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, benzyl, phenyl substituted with 0-1 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1
Rb;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3 , OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2d, at each occurrence, is selected from H, R4c, Cι_4 alkyl substituted with 0-2 Rc, C3-6 carbocycle substituted with 0-2 R4c, -(CH2)-C3_6 carbocycle substituted with
0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-0, 0-N, O-S, or 0-0 moiety; R2e, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, -(CH2)-C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p and substituted with 0-2 R c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from OH, OR2, CH2OR2, (CH2)2OR2, F, Br, Cl, I, CH3 , CH2CH3 , CH2CH2CH3 ,
CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, CF3, and CF2CF3 ;
R4a is selected from (CH2) rN(→0)R2dR2d, (CH2) v-NR2dC (0)R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2 ) v-NR2dC (0) 0R2d, and (CH2)v-NR2dS02R2d;
alternatively, R4a is selected from (CH2) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) OR2d, and
NR2dSθ2R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3,
CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02, NR3R3a, CH2NR R3 , C(0)R3, C(0)OR3c, NR3C(0)R3a, C(0)NR R3a, S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S02 -phenyl, S(0)p-Ci-4 alkyl, S (0) p-phenyl, and CF3 ;
R4c, at each occurrence, is selected from =0, OR2, CH OR2,
F, Br, Cl, CF3, C1-4 alkyl, -CN, N02 , NR2R2a, CH2NR2R2 ,
N(→0)R2R2 , CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c,
NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0) NR2R2a,
S02NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2S02R5a, S(0)pR5a, CH2S(0)pR5a, CF3, CF2CF3, C3-6 carbocycle substituted with 0-2 R4b, (CH2)C3_6 carbocycle substituted with 0-2 Rb, 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p and substituted with 0-2 R4b, and (CH2)-5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH ,
CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3 , CH2NR3R3a, C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NRR3a, NR3S02-Cι_4 alkyl, NR3S02-phenyl, S(0)p-Ci-4 alkyl, S (0)p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a, CH2NR2R2a , C ( O ) 2b , CH2C ( 0 ) R2b , NR2C ( 0 ) R2b , and Sθ2NR2R2a .
A compound according to Claim 4, wherein:
ring M is substituted with 0-1 Rla and is selected from the group :
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
ring P, including P1# P2 , P3 and P is selected from group :
Figure imgf000357_0001
one of P4 and M4 is -A-B and the other -G;
G is selected from:
Figure imgf000358_0001
Figure imgf000359_0001
A is selected from the group: piperidinyl, phenyl, 2- pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-C1- phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2- aminophenyl, and 2-methoxyphenyl;
B is selected from phenyl, pyridyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a; Rla ig selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH2F, CH2C1, Br, CH2Br, -CN, CH2CN, CF3 , CH2CF3 , OCH3 , CH20H, C(CH3)20H, CH2OCH3, NH2 , CH2NH2 , NHCH3 , CH2NHCH3 , N(CH3)2, CH2N(CH3)2, C02H, COCH3 , C02CH3 , CH2C02CH3, SCH3, CH2SCH3, S(0)CH3, CH2S(0)CH3, S(0)2CH3, CH2S(0)2CH3, C(0)NH2, CH2C(0)NH2, S02NH2 , CH2S02NH2, NHSO2CH3, CH2NHSO2CH3, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N- oxide, pyridin-4-yl-N-oxide, imidazol-1-yl, CH2- imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N,N- dimethylaminomethyl-oxazol-2-yl, 1,2,3, 4-tetrazol-l- yl, l,2,3,4-tetrazol-5-yl, CH2-1, 2 , 3 , 4-tetrazol-l-yl, and CH2-1, 2 , 3 ,
4-tetrazol-5-yl, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3, CHCH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3, and CH2CH3;
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 0-1 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p; R2b, at each occurrence, is selected from OH, OCH3, OCH2CH3 , CH3, and CH2CH3;
R2c, at each occurrence, is selected from OH, OCH3 , OCH2CH , CH3, and CH2CH3 ;
R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C- halo, S(0)p-halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, O-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 cycloalkyl substituted with 0-2 R c, phenyl substituted with 0-2 R c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) and substituted with 0-2
R c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R 4a is selected from CH2N(→0)R2dR2d, CH2NR2dC (0) R2e,
CH2NR2dC(0)NR2dR2d, CH2NR2dC (0) 0R2d, and CH2NR2dS02R2d;
R4b, at each occurrence, is selected from H, =0, OR3,
CH2OR3, F, Cl, CH3, CH2CH3, NR3R3a, CH2NR3R3a, C(0)R3, C(O)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R a, NR3S02-phenyl, S(0)2CH3, S (0) 2-phenyl , and CF ;
R c, at each occurrence, is selected from =0, OH, OCH3 , OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH(CH3)2, F, Br, Cl, CF3 , NR2R2a, CH2NR2R2a, N(→0)R2R2a, CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0) NR2R2a, S0 NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2S02R5a,
S(0)pR5a, CH2S(0)pR5a, CF3, cyclopropyl substituted with 0-1 R4b, cyclobutyl substituted with 0-1 R4b, cyclopentyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, -CH2-eyelopropyl substituted with 0-1 R4b, -CH2-cyclobutyl substituted with 0-1 R4b, -CH -cyclopentyl substituted with 0-1 Rb, benzyl substituted with 0-2 Rb, 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, and (CH2)-
5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
R4 ;
R5, at each occurrence, is selected from H, =0, CH3 ,
CH2CH3, OR3, CH2OR3, F, Cl, NR3R3a, CH2NR R3a, C(0)R3, C(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S0 -Ci-4 alkyl, NR3S02-phenyl, S(0)2-CH3, S (0) 2-phenyl , CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b,
NR2C(0)R2b, and S0NR2R2a.
6. A compound according to Claim 5 , wherein the compound is selected from:
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000365_0002
is -G;
M4 is -A-B;
G is selected from:
Figure imgf000366_0001
Figure imgf000366_0003
Figure imgf000366_0002
Figure imgf000366_0005
Figure imgf000366_0004
Figure imgf000366_0006
A-B is selected from:
Figure imgf000366_0007
R2d, at each occurrence, is selected from H, Cι_4 alkyl substituted with 0-1 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that Rd forms other than a N-halo, N-C-halo, S(0)p-halo, 0- halo, N-S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, Cι_4 alkyl substituted with 0-1 R c, C3_6 cycloalkyl substituted with 0-2 R4c, phenyl, substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
Ra is selected from CH2N(→0)R2dR2d, CH2NR2dC (0) R2e, CH2NR2dC(0)OR2d, and CH2NR2dS0 R2d; and,
R 4c is selected from OH, 0CH3 , OCH2CH3 , OCH2CH2CH3,
OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH (CH3 ) 2 , F, Br, Cl, CF3, NR2R2 , CH2NR2R2a, C(0)R2c, CH2C(0)R2c,
NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0) NR2R2a, Sθ2NR2R2a, CH2Sθ2NR2R2a, NR2S02R5a, CH2NR2S02R5a, S(0)pR5a, and CH2S(0)pR5a.
7. A compound according to Claim 6, wherein the compound is of the formula:
Figure imgf000368_0001
is -G;
M is -A-B;
A-B is selected from :
Figure imgf000368_0002
R2d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3 ) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl; and,
R2e, at each occurrence, is selected from CH3, CHCH3,
CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl.
8. A compound according to Claim 1, wherein the compound is selected from the group:
N- [ ( l- { 4- [ l- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c] pyridin-6- yl ] phenyl} -Iff-imidazol-2-yl ) methyl] -N-methylacetamide ;
Ν-[ (l-{4- [1- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6H-pyrazolo [3 , 4-c]pyridin-6- yl] phenyl }-lH-imidazol-2-yl) methyl] -N-methylacetamide;
methyl (l-{4- [1- (4-methoxyphenyl) -7-oxo-3-
( trifluoromethyl) -1,4,5, 7-tetrahydro-6ff-pyrazolo [3,4- c] pyridin-6-yl ] phenyl } -Iff-imidazol-2-yl ) methyl (methyl ) carbamate ;
N- [ (l-{4- [1- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl ] phenyl } -Iff-imidazol-2-yl ) methyl] -N- methylmethanesulfonamide ;
N- [ (l-{4- [1- (4-methoxyphenyl) -7-oxo-3- (trifluoromethyl) - 1,4,5, 7-tetrahydro-6H-pyrazolo[3, 4-c]pyridin-6- yl]phenyl}-lff-imidazol-2-yl)methyl] -N, 3 , 5-trimethyl-4- isoxazolesulfonamide;
6- [4- (2-{ [acetyl (methyl) amino] methyl} -Iff-imidazol-1- yDphenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
6-[4-(2-{ [ethylcarbonyl (methyl) amino] methyl} -Iff-imidazol- 1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
6-[4-(2-{ [n-propylcarbonyl (methyl) amino] methyl }-lff- imidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3- carboxamide;
6-[4-(2-{ [i-propylcarbonyl (methyl) amino] methyl } -lff- imidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3- carboxamide;
6- [4- (2-{ [i-butylcarbonyl (methyl) amino] methyl} -lff- imidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -7-oxo- 4,5,6, 7-tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3- carboxamide ;
1- (4-methoxyphenyl) -6-{4- [2- ( {methyl [
(methylamino) carbonyl] -amino}methyl) -lff-imidazol-1- yl] phenyl} -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c] pyridine-3-carboxamide;
methyl (l-{4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c] pyridin-6- yl ] phenyl} -lff-imidazol-2-yl ) methyl (methyl ) carbamate ; ethyl (l-{4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6- yl] phenyl} -lff-imidazol-2-yl) methyl (methyl) carbamate;
1- (4-methoxyphenyl) -6- [4- (2-{ [methyl
(methylsulfonyl) amino] -methyl } -Iff-imidazol-1- yl) phenyl] -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3 , 4- c] pyridine-3 -carboxamide;
1- (4-methoxyphenyl) -6- [4- (2-{ [methyl (n- propylsulfonyl) amino] -methyl} -Iff-imidazol-1- yl) phenyl] -7-oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3,4- c] pyridine-3-carboxamide;
6- [4- (2-{ [ [ (3, 5-dimethyl-4-isoxazolyl) sulfonyl] (methyl) - amino] methyl} -Iff-imidazol-1-yl) phenyl] -1- (4- methoxypheny1 ) -7-oxo-4 ,5,6, 7-tetrahydro-lff- pyrazolo [3 , 4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -6- [4- (2- { [methyl (phenylsulfonyl) amino] methyl } -lff-imidazol-1-yl) phenyl] -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
6- [4- (2-{ [acetyl (ethyl) amino] methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
6- [4- (2-{ [acetyl (n-propyl) amino]methyl}-lff-imidazol-l- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-Iff-pyrazolo [3 , 4-c]pyridine-3-carboxamide; 6- [4- (2-{ [acetyl (n-propyl) amino]methyl} -Iff-imidazol-1- yl) phenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
6-[4-(2-{ [ethylcarbonylamino]methyl}-lff-imidazol-l- yDphenyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c]pyridine-3-carboxamide;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl] phenyl} -Iff-imidazol-2-yl) methyl] -N-methylacetamide ;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl]phenyl}-lff-imidazol-2-yl)methyl] -N- methylpropanamide;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl]phenyl}-lff-imidazol-2-yl)methyl] -N- methylbutanamidetrifluoroacetic acid salt;
N- [ ( l- { 4- [ l- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl]phenyl}-lff-imidazol-2-yl)methyl] -N, 2- dimethylpropanamide;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6- yl]phenyl}-lff-imidazol-2-yl)methyl] -N- methylcyclopropanecarboxamide; methyl (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4, 5,7-tetrahydro-6ff-pyrazolo[3, 4-c]pyridin-6- yl]phenyl} -Iff-imidazol-2-yl)methyl (methyl) carbamate;
N-ethyl-N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7- oxo-1, 4,5, 7-tetrahydro-6ff-pyrazolo [3, 4-c]pyridin-6- yl]phenyl} -Iff-imidazol-2-yl)methyl] acetamide;
N-isopropyl -N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo-l, 4, 5 , 7-tetrahydro-6ff- pyrazolo [3 , 4-c] pyridin-6-yl] phenyl} -Iff-imidazol-2- yl)methyl] acetamide;
N- [ (l-{4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -7-oxo- 1,4,5, 7-tetrahydro-6ff-pyrazolo [3 , 4-c] pyridin-6- yl] phenyl}-Iff-imidazol-2-yl)methyl] -N-propylacetamide,-
1- (4-methoxyphenyl) -6- [2 ' - ( {methyl [ (methylamino) carbonyl] - amino}methyl) -1,1' -biphenyl-4-yl] -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -6- (2 ' - { [methyl (methylsulfonyl) amino] - methyl}-l, 1 ' -biphenyl-4-yl) -7-oxo-4, 5,6, 7-tetrahydro- lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
N- (2-{4- [3-cyano-l- (4-methoxyphenyl) -7-oxo-l, 4 , 5,7- tetrahydro-6ff-pyrazolo [3 , 4-c]pyridin-6-yl] -1- piperidinyl}benzyl) -N-methylacetamide ;
6- [1- (2-{ [acetyl (methyl) amino]methyl}phenyl) -4- piperidinyl] -1- (4-methoxyphenyl) -7-oxo-4, 5,6,7- tetrahydro-lff-pyrazolo [3 , 4-c] pyridine-3-carboxamide; - (4-methoxyphenyl) -6- [1- (2-{ [methyl
(methylsulfonyl) amino]methyl}phenyl) -4-piperidinyl] -1 ■ oxo-4, 5,6, 7-tetrahydro-lff-pyrazolo [3, 4-c]pyridine-3- carboxamide;
- (4-{2- [ (dimethylnitroryl) methyl] -Iff-imidazol-1- yl}phenyl) -1- (4-methoxyphenyl) -3- (trifluoromethyl) - 1,4,5, 6-tetrahydro-7ff-pyrazolo [3 , 4-c] pyridin-7-one;
- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2 ' -{ [bis (2- hydroxyethyl) amino]methyl}-l, 1' -biphenyl-4-yl) -3- (trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pryazolo [3 , 4- c] pyridin-7-one;
- (3-amino-l, 2-benzisoxazol-5-yl) -6- (2 ' -{ [ (3-aminopropyl) (methyl) amino]methyl}-l, 1' -biphenyl-4-yl) -3- (trifluoromethyl) -1,4,5, 6-tetrahydro-7ff-pryazolo [3 , 4- c]pyridin-7-one;
- (2 '-{[ (2-hydroxyethyl) (methyl) amino]methyl}-l, 1 ' - biphenyl-4-yl) -1- (4-methoxyphenyl) -7-oxo-4 ,5,6,7- tetrahydro-lff-pryazolo [3 , 4-c] pyridine-3-carboxamide;
- (2 ' -{ [bis (2-hydroxyethyl) amino] methyl}-l, 1 ' -biphenyl-4- yl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pryazolo [3 , 4-c] pyridine-3-carboxamide;
- (2 ' -{ [ (3-aminopropyl) (methyl) amino]methyl}-l, 1' -biphenyl- 4-yl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-lff- pryazolo [3 , 4-c]pyridine-3-carboxamide;
- (2'-{ [ (2-hydroxyethyl) (methyl) amino]methyl}-l, 1 ' - biphenyl-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) - 1,4,5, 6-tetrahydro-lff-pryazolo [3, 4-c] pyridin-7-one; or a pharmaceutically acceptable salt form thereof.
9. A compound according to Claim 1, wherein the compound is of Formula Ilia, Illb, or IIIc:
Figure imgf000375_0001
Ilia Illb IIIc or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M, including 1# M2 , and, if present, M3 , is phenyl or a 3-10 membered carbocyclic or 4-10 membered heterocyclic ring consisting of: carbon atoms and 1-4 heteroatoms selected from 0, S(0)p, N, and NZ2;
ring M is substituted with 0-3 Rla and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
one of P4 and M is -Z-A-B and the other -Gi-G;
G is a group of formula Ila or lib:
Figure imgf000375_0002
Ila lib
ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p;
ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2 R;
alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds ;
R is selected from H, ^-4 alkyl, F, Cl, OH, 0CH3 , OCH2CH3 , OCH(CH3)2, CN, C(=NH)NH2, C(=NH)NHOH, C (=NH) NHOCH3 , NH2, NH(Cι_3 alkyl), N(Cι_3 alkyl) 2, C(=NH)NH2, CH2NH2 , CH2NH(Cι_3 alkyl), CH2N(Cι_3 alkyl) 2 # (CR8R9) tNR7R8, C(0)NR7R8, CH2C(0)NR7R8, S(0)2R3, S(0)pNR7R8, CH2S(0)pNR7R8, and OCF3 ;
alternatively, when 2 R groups are attached to adjacent atoms , they combine to form methylenedioxy or ethylenedioxy; A is selected from:
C5-10 carbocycle substituted with 0-2 R4, and
5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4;
X is selected from - (CR2R2a) !-4- , -C(O)-, -C(=NRlb)-,
-CR2(NRlbR2)-, -C(0)CR2R2a-, -CR2R2aC(0), -C(0)NR2-, -NR2C(0)-, -C(0)NR2CR2R2a-, -NR2C (0) CR2R2a- , -CR2R2aC(0)NR2-, -CR2R2aNR2C(0)-, -NR2C (O)NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2aO-, and -0CR2R2a-;
Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-2 R : cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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;
Z is selected from a bond, CH2 , CH2CH , CH2O, OCH2, C(0), NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)NH, NHC(0)CH2C(0)NH, C(0)NHS(0)2/ S(0)2, CH2S(0)2, S(0)2(CH2), S02NH, and NHS02, provided that Z does not form a N-S, NCH2N, NCH20, or NCH S bond with either group to which it is attached;
Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(0)R3b, S(0)R3f, and S(0)2R3f;
Rla, at each occurrence, is selected from H, -(CH2)r~Rlb -(CH(CH3) )r-Rlb, -(C(CH3)2)r-Rlb' -0- (CR3R3a) r-Rlb, -NR2- (CR3R3a)r-Rlb, and -S- (CR3R3a) r-Rlb, provided that Rla forms other than an N-halo, N-S, O-O, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 R4b and 0-3 ring double bonds;
Rlb ig selected from H, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, F,
Cl, Br, I, -CN, -CHO, CF3, OR2, NR2R2a, C(0)R2b, C02R2b, 0C(0)R2, C02R2a, S(0)pR2, NR2 (CH2) rOR2 , NR2C(0)R2b, NR2C(0)NHR2, NR2C(0)2R2 , OC(0)NR2R2 , C(0)NR2R2a, C(0)NR2(CH2)rOR2, S02NR2R2a, NR2S02R2, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond; R2, at each occurrence, is selected from H, CF3 , CH3 ,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5_6 carbocycle substituted with 0-2 Rb, a C5-6 carbocyclic-CH2-group substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3 , CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2,
CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-.6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb;
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 consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from CF3 , C1-4 alkoxy, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b; R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, C5-6 carbocycle substituted with 0-2 Rb, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, - (CR3R3a) r-C3_6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S (Op- halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, 0-N, O-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R c, - (CR3R3a) r-C3-6 carbocycle substituted with 0-2 R4c, and - (CR3R3a) r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R3, at each occurrence, is selected from H, CH3, CHCH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl; R3a, at each occurrence, is selected from H, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R3 and R3a are attached;
R3c, at each occurrence, is selected from CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
Rd, at each occurrence, is selected from H, CH3, CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2-phenyl, CH2CH2-phenyl, and C(=0)R3c;
R3^, at each occurrence, is selected from H, CH3 , CH2CH3 ,
CH2CH2CH3, CH(CH3) , cyclopropyl, cyclopropyl-methyl, benzyl, and phenyl;
alternatively, when R3 and R39 are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
R4, at each occurrence, is selected from H, =0, OR2,
CH2OR2, (CH2)2θR2, F, Cl, Br, I, C1-4 alkyl, -CN, N0 , NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, C(0)R2c, NR2C(0)R2b, C(0)NR2R2a, S02NR2R2a, S(0)pR5a, CF3, CF2CF3 , 5-6 membered carbocycle substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R5; R4a is selected from (CR3R39) rN(→0)R2dR2d,
(CR3R39)v-NR2dC(0)R2e, (CR3R39)v-NR2dC(0)NR2dR2d, (CR3R39)v-NR2dC(0)OR2d, (CR3R39) v-NR2dS02NR2dR2d, and (CR3R39)v-NR2dS02R2d;
alternatively, R4a is selected from (CR3R3S) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) OR2d, NR2dS02NR2dR2d, and NR2dS02R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN,
N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)0R3c, CH2C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH2C(0)NR3R3a, NR3C(0)NR3R3a, CH2NR3C (O) NR3R3a, C(=NR3)NR R3a, CH2C(=NR3)NR3R3a, NR3C (=NR3 ) NR3R a, CH2NR3C(=NR3)NR3R3a, Sθ2NR3R3a, CH2S02NR3R3a,
NR3S02NR3R3a, CH2NR3S02NR3R3a, NR3S02-Cι_4 alkyl, CH NR3S02-Ci-4 alkyl, NR3S02CF3, CH2NR3S02CF3, NR3S02 -phenyl, CH2NR3S0 -phenyl, S(0)pCF3, CH2S(0)pCF3, S(Op-Cι_4 alkyl, CH2S (0)p-Cι- alkyl, S(0) p-phenyl, CH2S(0) p-phenyl, CF3 , and CH2-CF3;
R c, at each occurrence, is selected from =0, (CR3R3a) r0R2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3 ) rCF3 , Cι_4 alkyl, (CR3R3a)rCN, (CR3R3a) rN02, (CR3R3a) rNR2R2a, (CR3R3a)rN(→0)R2R2a, (CR3R3 ) rC (0) R2c, (CR3R3a) rNRC (0) R2b, (CRR3a) rC (0) NR2R2a, (CR3R3a) rNR2C (0)NR2R2a, (CR3R3a) rS02NR2Ra, (CR3R3a)rNR2S02NR2R2a, (CR3R3a) rNR2S02R5a, (CR3R3a)rS(0)pR5a, (CF2)rCF3, (CR3R3a) rC3-io carbocycle substituted with 0-2 R4b, and (CR3R3a) r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3, F, Cl, -CN, N02 , NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)OR3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, NR3C (0) NR3R3 , CH(=N0R3d), C(=NR3)NR3R3a, NR3C (=NR3 ) NR3R3a, S02NR3R3a, NR3S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S02CF3, NR3S02- phenyl, S(0)pCF3, S(0)p-Cι_4 alkyl, S (0) p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2» CH2CH2CH2CH ,
CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, -CN, N02 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, NR2C(0)NR2R2a, C(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2Sθ2NR2R2a, and NR2S02Ci-4 alkyl;
r, at each occurrence, is selected from 0, 1, and 2; and,
v, at each occurrence, is selected from 1, 2, and 3.
10. A compound according to Claim 9, wherein:
ring M, including M1# M2 , and, if present, M3, is selected from phenyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1, 2, 3-triazole, 1, 2 , 4-triazole, 1, 3 , 4-triazole, 1,2,3- oxadiazole, 1, 2 , 4-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2 , 3 , 4-tetrazole, 1, 2 , 3 , 5-tetrazole, pyran, thiopyran, thiopyran=l, 1-dioxide, pyridine, pyrimidine, pyridazine, pyrazine, 1, 2 , 3-triazine, 1, 2 , 4-triazine, 1, 2 , 3 , 4-tetrazine, dihydro-pyrrole, dihydro-furan, dihydro-thiophene, dihydro-pyrazole, dihydro-imidazole, dihydro-isoxazole, dihydro-oxazole, dihydro-isothiazole, dihydro-thiazole, dihydro-1, 2 , 3- triazole, dihydro-1, 2 , 4-triazole, dihydro-1, 3 , 4- triazole, dihydro-1, 2 , 3-oxadiazole, dihydro-1, 2 , 4- oxadiazole, dihydro-1, 3 , 4-oxadiazole, dihydro-1, 2 , 3- thiadiazole, dihydro-1, 2 , 4-thiadiazole, dihydro-1, 3 , 4- thiadiazole, dihydro-1, 2 , 3 , 4-tetrazole, dihydro- 1, 2, 3 , 5-tetrazole, dihydro-pyran, dihydro-thiopyran, dihydro-thiopyran=l, 1-dioxide, dihydro-pyridine, dihydro-pyrimidine, dihydro-pyridazine, dihydro- pyrazine, dihydro-1, 2 , 3-triazine, dihydro-1, 2 , 4- triazine, dihydro-1, 2 , 3 , 4-tetrazine, cyclopentene, cyclopentane, cyclohexene, cyclohexane, tetrahydro- pyrrole, tetrahydro-furan, tetrahydro-thiophene, tetrahydro-thiophene-1, 1-dioxide, tetrahydro-pyrazole, tetrahydro-imidazole, tetrahydro-isoxazole, tetrahydro-oxazole, tetrahydro-isothiazole, tetrahydro-thiazole, tetrahydro-1, 2 , 3-triazole, tetrahydro-1, 2, 4-triazole, tetrahydro-1, 3, 4-triazole, tetrahydro-1, 2, 3-oxadiazole, tetrahydro-1, 2, 4- oxadiazole, tetrahydro-1, 3 , 4-oxadiazole, tetrahydro- 1,2, 3-thiadiazole, tetrahydro-1, 2, 4-thiadiazole, tetrahydro-1, 3 , 4-thiadiazole, tetrahydro-1, 2,3,4- tetrazole, tetrahydro-1, 2 , 3 , 5-tetrazole, tetrahydro- pyran, tetrahydro-thiopyran, tetrahydro-thiopyran-1, 1- dioxide, tetrahydro-pyridine, tetrahydro-pyrimidine, tetrahydro-pyridazine, tetrahydro-pyrazine, tetrahydro-1 , 2 , 3-triazine, tetrahydro-1, 2 , 4-triazine, and tetrahydro-1, 2,3, 4-tetrazine;
ring M is substituted with 0-3 Rla and 0-1 carbonyl group;
G is selected from the group:
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
388
Figure imgf000390_0001
G1 is absent or is selected from (CR3R3a)1_3,
(CR3R3a)uC(0) (CR3R3a)w, (CR3R3a)uO(CR3R a)w, (CR3R3a)uNR3b(CR3R3a)w, (CR3R3a) UC (0)NR3b (CR3R3a) w, (CR3R3a)uNR3bC(0) (CR3R3a)w,
(CR3R3a)uNR3bC(0) (CR3R3a)uC(0)NR3b(CR3R3a)w, (CR3R3a)uS(CRRa)w, (CR3R3a)uS(0) (CR3R3a)w, (CR3R3a)uS(0)2(CR3R3a)w, (CR3R3a)uS(0)NR3b(CR3R3a)w, (CR3R3a)uNR3bS(0)2(CR3R3a)w, (CR3R a)uS (0) 2NR3b(CR3R3a) w, and (CRR3a)uC(0)NR3bS(0)2(CR3R3a)w, wherein u + w total 0, 1, or 2, provided that Gx does not form a N-S, NCH2N, NCH20, or NCH2S bond with either group to which it is attached; Rla ig selected from H, Rlb, CH(CH3)Rlb, C(CH3)2Rlb, CH2Rlb, and CH2CH2Rlb, provided that Rla forms other than an N- halo, N-S, or N-CN bond;
alternatively, when two Rla groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S(0)p, this ring being substituted with 0-2 R4b and 0-3 ring double bonds;
Rlb is selected from H, CH3, CH2CH3, F, Cl, Br, -CN, -CHO, CF , OR2, NR2R2a, C(0)R2b, C02R2b, OC(0)R2, C02R2a, S(0)pR2, NR2(CH2)rOR2, NR2C(0)R2b, C(0)NR2R2a,
Sθ2NR2R2a, NR2S02R2, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an 0-0, N-halo, N-S, or N-CN bond;
A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 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, indolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
X is selected from -C(0)-, -C(=NRlb)-, -C(0)NR2-,
-NR2C(0)-, -NR2C(0)CR2R2a-, -NR2C (0) NR2- , and 0;
Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 Ra and 0-1
R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2, 3-oxadiazole, 1,2,4- oxadiazole, 1, 2, 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2 , 5-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2 , 3-triazole, 1, 2 , 4-triazole, 1, 2 , 5-triazole, 1, 3 , 4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
R2, at each occurrence, is selected from H, CF3, CH3,
CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with
0-2 R4b, a benzyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
R4b; R2a, at each occurrence, is selected from H, CF3, CH3 ,
CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
Rb, at each occurrence, is selected from CF3, Cι_4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, 0CH3,
OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R2d, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 Rc, C3-.6 carbocycle substituted with 0-2 R4 , -(CR3R3a) -C3_6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rc, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R c, C3-.6 carbocycle substituted with 0-2 R c, -(CR3R3a)-C3_6 carbocycle substituted with 0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and - (CR3R3a) -5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rc, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from H, (CH2) OR2, CH2OR2, OR2, F, Cl, Br, I, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH (CH3 ) CH2CH3 , C(CH3)3, -CN, N02, NR2R2a, CH2NR2R2a, (CH2 ) NR2R2a,
C(0)R2c, NR2C(0)R2b, C(0)NR2R2a, S02NR2R2 , CF3 , and CF2CF3 ;
R 4a is selected from (CH2) rN(→0)R2dR2d, (CH2) v-NR2dC (0)R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2) v-NR2dC (0) 0R2d, and (CH2)v-NR2dS02R2d; alternatively, Ra is selected from (CH2) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC(0)OR2d, and NR2dS02R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R4c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3,
CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CH2-C(0)R3, C(0)OR3c,
CH2-C(0)OR3c, NR3C(0)R3a, CH2NR3C (0) R3a, C(0)NR3R3a, CH2-C(0)NR3R3a, S02NR3R3a, CH2S02NR3R3a, NR3S0 -Cι_4 alkyl, CH2NR3Sθ2-Cι_4 alkyl, NR3 S02 -phenyl , CH2NR3S02- phenyl, S(0)pCF3, CH2S(0)pCF3, S(0)p-Cι_4 alkyl, CH2S(0)p-Ci-4 alkyl, S (0)p-phenyl , CH S (0) p-phenyl, and
CF3;
R4c, at each occurrence, is selected from =0, OR2,
(CR3R3a)OR2, F, (CR3R3a)F, Br, (CR3R3a)Br, Cl, (CR3R3a)Cl, CF3, (CR3R3a)CF3, Cι_ alkyl, -CN,
(CR3R3a)CN, N02, (CR3R3a)N02, NR2R2a, (CR3R3a) NR2R2 ,
N(→0)R2R2a, (CR3R3 )N(→0)R2R2a, C(0)R2c, (CR3R3a)C(0)R2c, NR2C(0)R2b, (CR3R3a) NR2C (0) R2b,
C(0)NR2R2a, (CR3R3a)C(0)NR2R2a, NR2C (0) NR2R2a, (CR3R3a)NR2C(0)NR2R2a, Sθ2NR2R2 , (CR3R3a) S02NR2R2a,
NR2S02NR2R2a, (CR3R3a)NR2S02NR2R2a, NR2S02R5a, (CR3R3 )NR2S02R5a, S(0)pR5a, (CR3R3a) S (0) pR5a, CF3 ,
CF2CF3, C3-10 carbocycle substituted with 0-2 R4b, (CR3R3 )C3_ιo carbocycle substituted with 0-2 R4b, 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb, and (CR3R3 )5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5 , at each occurrence, is selected from H, =0, CH3 ,
CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, CHC(0)R3, C(0)0R3c, CH2C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a,
NR3S02-Cι_4 alkyl, NR3S02CF3, NR3S02-phenyl, S(0)pCF3, S(0)p-Ci-4 alkyl, S (0)p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, NO2 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, S02NR2R2a, and NR2S02Cι_4 alkyl; and,
v, at each occurrence, is selected from 1 and 2.
11. A compound according to Claim 10, wherein the compound is selected from:
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Rla Rla
Figure imgf000398_0003
Figure imgf000398_0002
Figure imgf000398_0004
Figure imgf000399_0001
Figure imgf000400_0001
s selected from 0, S, NH, and NRla; G is selected from the group:
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000402_0002
Figure imgf000403_0001
Gi is absent or is selected from CH2, CH2CH2, CH2O, OCH2, NH, CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)NH, C(0)NHS(0)2 CH2S(0)2, S(0)2(CH2), S02NH, and NHSO2, provided that Gλ does not form a N-S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
A is selected from indolinyl, piperidinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4;
B is selected from phenyl, pyridyl, pyrrolidino, N- pyrrolidino-carbonyl, morpholino, N-morpholino- carbonyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a and 0-1 R4; Rla is selected from H, Rlb, C(CH3)2Rlb, and CH2Rlb, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
Rlb is selected from CH3, CH2CH3, F, Cl, Br, -CN, CF3 , OR2, NR2R2a, C(0)R2b, C02R2b, C02R2a, S(0)pR2, C(0)NR2R2a, Sθ2NR2R2a, NR2Sθ2R2, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, provided that Rlb forms other than an O-O, N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3, CH CH3 , CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with
0-1 Rb, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from 0CH3 , OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, benzyl, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3 , OCH2CH2CH3, 0CH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, benzyl, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2d, at each occurrence, is selected from H, R c, C1-4 alkyl substituted with 0-2 R c, C3-6 carbocycle substituted with 0-2 R4c, -(CH2)-C3_6 carbocycle substituted with
0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0-halo, N- S, S-N, S(0)p-S(0)p, S-0, 0-N, 0-S, or 0-0 moiety; R2e, at each occurrence, is selected from H, R c, C1-.4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, -(CH2)-C3_6 carbocycle substituted with
0-2 R c, 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0) and substituted with 0-2 R4c, and -(CH2)-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4, at each occurrence, is selected from OH, OR2, CH2OR2 , (CH2)2θR2, F, Br, Cl, I, CH3 , CH2CH3 , CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3 , CH2CH(CH3)2, CH (CH3) CH2CH3 , C(CH3)3, NR2R2a, CH2NR2R2a, (CH2 ) 2NR2R2a, CF3 , and CF2CF3;
R4a is selected from (CH2) rN(→0)R2dR2d, (CH2) v-NR2dC (0) R2e, (CH2)v-NR2dC(0)NR2dR2d, (CH2 ) v-NR2dC (0) OR2d, and (CH2)v-NR2dS02R2d;
alternatively, R4a is selected from (CH2) rNR2dR2d, NR2dC(0)R2e, NR2dC(0)NR2dR2d, NR2dC (0) 0R2d, and NR2dS02R2d, provided that at least one of R2d and R2e is alkyl substituted with at least one R c that is other than alkyl;
R4b, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, C(0)0R3c, NR3C(0)Ra, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_ alkyl, NR3S02-phenyl, S(0)p-Cι-4 alkyl, S (0)p-phenyl, and CF3 ;
R4c, at each occurrence, is selected from =0, OR2, CH2OR2, F, Br, Cl, CF3, C1-4 alkyl, -CN, N02 , NR2R2a, CH2NR2R2a,
N(→0)R2R2a, CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c,
NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0)NR2R2a,
S0NR2R2a, CH2S02NR2R2 , NR2S0 R5a, CH2NR2S0 R5a,
S(0)pR5a, CH2S(0)pR5a, CF3, CF2CF3, C3-6 carbocycle substituted with 0-2 R4b, (CH2)C3_6 carbocycle substituted with 0-2 Rb, 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 Rb, and (CH2)-5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b;
R5, at each occurrence, is selected from H, =0, CH3 , CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, -CN, N02, NR3R3a, CH2NR3R3a, C(0)R3, C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_ alkyl, NR3S02-phenyl, S(0)p-Ci_4 alkyl, S (0)p-phenyl, CF3 , phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -CN, N02 , NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, and S02NR2R2a.
12. A compound according to Claim 11, wherein the compound is selected from:
Figure imgf000408_0001
Figure imgf000409_0001
J is selected from 0, S, NH, and NRla;
Figure imgf000409_0002
M4 is -Z-A-B;
G is selected from:
Figure imgf000410_0001
Figure imgf000410_0002
Figure imgf000411_0001
Figure imgf000411_0003
Figure imgf000411_0002
Figure imgf000411_0004
Gλ is absent or is selected from CH2NH, NHCH2, CH2C(0), C(0)CH2, C(0)NH, NHC(O), NHC(0)NH, CH2S(0)2,
S(0)2(CH2), SO2NH, and NHSO2 , provided that G;L does not form a N-S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
A is selected from the group: indolinyl, piperidinyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C1- phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2- methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;
B is selected from phenyl, pyridyl, 1, 2 , 3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a;
Rla is selected from H, CH3, CH2CH3 , CH2CH2CH3 , CH2F, CH2C1, Br, CH2Br, -CN, CH2CN, CF3, CH2CF3 , OCH3 , CH2OH, C(CH3)2OH, CH2OCH3, NH2 , CH2NH2 , NHCH3 , CH2NHCH3 ,
N(CH3)2, CH2N(CH3)2, C02H, COCH3 , C02CH3, CH2C02CH3 , SCH3, CH2SCH3, S(0)CH3, CH2S(0)CH3, S(0)2CH3, CH2S(0)2CH3, C(0)NH2, CH2C(0)NH2, S02NH2 , CH2S02NH2, NHSO2CH3, CH2NHS02CH3, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N- oxide, pyridin-4-yl-N-oxide, imidazol-1-yl, CH - imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N,N- dimethylaminomethyl-oxazol-2-yl, 1,2,3, 4-tetrazol-l- yl, l,2,3,4-tetrazol-5-yl, CH2-1, 2 , 3 , 4-tetrazol-l-yl, and CH2-1, 2 , 3 , 4-tetrazol-5-yl, provided that Rla forms other than an N-halo, N-S, or N-CN bond;
R2, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 Rb, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-1 R4b;
R2a, at each occurrence, is selected from H, CH3, and CH2CH3 ; 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 0-1 Rb and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, 0, and S(0)p;
R2b, at each occurrence, is selected from OH, 0CH3, OCH2CH3, CH3, and CH2CH3;
R2c, at each occurrence, is selected from OH, OCH3 , OCH2CH3 , CH3, and CH2CH3;
R2d, at each occurrence, is selected from H, Rc, C1-4 alkyl substituted with 0-2 Rc, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2d forms other than a N-halo, N-C- halo, S(0)p-halo, O-halo, N-S, S-N, S(0)p-S(0)p, S-O, 0-N, 0-S, or 0-0 moiety;
R2e, at each occurrence, is selected from H, Rc, C1-4 alkyl substituted with 0-2 Rc, C3-.6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4c, provided that R2e forms other than a C(0)-halo or C(O) -S(0)p moiety; R4a is selected from CH2N(→0)R2dR2d, CH2NR2dC (0) R2e,
CH2NR2dC(0)NR2dR2d, CH2NR2dC (0) 0R2d, and CH2NR2dSθ2R2d;
R4b, at each occurrence, is selected from H, =0, OR3, CH2OR3, F, Cl, CH3, CH2CH3, NRR3a, CH2NR3R3a, C(0)R3,
C(0)OR3c, NR3C(0)R3a, C(0)NR3R3 , S02NR3R3a, NR3S02-phenyl, S(0)2CH3, S (0) 2-phenyl, and CF3;
Rc, at each occurrence, is selected from =0, OH, 0CH3 , OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3 , CH2CH3 , CH2CH2CH3 , CH(CH3)2, CH20H, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH(CH3)2, F, Br, Cl, CF3 , NR2R2a, CH2NR2R2a, N(→0)R2R2a, CH2N(→0)R2R2a, C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2 , CH2C (0) NR2R2a, S02NR2R2a, CH2S0NR2R2a, NR2S02R5a, CH2NR2S0 R5a,
S(0)pR5a, CH2S(0)pR5a, CF , cyclopropyl substituted with 0-1 R4b, cyclobutyl substituted with 0-1 Rb, cyclopentyl substituted with 0-1 R4b, phenyl substituted with 0-1 Rb, -CH2-eyelopropyl substituted with 0-1 R4b, -CH2-cyclobutyl substituted with 0-1 R4b, -CH2-cyclopentyl substituted with 0-1 Rb, benzyl substituted with 0-2 R4b, 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2 R4b, and (CH2)-
5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p and substituted with 0-2
R4b; R5, at each occurrence, is selected from H, =o, CH3,
CH2CH3, OR3, CH2OR3, F, Cl, NR3R3a, CH2NR3R3a, C(0)R3, C(0)OR3c, NR3C(0)R3a, C(0)NR3R3a, S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S02-phenyl, S(0)2-CH3, S (0) 2-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and,
R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(0)R2b, CH2C(0)R2b, NR2C(0)R2b, and S02NR2R2a.
13. A compound according to Claim 12 , wherein the compound is selected from:
Figure imgf000415_0001
G is selected from:
Figure imgf000416_0001
A-B is selected from:
Figure imgf000417_0001
R2d, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R c, C3-.6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2d forms other than a N-halo, N-C-halo, S(0)p-halo, 0- halo, N-S, S-N, S(0)p-S(0)p, S-O, O-N, O-S, or 0-0 moiety;
R e, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 Rc, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl, substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p, provided that R2e forms other than a C(0)-halo or C(0)-S(0)p moiety;
R4a is selected from CH2N(→0)R2dR2d, CH2NR2dC (0) R2e, CH2NR2dC(0)OR2d, and CH2NR2 S02R2d; and, R4c is selected from OH, OCH3, OCH2CH3 , OCH2CH2CH3,
OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3 , CH(CH3)2, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3 , CH2OCH (CH3) 2 , F, Br, Cl, CF3, NR2R2a, CH2NR2R2a, C(0)R2c, CH2C(0)R2c, NR2C(0)R2b, CH2NR2C(0)R2b, C(0)NR2R2a, CH2C (0) NR2R2a, S02NR2R2a, CH2S02NR2R2a, NR2S02R5a, CH2NR2Sθ2R5a, S(0)pR5a, and CH2S(0)pR5a.
14. A compound according to Claim 13, wherein the compound is selected from:
Figure imgf000418_0001
Figure imgf000418_0002
A-B is selected from:
Figure imgf000419_0001
R2d, at each occurrence, is selected from H, CH3 , CHCH3 , CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl; and,
R2e, at each occurrence, is selected from CH3, CH2CH3,
CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH (CH3 ) 2 , CH2- cyclopropyl, cyclopropyl, and cyclopentyl.
15. A compound according to Claim 1, wherein the compound is selected from the group: N- [4-(2-{ [acetyl (methyl) amino]methyl}-lH-imidazol-l-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -lff-pyrazole-5-carboxamide;
N- [4- (2-{ [acetyl (methyl) amino] methyl}-lff-imidazol-l-yl) -2- fluorophenyl] -1- (3-amino-l, 2-benzisoxazol-5-yl) -3- (methylsulfonyl) -Iff-pyrazole-5-carboxamide;
N- [4- (2-{ [methylsulfonylamino]methyl}-lff-imidazol-l-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (methylsulfonyl) - lff-pyrazole-5-carboxamide;
N- [4- (2-{ [methylsulfonylamino]methyl}-Iff-imidazol-1-yl) -2- fluorophenyl] -1- (4-methoxyphenyl) -3- (aminocarbonyl) - Iff-pyrazole-5-carboxamide;
5- { [5- (2- { [acetyl (methyl) amino]methyl} -lff-imidazol-1-yl) - 2 , 3-dihydro-Iff-indol-1-yl] carbonyl}-l- (3-amino-l, 2- benzisoxazol-5-yl) -lff-pyrazole-3-carboxamide;
1- (3-amino-l, 2-benzisoxazol-5-yl) -5-{ [5- (2-{ [methyl
(methylsulfonyl) amino] methyl} -Iff-imidazol-1-yl) -2,3- dihydro-Iff-indol-1-yl] carbonyl} -lff-pyrazole-3- carboxamide;
2- (3-aminobenzo [d] isoxazol-5-yl) -5-trifluoromethyl-2H- pyrazole-3-carboxylic acid (l-{2- [ (acetylmethylamino) - methyl]phenyl} -piperidin-4-y1) amide;
2- (3-aminobenzo [d] isoxazol-5-yl) -5-trifluoromethyl-2H- pyrazole-3-carboxylic acid (l-{2-[
(methanesulfonylmethyl-amino) methyl]phenyl}piperidin- 4-yl) amide; 2- (4-methoxyphenyl) -5-trifluoromethyl-2H-pyrazole-3- carboxylic acid [1- (2-{ [ (2-hydroxyethyl) methylamino] - methyl}phenyl) piperidin-4-yl ] amide ;
or a pharmaceutically acceptable salt form thereof.
16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or a pharmaceutically acceptable salt form thereof.
17. A compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 for use in therapy.
18. Use of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 for the manufacture of a medicament for the treatment of a thromboembolic disorder.
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EP4180424A1 (en) 2014-03-07 2023-05-17 BioCryst Pharmaceuticals, Inc. Substituted pyrazoles as human plasma kallikrein inhibitors
JP2017516845A (en) * 2014-05-22 2017-06-22 ノース チャイナ ファーマシューティカル カンパニー リミテッド Hydrazide compounds as blood coagulation factor Xa inhibitors
CN104311574A (en) * 2014-09-19 2015-01-28 广东东阳光药业有限公司 Pyrazolo piperidone compound containing thiazole and composition and application thereof
CN104311575A (en) * 2014-09-19 2015-01-28 广东东阳光药业有限公司 Pyrazolo piperidone compound containing condensed ring and composition and application thereof
CN106214681A (en) * 2016-07-28 2016-12-14 三峡大学 Compound suppresses the application on the medicine of kallikrein KLK7 and synthetic method thereof in preparation
CN106333949A (en) * 2016-07-28 2017-01-18 三峡大学 Application of compound in preparation of kallikrein KLK7 inhibition medicines, and synthesis method of compound
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AR037644A1 (en) 2004-11-17
EP1450800A2 (en) 2004-09-01
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