WO2008033934A1 - Substituted heteroaryl carboxylic acid derivatives as ptb-1b inhibitors - Google Patents

Substituted heteroaryl carboxylic acid derivatives as ptb-1b inhibitors Download PDF

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WO2008033934A1
WO2008033934A1 PCT/US2007/078285 US2007078285W WO2008033934A1 WO 2008033934 A1 WO2008033934 A1 WO 2008033934A1 US 2007078285 W US2007078285 W US 2007078285W WO 2008033934 A1 WO2008033934 A1 WO 2008033934A1
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alkyl
alkoxy
independently
alkenyl
alkynyl
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PCT/US2007/078285
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French (fr)
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Michael C. Van Zandt
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The Institutes For Pharmaceutical Discovery, Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to substituted heteroaryl carboxylic acid derivatives and more specifically to such compounds that are useful in the treatment of syndrome X (consisting of such abnormalities as obesity, dyslipidemia, hypercoagulation, hypertension, insulin resistance and leading to heart disease and diabetes) , obesity, diabetes, immunological disease, bleeding disorders, and/or cancer. More specifically, it relates to such compounds that are capable of inhibiting Protein tyrosine phosphatases (PTPs) , in particular Protein tyrosine phosphatase-lB (PTP-IB) which is a negative regulator of the insulin and leptin signaling pathway and improves insulin-sensitivity.
  • PTPs Protein tyrosine phosphatases
  • PTP-IB Protein tyrosine phosphatase-lB
  • Protein tyrosine phosphatases are a large family of transmembrane or intracellular enzymes that dephosphorylate substrates involved in a variety of regulatory processes (Fischer et al . , 1991, Science 253:401-406).
  • Protein tyrosine phosphatase-lB (PTP-IB) is an approximately 50 kd intracellular protein, which is present in abundant amounts in various human tissues (Charbonneau et al . , 1989, Proc. Natl. Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1- 15) .
  • Ahmad et al . , 1995, J. Biol. Chem. 270:20503-20508 used osmotic loading to introduce PTP-IB neutralizing antibodies into rat KRC-7 hepatoma cells.
  • the presence of the antibody in the cells resulted in an increase of 42% and 38%, respectively, in insulin stimulated DNA synthesis and phosphatidyinositol 3' kinase activity.
  • Insulin receptor autophosphorylation and insulin receptor substrate-1 tyrosine phosphorylation were increased 2.2 and 2.0-fold, respectively, in the antibody-loaded cells.
  • the antibody-loaded cells also showed a 57% increase in insulin stimulated insulin receptor kinase activity toward exogenous peptide substrates.
  • PTP-IB is a negative regulator of leptin signaling (Kaszua et al . MoI. Cell. Endocrinology, 195:109-118, 2002). PTP-IB deficient mice show enhanced potency for exogenous leptin to suppress food intake (Cheng, et al . Developmental Cell 2:497-503, 2002). Thus, inhibitors of PTP-IB augment the beneficial effects of leptin on food intake, body weight regulation and metabolism, in normal individuals and leptin resistant individuals.
  • inhibitors of PTPs are useful in controlling or treating obesity, syndrome X, Type 2 diabetes, in improving glucose tolerance, Docket 05-869-WO and in improving insulin sensitivity in patients in need thereof.
  • Such compounds are also useful in treating or controlling other PTP mediated diseases, such as the treatment of neurodegenerative diseases, cancer, immunological disorders, bleeding and cardiovascular disorders, and the like.
  • the invention encompasses the compounds of formula (I) shown below, pharmaceutical compositions containing the compounds and methods employing such compounds or compositions in the treatment of diabetes and/or cancer.
  • the invention encompasses compounds of formula (I) :
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S(O) 2 -, -N(RN 4 )-, -N (R 114 ) C (0) -, -C(O)N(R 114 )-, Docket 05-869-WO
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • n 0, 1, 2, 3, or 4;
  • each R B is aryl- or heteroaryl-; each R B is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention also includes synthetic intermediates that are useful in making the compounds of the invention. Docket 05-869-WO
  • the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods .
  • the invention also provides pharmaceutical compositions comprising a compound or salt of formula (I) and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent .
  • the compounds of formula (I) bind to PTPs, and in particular to PTP-IB.
  • the invention provides a method for inhibiting protein tyrosine phosphatases, preferably PTP-IB, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention further provides methods of treating diseases such as Type I and Type II diabetes, syndrome X, obesity, cancer, neurodegenerative disease, immunological disease, bleeding disorders, and cardiovascular disease in a patient in need of such treatment, comprising administering to the patient a compound or pharmaceutically acceptable salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention provides a method for treating metabolic disorders related to insulin resistance or hyperglycemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention provides formulations and pharmaceutical compositions, as well as methods for combination therapy for treating Type I diabetes, Type II diabetes, and Syndrome X Docket 05-869-WO with the compounds of formula (I) plus therapeutically- effective amounts additional compounds and medicaments.
  • Treatment methods of the invention for Type I diabetes, Type II diabetes, and Syndrome X comprise administration of the inventive compounds of formula (I) as disclosed herein concomitantly, simultaneously or together with a therapeutically-effective amount of said additional compounds and medicaments.
  • the invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament for use in treating diabetes or cancer or other diseases related to PTPs.
  • the invention comprises compounds of formula (I) ,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl
  • B, L, R A , R B , Ri, Xi, X2, Y, n, and p are as defined in formula (I) .
  • the present invention comprises compounds of formula (I), wherein
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; and L, R A , R B , Ri, Xi, X2, Y, n, and p are as defined in formula
  • the present invention comprises compounds of formula (I), wherein Docket 05-869-WO
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H; and L, R A , R B , Ri, Xi, X 2 , n, and p are as defined in formula (D •
  • the invention comprises compounds of formula (I), wherein
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, Docket 05-869-WO pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C(O) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • R A , R B , Ri, Xi, X 2 , n, and p are as defined in formula (I) .
  • the invention comprises compounds of formula (I), wherein
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, Docket 05-869-WO wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(R N4 )C(0)-, -C (0) N (R N4 ) -,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, XI, X2, n, and p are as defined in formula (I) .
  • the invention comprises compounds of formula ( II ) ,
  • Xi is O, S, or N (R N] _) , wherein R N1 is -H or - (Ci-C 6 ) alkyl; X 2 is CH or N; Ri is -H, - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkyl-phenyl, or
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, -(Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C(O) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S(O) 2 -, -N(R N4 )-, -N (R N4 ) C (0) -, -C (0) N (R N4 ) -, -S(O) 2 N(RN 4 )-, -N(RN 4 )S(O) 2 -, - (CI-C 6 ) alkyl-O-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • n 0, 1, 2, 3, or 4;
  • each R B is aryl- or heteroaryl-; each R B is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (II), wherein
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, Docket 05-869-WO benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; and L, R A , R B , Ri, Xi, X2, Y, n, and p are as defined in formula
  • the invention comprises compounds of formula (II), wherein
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isox
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H; and L, R A , RB, RI, Xi, X2, n, and p are as defined in formula
  • the invention comprises compounds of formula (II), wherein
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • the invention comprises compounds of formula (II), wherein
  • B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isox
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(RN 4 )-, -N(R N4 )C(0)-, -C(O)N(R 114 )-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, XI, X2, n, and p are as defined in formula (II) .
  • the invention comprises compounds of formula (III), Docket 05-869-WO
  • Xi is 0, S, or N (R N1 ) , wherein R N i is -H or - (Ci-C 6 ) alkyl; X 2 is CH or N; Ri is -H, - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkyl-phenyl, or
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S(O) 2 -, -N(RN 4 )-, -N (R 114 ) C (0) -, -C(O)N(R 114 )-, -S(O) 2 N(RN 4 )-, -N(RN 4 )S(O) 2 -, - (C I -C 6 ) alkyl-O-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (III), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N 3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • the invention comprises compounds of formula (III), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • R A , R B , Ri, Xi, X 2 , n, and p are as defined in formula
  • the invention comprises compounds of formula (III), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • L is -0-, -S-, -N(R N4 )-, -N(R N4 )C(O)-, -C (0) N (R N4 ) -,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, XI, X2, n, and p are as defined in formula (III) .
  • the invention comprises compounds of formula (IV) ,
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S(O) 2 -, -N(RN 4 )-, -N (R 114 ) C (0) -, -C(O)N(R 114 )-, -S(O) 2 N(RN 4 )-, -N(RN 4 )S(O) 2 -, - (C I -C 6 ) alkyl-O-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • each R A is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl,
  • each R B is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (IV), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H; and L, R A , RB, RI, n, and p are as defined in formula (IV) .
  • the invention comprises compounds of formula (IV), wherein Docket 05-869-WO
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C(O) (C 1 -C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • R N4 and R N s are independently -H or -(Ci-C 6 ) alkyl, Docket 05-869-WO wherein R N6 and R N7 are each independently -H,
  • R A , RB, RI, n, and p are as defined in formula (IV) .
  • the invention comprises compounds of formula (IV), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(RN 4 )-, -N(R N4 )C(0)-, -C(O)N(R 114 )-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (IV) .
  • the invention comprises compounds of formula (V) ,
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S (O) 2 -, -N (RN 4 ) -, -N (R 114 ) C (0) -, -C (0) N (R N4 ) -, -S (O) 2 N (R N4 ) -, -N (R N4 ) S (O) 2 -, - (CI-C 6 ) alkyl-0-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-0- (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (V) , wherein,
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (C 1 -C 6 JaIkOXy, -C(O) (C 1 -C 6 ) alkyl, or -C(O)H; and L, R A , R B , R 1 , n, and p are as defined in formula (V) .
  • the invention comprises compounds of formula (V) , wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N 3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • R A , RB, RI, n, and p are as defined in formula (V) .
  • the invention comprises compounds of formula (V) , wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, Docket 05-869-WO wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(R N4 )C(0)-, -C (0) N (R N4 ) -,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (V) .
  • the invention comprises compounds of formula (VI),
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C(O) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S(O) 2 -, -N(R N4 )-, -N (R N4 ) C (0) -, -C (0) N (R N4 ) -, -S(O) 2 N(RN 4 )-, -N(RN 4 )S(O) 2 -, - (CI-C 6 ) alkyl-O-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (VI), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • the invention comprises compounds of formula (VI), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • R A , RB, RI, n, and p are as defined in formula (VI) .
  • the invention comprises compounds of formula (VI), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, Docket 05-869-WO
  • L is -0-, -S-, -N(R N4 )-, -N(R N4 )C(O)-, -C (0) N (R N4 ) -,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VI) .
  • the invention comprises compounds of formula (VI), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently Docket 05-869-WO
  • R N2 and R N 3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is - (Ci-C 6 ) alkyl-O-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VI) .
  • the invention comprises compounds of formula (VI), wherein
  • Y is a bond, phenyl, or pyridyl
  • L is - (Ci-C 6 ) alkyl-O-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VI) .
  • the invention comprises compounds of formula (VII) ,
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, Docket 05-869-WO
  • L is -0-, -S-, -S(O) 2 -, -N(RN 4 )-, -N (R 114 ) C (0) -, -C(O)N(R 114 )-, -S(O) 2 N(RN 4 )-, -N(RN 4 )S(O) 2 -, - (C 1 -C 6 ) alkyl-0-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-0- (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (VII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, Docket 05-869-WO pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H; and L, R A , R B , Ri, n, and p are as defined in formula (VII) .
  • the invention comprises compounds of formula (VII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • L is -0-, -S-, -N(RN 4 )-, -N(R N4 )C(0)-, -C(O)N(R 114 )-,
  • the invention comprises compounds of formula (VII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently Docket 05-869-WO
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(R N4 )C(0)-, -C (0) N (R N4 ) -,
  • the invention comprises compounds of formula (VII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is - (C 1 -C 6 ) alkyl-O-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R N6 and R N7 are each independently -H,
  • the invention comprises compounds of formula (VII), wherein
  • Y is a bond, phenyl, or pyridyl
  • L is - (Ci-C 6 ) alkyl-O-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • R N6 and R N7 are each independently -H
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VII) .
  • the invention comprises compounds of formula (VII), wherein
  • L is - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-, or
  • R N6 and R N7 are each independently -H
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VII) . Docket 05-869-WO
  • the invention comprises compounds of formula (VII), wherein
  • Y is pyridyl
  • L is - (Ci-C 6 ) alkyl-O- or - (Ci-C 6 ) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y;
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VII) .
  • the invention comprises compounds of formula (VII), wherein
  • L is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-, or - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N6 and R N7 are each independently -H, - (C 1 -C 6 ) alkyl, allyl, propargyl, acetyl, or -C (0) (C 1 -C 6 ) alkoxy;
  • R 1 is H; and
  • R A , R B , n, and p are as defined in formula (VII) .
  • the invention comprises compounds of formula (VII), wherein
  • Y is pyridyl
  • L is - (C 1 -C 6 ) alkyl-O- or - (C 1 -C 6 ) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y;
  • R 1 is H; and R A , R B , n, and p are as defined in formula (VII) . Docket 05-869-WO
  • the invention comprises compounds of formula (VIII) ,
  • Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C(O)H;
  • L is -0-, -S-, -S(O) 2 -, -N(R 114 )-, -N(R N4 )C(O)-, -C(O)N(R 114 )-, -S(O) 2 N(RN 4 )-, -N(RN 4 )S(O) 2 -, - (CI-C 6 ) alkyl-O-, -0- (Ci-C 6 ) alkyl-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention comprises compounds of formula (VIII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • the invention comprises compounds of formula (VIII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(R N4 )-, -N(RN 4 )C(O)-, -C (0) N (R N4 ) -,
  • the invention comprises compounds of formula (VIII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is -0-, -S-, -N(RN 4 )-, -N(R N4 )C(0)-, -C(O)N(R 114 )-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, n, and p are as defined in formula (VIII) .
  • the invention comprises compounds of formula (VIII), wherein
  • Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N2 and R N3 are each independently -H, - (Ci-C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • L is - (Ci-C 6 ) alkyl-O-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VIII) .
  • the invention comprises compounds of formula (VIII), wherein
  • Y is a bond, phenyl, or pyridyl
  • L is - (Ci-C 6 ) alkyl-O-, - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-,
  • R N6 and R N7 are each independently -H
  • the invention comprises compounds of formula (VIII), wherein
  • L is - (Ci-C 6 ) alkyl-O- (Ci-C 6 ) alkyl-, or
  • R N6 and R N7 are each independently -H
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VIII) .
  • the invention comprises compounds of formula (VIII), wherein
  • Y is pyridyl
  • L is - (Ci-C 6 ) alkyl-O- or - (Ci-C 6 ) alkyl-S- , wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y;
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , n, and p are as defined in formula (VIII) .
  • the present invention comprises compounds of formula (VIII), wherein Docket 05-869-WO
  • R N6 and R N7 are each independently -H, - (Ci-C 6 ) alkyl, allyl, propargyl, acetyl, or -C (0) (Ci-C 6 ) alkoxy;
  • Ri is H; and
  • R A , R B , n, and p are as defined in formula (VIII) .
  • the invention comprises compounds of formula (VIII), wherein
  • Y is pyridyl
  • L is - (Ci-C 6 ) alkyl-O- or - (Ci-C 6 ) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y;
  • Ri is H; and R A , R B , n, and p are as defined in formula (VIII) .
  • the invention includes synthetic intermediates that are useful in making the compounds of the invention .
  • the invention provides methods of preparing the compounds of the invention and the intermediates used in those methods.
  • the invention provides a pharmaceutical composition comprising a compound of formula
  • the invention provides a methods of treating Type I diabetes, Type II diabetes, and Syndrome X
  • the compounds of the invention inhibit PTP-IB, and therefore, are useful in the treating or controlling other PTP-IB mediated diseases, including controlling or treating Type 2 diabetes, improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof.
  • the invention encompasses a method of inhibiting PTP-IB comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention encompasses a method of treating cancer comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound or salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention encompasses a method of treating neurodegenerative diseases comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound or salt of formula (I), or a Docket 05-869-WO pharmaceutical composition comprising a compound or salt of formula ( I ) .
  • the invention provides a method of treating immunological disease comprising administering either a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • the invention provides a method of treating bleeding disorders comprising administering either a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • the invention also provides methods of using PTP-IB inhibitors of formula (I) for improving the cardiovascular or cerebrovascular risk profile in patients experiencing or subject to type II diabetes (non-insulin-dependent diabetes mellitus) or Syndrome X, preferably in patients experiencing or subject to human type II diabetes. These methods may also be characterized as the reduction of risk factors for heart disease, stroke, or heart attack in patients experiencing or subject to type II diabetes or Syndrome X.
  • the invention also provides methods and compositions for combination therapy of Type I diabetes, Type II diabetes, and Syndrome X.
  • Table 1 methods for using a pharmacological combination of one or more PTP-IB inhibitor and one or more combination agent are described for the treatment of Type II diabetes or Syndrome X in a patient in need of such treatment.
  • such treatments comprise administration of the inventive compounds of formula (I) as disclosed herein either concomitantly, simultaneously, or together with a therapeutically-effective Docket 05-869-WO amount of said additional compounds and medicaments.
  • combination therapy methods involving insulins as the associated agent the methods are for the treatment of Type I or Type II diabetes in a patient in need of such treatment.
  • Insulins useful with the methods and combinations of this invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combinations of intermediate and rapid acting insulins.
  • Rapid acting commercially available insulin products include HUMALOG ® Brand Lispro Injection (rDNA origin); HUMULIN ® Regular Human Injection, USP [rDNA origin]; HUMULIN ® Regular U- 500 Concentrated Human Injection, USP [rDNA origin] ; REGULAR ILETIN ® II (insulin injection, USP, purified pork) available from Eli Lilly and Co.; and the NOVALIN ® Human Insulin Injection and VENOSULIN ® BR Buffered Regular Human Injection, each available from Novo Nordisk Pharmaceuticals.
  • intermediate acting insulins useful with this invention include, but are not limited to, the HUMULIN ® L brand LENTE ® human insulin [rDNA origin] zinc suspension, HUMULIN ® N NPH human insulin [rDNA origin] isophane suspension, LENTE ® ILETIN. RTM.
  • HUMALOG ® Mix 75/25 (75% Insulin Lispro Protamine Suspension and 25% Insulin Lispro Injection)
  • HUMULIN ® 50/50 (50% Human Insulin Isophane Suspension and 50% Human Insulin Injection)
  • HUMULIN ® 70/30 70% Human Insulin Docket 05-869-WO
  • a commercially available long acting insulin for use with this invention is the HUMULIN ® U Ultralente ® human insulin [rDNA origin] extended zinc suspension, available from Eli Lilly and Company.
  • inhaled insulin products such as the EXUBERA ® inhaled insulin product developed by Pfizer Inc. and Aventis SA.
  • Each of these insulin products can be administered as directed by a medical professional using administrations, dosages and regimens known in the art, such as those published for each product in the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics Company, Inc. at Montvale, N.J., the relevant sections of which are incorporated herein by reference.
  • the compounds of general Formula (I) may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation comprising a compound of general Formula (I) and a pharmaceutically acceptable carrier.
  • One or more compounds of Docket 05-869-WO general Formula (I) may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients.
  • compositions containing compounds of general Formula (I) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, Docket 05-869-WO calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, Docket 05-869-WO calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Formulations for oral use may also be presented as lozenges .
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations.
  • These compositions Docket 05-869-WO may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring, and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of the present invention may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
  • the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene Docket 05-869-WO glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the compounds of this invention can also be administered by a transdermal device.
  • topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner.
  • the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier (s) with or without stabilizer (s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of Docket 05-869-WO the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients.
  • suitable carrier especially an aqueous solvent for the active ingredients.
  • the antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
  • the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, Docket 05-869-WO polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
  • the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
  • Preferred non-human animals include domesticated animals.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge.
  • alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl .
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing the designated number of carbon atoms and containing at least one carbon-carbon double bond.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1- heptenyl, and 3-decenyl. Docket 05-869-WO
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing the designated number of carbon atoms and containing at least one carbon- carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl refers to an aromatic hydrocarbon ring system containing at least one aromatic ring.
  • the aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.
  • aryl groups include, for example, phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthalene and biphenyl .
  • Preferred examples of aryl groups include phenyl, naphthyl, and anthracenyl . More preferred aryl groups are phenyl and naphthyl. Most preferred is phenyl.
  • cycloalkyl refers to a cyclic hydrocarbon.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • halogen or halo indicate fluorine, chlorine, bromine, and iodine.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy .
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl . Docket 05-869-WO
  • heterocycloalkyl refers to a ring or ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring.
  • the heterocycloalkyl ring is optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings.
  • Preferred heterocycloalkyl groups have from 3 to 7 members.
  • heterocycloalkyl groups include, for example, 1 , 2 , 3, 4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl .
  • Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, and pyrrolidinonyl .
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • heteroaryl groups include, for example, pyridine, furan, thienyl, 5, 6, 7, 8-tetrahydroisoquinoline and pyrimidine.
  • heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl .
  • the compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers . In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
  • Resolution of the racemates can Docket 05-869-WO be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.
  • R A , R B , n and p are as defined in formula (I) .
  • Variable L represents a linker, and Z represents 0, S, or NR, where R is H or any functionality which does not interefer with the required reactivity outlined below; protecting groups are designated by P.
  • X represents a halogen or leaving group such as tosylate, triflate and the like, which are familiar to those skilled in the art.
  • the following scheme is a representation of a specific example to illustrate the general synthetic methods. Those skilled in the art will recognize that the regiochemistry of the products in the following scheme can be readily adjusted without modification of the particular synthetic steps by substitution of the appropriate starting materials.
  • substitution of 3-bromo- ⁇ - bromoacetophenone for 4-bromo- ⁇ -bromoacetophenone in the initial synthetic step would impart a meta- regiochemistry between the halogen and thiazole in Al, and ultimately a meta- regiochemistry between the thaizole and dibenzofuran in the final product, A5. Docket 05-869-WO
  • a dehydrative cyclization reaction between 4-halo- ⁇ -bromoacetophenone and for example, 2, 2-dimethylpropionic acid thiocarbamoylmethyl ester yields a thiazole of structure Al, where R' is t-butyl .
  • R' may be any group which will not interfere with the subsequently required reactivity, such as phenyl, n-alkyl, s-alkyl, t-alkyl, and the like.
  • Al and 4-dibenzofuranylboronic acid are coupled according to standard Suzuki palladium catalyzed conditions, involving Pd (PPh 3 ) 4 and a base, such as Na 2 CO 3 t0 yield A2.
  • This conversion of may also be performed via palladium catalysis utilizing organozinc (Negishi) , organomagnesium (Kumada) , or organotin (Stille) reactants with aryl halides with suitably protected starting materials if chemical incompatibilities would exist otherwise.
  • the haloarene may be an iodo- , bromo- , or chloroarene.
  • the palladium source may be, for example, Pd (PPh 3 ) 4, Pd 2 (dba) 3 , Pd(OAc) 2 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (MeCN) 2, PdCl 2 (PhCN) 2 , PdCl 2 (dppf), PdCl 2 (dppp) , PdCl 2 (dppe) , PdCl 2 (COD), Pd (PCy 3 ) 2, or Pd(tBu 3 P) 2 , all of which are available commercially from either Aldrich Chemical (Milwaukee, WI) or Strem Chemical (Newburyport, MA) .
  • palladium Docket 05-869-WO catalysts may be prepared from P0I2 (dba) 3 in situ by the addition of a ligand source, such as dppf, dppe, dppp, PCy3,
  • A4 is prepared by treatment of A3 with a nucleophilic activation and reaction agent such as PPh 3 Br 2 , PBr 3 , POBr 3 , or PPh 3 and CBr 4 .
  • a nucleophilic activation and reaction agent such as PPh 3 Br 2 , PBr 3 , POBr 3 , or PPh 3 and CBr 4 .
  • the benzyl chloride may be prepared anagously with PPh 3 Cl 2 , POCl 3 , PCl 5 , or PPh 3 and CCl 4 .
  • the benzyl iodide may be prepared using PPh 3 I 2 .
  • A5 can be prepared by two final steps; first, alkylation of a thiol, alcohol, or amine in the presence of a base with A4, then deprotection of the carboxylic acid.
  • an ester protecting group may be hydrolyzed under basic conditions to yield the carboxylic acid.
  • L represents a linker
  • Z represents 0, S, or NR, where R is H or any functionality which does not interefer with the required reactivity.
  • the thiol, alcohol, or amine necessarily includes an appropriately protected carboxylic acid.
  • bases include, but are not limited to, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , triethylamine, diethylisopropylamine, NaOH, and KOH.
  • Catalysts may be added to facilitate the reaction, including KI, n-Bu 4 NI, and the like.
  • Appropriate thiols, alcohols, and amines for preparation of compounds of the present invention include, but are not limited to, BOC-protected amino acid esters, such as, alkyl N-BOC-Cys, alkyl N-BOC-Ser, alkyl N- BOC-Thr, alkyl N-BOC-His, alkyl N-BOC-Lys, alkyl N-BOC-Tyr, alkyl N-BOC homoserine, alkyl N-BOC homocysteine; straight and branched alkyl thiols, alcohols, and amines such as alkyl Docket 05-869-WO mercaptoacetates, alkyl 2-mercaptopropanoates, alkyl 3- mercaptopropanoates, alkyl hydroxyacetates, alkyl 2-
  • the title compound (alternatively named 5- ⁇ [2-(3- dibenzo [b, d] furan-4-ylphenyl) -1, 3-thiazol-4- yl] methoxyjnicotinic acid) is prepared in a manner analogous to that set forth above in Example 1, except 5-hydroxy- nicotinic acid methyl ester is used instead of 2-tert- butoxycarbonylamino-3-mercapto-propionic acid methyl ester in step 4 to give, after saponification using the conditions outlined in step 5, 5- [2- (3-dibenzofuran-4-yl-phenyl) -thiazol- 4-ylmethoxy] -nicotinic acid .
  • test compounds are evaluated for their in vitro inhibitory activity against recombinant human PTP-IB with phosphotyrosyl dodecapeptide TRDI(P)YETD(P)Y(P)YRK.
  • TRDI(P)YETD(P)Y(P)YRK phosphotyrosyl dodecapeptide
  • This corresponds to the 1142-1153 insulin receptor kinase regulatory domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues; IR-triphosphopeptide as a source of substrate.
  • Enzyme reaction progression is monitored via the release of inorganic phosphate as detected by the malachite green - ammonium molybdate method for the phosphopeptide .
  • Preferred compounds of the invention exhibit IC 5O values of less than 10 ⁇ M; more preferred compounds of the invention exhibit IC 50 values of less than 1 ⁇ M. Particularly preferred compounds exhibit IC 5 O values of less than 300 nM.

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Abstract

Disclosed are compounds and pharmaceutically acceptable salts of formula (I) : which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-lB (PTP-IB), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.

Description

SUBSTITUTED HETEROARYL CARBOXYLIC ACID DERIVATIVES AS PTB-IB INHIBITORS
BACKGROUND OF THE INVENTION
This application claims the benefit of Provisional Application No. 60/825539, filed September 13, 2006, the dislosure of which in incorporated herein in its entirety.
Field of the Invention
The invention relates to substituted heteroaryl carboxylic acid derivatives and more specifically to such compounds that are useful in the treatment of syndrome X (consisting of such abnormalities as obesity, dyslipidemia, hypercoagulation, hypertension, insulin resistance and leading to heart disease and diabetes) , obesity, diabetes, immunological disease, bleeding disorders, and/or cancer. More specifically, it relates to such compounds that are capable of inhibiting Protein tyrosine phosphatases (PTPs) , in particular Protein tyrosine phosphatase-lB (PTP-IB) which is a negative regulator of the insulin and leptin signaling pathway and improves insulin-sensitivity.
Description of Related Art
Protein tyrosine phosphatases are a large family of transmembrane or intracellular enzymes that dephosphorylate substrates involved in a variety of regulatory processes (Fischer et al . , 1991, Science 253:401-406). Protein tyrosine phosphatase-lB (PTP-IB) is an approximately 50 kd intracellular protein, which is present in abundant amounts in various human tissues (Charbonneau et al . , 1989, Proc. Natl. Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1- 15) .
Determining which proteins are substrates of PTP-IB has been of considerable interest. One substrate which has aroused Docket 05-869-WO especial interest is the insulin receptor. The binding of insulin to its receptor results in autophosphorylation of the domain. This causes activation of the insulin receptor tyrosine kinase, which phosphorylates the various insulin receptor substrate (IRS) proteins that propagate the insulin signaling event further downstream to mediate insulin's various biological effects.
Seely et al . , 1996, Diabetes 45:1379-1385 ("Seely") studied the relationship of PTP-IB and the insulin receptor in vitro. Seely constructed a glutathione S-transferase (GST) fusion protein of PTP-IB that had a point mutation in the PTP- IB catalytic domain. Although catalytically inactive, this fusion protein was able to bind to the insulin receptor, as demonstrated by its ability to precipitate the insulin receptor from purified receptor preparations and from whole cell lysates derived from cells expressing the insulin receptor .
Ahmad et al . , 1995, J. Biol. Chem. 270:20503-20508 used osmotic loading to introduce PTP-IB neutralizing antibodies into rat KRC-7 hepatoma cells. The presence of the antibody in the cells resulted in an increase of 42% and 38%, respectively, in insulin stimulated DNA synthesis and phosphatidyinositol 3' kinase activity. Insulin receptor autophosphorylation and insulin receptor substrate-1 tyrosine phosphorylation were increased 2.2 and 2.0-fold, respectively, in the antibody-loaded cells. The antibody-loaded cells also showed a 57% increase in insulin stimulated insulin receptor kinase activity toward exogenous peptide substrates.
Kennedy et al . , 1999, Science 283: 1544-1548 showed that protein tyrosine phosphatase PTP-IB is a negative regulator of the insulin signaling pathway, indicating that inhibitors of this enzyme are beneficial in the treatment of Type 2 diabetes, which appears to involve a defect in an early Docket 05-869-WO process in insulin signal transduction rather than a structural defect in the insulin receptor itself. (J. M. Olefsky, W. T. Garvey, R. R. Henry, D. Brillon, S. Matthai and G. R. Freidenberg, G. R. (1988).) Cellular mechanisms of insulin resistance in non-insulin-dependent (Type II) diabetes. (Am. J. Med. 85: Suppl . 5A, 86-105.) A drug that improved insulin sensitivity would have several advantages over traditional therapy of NIDDM using sulfonylureas, which do not alleviate insulin resistance but instead compensate by increasing insulin secretion.
Ragab et al (2003, J. Biol. Chem 278(42), 40923-32) showed that PTP-IB is involved in regulating platelet aggregation. Hence, inhibition of PTP-IB can be predicted to have an effect on bleeding disorder, and cardiovascular disease .
Romsicki et al . , (2003, Arch Biochem. Biophys 414(1), 40- 50) showed that TC PTP is structurally and functionally very similar. A PTP-IB inhibitor is very likely to also inhibit TC PTP. A knockout of the TC PTP gene produces a phenotype with impaired immune function. (You-Ten et al . , 1997, J. Exp. Med. 186(5), 683-93). Hence, inhibitors of PTP IB can be predict to inhibit TC PTP and modulate immune response.
It has also been demonstrated that PTP-IB is a negative regulator of leptin signaling (Kaszua et al . MoI. Cell. Endocrinology, 195:109-118, 2002). PTP-IB deficient mice show enhanced potency for exogenous leptin to suppress food intake (Cheng, et al . Developmental Cell 2:497-503, 2002). Thus, inhibitors of PTP-IB augment the beneficial effects of leptin on food intake, body weight regulation and metabolism, in normal individuals and leptin resistant individuals.
Therefore, inhibitors of PTPs, and inhibitors of PTP-IB in particular, are useful in controlling or treating obesity, syndrome X, Type 2 diabetes, in improving glucose tolerance, Docket 05-869-WO and in improving insulin sensitivity in patients in need thereof. Such compounds are also useful in treating or controlling other PTP mediated diseases, such as the treatment of neurodegenerative diseases, cancer, immunological disorders, bleeding and cardiovascular disorders, and the like.
Docket 05-869-WO
SUMMARY OF THE INVENTION
In a broad aspect, the invention encompasses the compounds of formula (I) shown below, pharmaceutical compositions containing the compounds and methods employing such compounds or compositions in the treatment of diabetes and/or cancer.
In one aspect, the invention encompasses compounds of formula (I) :
Figure imgf000006_0001
(D and the pharmaceutically acceptable salt thereof, wherein Xi is O, S, or N (RN1) , wherein RNi is -H or - (Ci-C6) alkyl; X2 is CH or N; Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl; Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (R114) C (0) -, -C(O)N(R114)-, Docket 05-869-WO
-S(O)2N(RN4)-, -N(RN4)S(O)2-, - (C1-C6) alkyl-0-, -O- (Ci-C6) alkyl-, - (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) -, -N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(Ru4) -, -C(0)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (0) N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N (RN5)- (CI-C6) alkyl-, -N (RN4) C (0) 0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC (O)N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N(RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C(O) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (O) OH, Docket 05-869-WO
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7) , - (Ci-C6) alkyl-N(RN6RN7) , or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (C1-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
A is -aryl- or -heteroaryl-; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4;
B is aryl- or heteroaryl-; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) , -(Ci-C6) alkyl-N (RNIORNII), or -C (0) N (RNIORNII) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
The invention also includes synthetic intermediates that are useful in making the compounds of the invention. Docket 05-869-WO
The invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods .
The invention also provides pharmaceutical compositions comprising a compound or salt of formula (I) and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent .
The compounds of formula (I) bind to PTPs, and in particular to PTP-IB. The interaction with the enzyme, specifically PTP-IB, preferably results in inhibition of the enzyme .
In another aspect, the invention provides a method for inhibiting protein tyrosine phosphatases, preferably PTP-IB, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound or salt of formula (I) .
The invention further provides methods of treating diseases such as Type I and Type II diabetes, syndrome X, obesity, cancer, neurodegenerative disease, immunological disease, bleeding disorders, and cardiovascular disease in a patient in need of such treatment, comprising administering to the patient a compound or pharmaceutically acceptable salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
In another aspect, the invention provides a method for treating metabolic disorders related to insulin resistance or hyperglycemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound or salt of formula (I) .
The invention provides formulations and pharmaceutical compositions, as well as methods for combination therapy for treating Type I diabetes, Type II diabetes, and Syndrome X Docket 05-869-WO with the compounds of formula (I) plus therapeutically- effective amounts additional compounds and medicaments. Treatment methods of the invention for Type I diabetes, Type II diabetes, and Syndrome X comprise administration of the inventive compounds of formula (I) as disclosed herein concomitantly, simultaneously or together with a therapeutically-effective amount of said additional compounds and medicaments.
The invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament for use in treating diabetes or cancer or other diseases related to PTPs.
Docket 05-869-WO
DETAILED DESCRIPTION OF THE INVENTION
In another embodiment, the invention comprises compounds of formula (I) ,
Figure imgf000011_0001
(D
or a pharmaceutically acceptable salt thereof, wherein A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, and B, L, RA, RB, Ri, Xi, X2, Y, n, and p are as defined in formula (I) .
In another embodiment, the present invention comprises compounds of formula (I), wherein
A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; and L, RA, RB, Ri, Xi, X2, Y, n, and p are as defined in formula
(D •
In another embodiment, the present invention comprises compounds of formula (I), wherein Docket 05-869-WO
A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, Ri, Xi, X2, n, and p are as defined in formula (D •
In another embodiment, the invention comprises compounds of formula (I), wherein
A is phenyl, naphthyl, furanyl, thienyl, pyridyl, Docket 05-869-WO pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H; L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or Docket 05-869-WO
- ( Ci-C6 ) al kyl -N (RN4 ) - ( Ci-C6 ) al kyl - , wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and RA, RB, Ri, Xi, X2, n, and p are as defined in formula (I) .
In another embodiment, the invention comprises compounds of formula (I), wherein
A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, Docket 05-869-WO wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (C1-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N(RN4) -, -N (RN4) - (Ci-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (C1-C6) alkyl, or -C(O)H; Docket 05-869-WO
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, XI, X2, n, and p are as defined in formula (I) .
In another embodiment, the invention comprises compounds of formula ( II ) ,
Figure imgf000016_0001
(ii:
or a pharmaceutically acceptable salt thereof, wherein Xi is O, S, or N (RN]_) , wherein RN1 is -H or - (Ci-C6) alkyl; X2 is CH or N; Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl;
Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, -(Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (RN4) C (0) -, -C (0) N (RN4) -, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (CI-C6) alkyl-O-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) -, -N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4)-, -C(0)N(RN4)- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- , -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N (RN5)- (CI-C6) alkyl-, -N (RN4) C (0) 0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC(O)N(RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N (RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4)- (CI-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C (0) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (O) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7) , - (Ci-C6) alkyl-N (RN6RN7) , or
Figure imgf000017_0001
, Docket 05-869-WO wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4;
B is aryl- or heteroaryl-; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) , -(Ci-C6) alkyl-N (RNIORNII), or -C (0) N (RNIORNII) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
In another embodiment, the invention comprises compounds of formula (II), wherein
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, Docket 05-869-WO benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; and L, RA, RB, Ri, Xi, X2, Y, n, and p are as defined in formula
(H) •
In another embodiment, the invention comprises compounds of formula (II), wherein
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, RI, Xi, X2, n, and p are as defined in formula
(H) • Docket 05-869-WO
In another embodiment, the invention comprises compounds of formula (II), wherein
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl;
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, Docket 05-869-WO wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H; and RA, RB, Ri, Xi, X2, n, and p are as defined in formula (II) . In another embodiment, the invention comprises compounds of formula (II), wherein
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl; Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, Docket 05-869-WO
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (O) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C(O)N(R114)-,
- (Ci-C6) alkyl-0-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N (R114)-, -N (R114) - (Ci-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, XI, X2, n, and p are as defined in formula (II) .
In another embodiment, the invention comprises compounds of formula (III), Docket 05-869-WO
Figure imgf000023_0001
: i i i )
or a pharmaceutically acceptable salt thereof, wherein Xi is 0, S, or N (RN1) , wherein RNi is -H or - (Ci-C6) alkyl; X2 is CH or N; Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl;
Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (R114) C (0) -, -C(O)N(R114)-, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (CI-C6) alkyl-O-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) -, -N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4)-, -C(0)N(RN4)- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N(RN5)- (CI-C6) alkyl-, -N (RN4) C (0) 0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC(O)N(RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N (RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4)- (CI-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C (0) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (0) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7) , - (Ci-C6) alkyl-N (RN6RN7) , or
Figure imgf000024_0001
, wherein RN4 and RNs are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, Docket 05-869-WO
-C (O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNI0RNII) ,
- ( Ci -C6 ) al kyl -N ( RNI ORNI I ) , or -C ( 0 ) N ( RNi0RNii ) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
In another embodiment, the invention comprises compounds of formula (III), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, Docket 05-869-WO
-OH, - ( Ci-C6 ) al kyl -OH, -NO2 , -N (RN2RN3 ) ,
- ( C1-C6 ) al kyl -N (RN2RN3 ) , or -C ( 0) N (RN2RN3 ) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, Ri, Xi, X2, n, and p are as defined in formula
(III) •
In another embodiment, the invention comprises compounds of formula (III), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or Docket 05-869-WO
- ( Ci-C6 ) al kyl -N (RN4 ) - ( Ci-C6 ) al kyl - , wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and RA, RB, Ri, Xi, X2, n, and p are as defined in formula
(III) •
In another embodiment, the invention comprises compounds of formula (III), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3), -(Ci-C6) alkyl-N (RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, Docket 05-869-WO
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-0-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C (0) N (RN6RN7) , wherein RN4 and RNs are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, XI, X2, n, and p are as defined in formula (III) .
In another embodiment, the invention comprises compounds of formula (IV) ,
Figure imgf000028_0001
(IV) Docket 05-869-WO or a pharmaceutically acceptable salt thereof, wherein Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl;
Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (R114) C (0) -, -C(O)N(R114)-, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (CI-C6) alkyl-O-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) -, -N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (R114) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N (R114) -, -C(O)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N (RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (R114) -, -S (0) 2N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) S (0) 2-, -N (R114) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (C1-C6) alkyl-N (RN4) S (0) 2N (RN5) - (C1-C6) alkyl-, -N (RN4) C (0) N (RN5) - (C1-C6) alkyl-,
- (C1-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (C1-C6) alkyl-N (RN4)C (O)N(RN5)- (C1-C6) alkyl-, -N (RN4) C (0) 0- (C1-C6) alkyl-,
- (C1-C6) alkyl-N (RN4) C (0) 0-,
- (C1-C6) alkyl-N (RN4) C (0) 0- (C1-C6) alkyl-, -OC(O)N(RN4)- (C1-C6) alkyl-,
- (C1-C6) alkyl-OC (O)N (RN4) -, or
- (C1-C6) alkyl-OC (0) N (RN4) - (C1-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (C1-C6JaIkOXy,
-C(O) (C1-C6) alkyl, -C(O)OH, - (C1-C6) alkyl-C (0) OH,
- (C1-C6) haloalkoxy, - (C1-C6) haloalkyl, -halogen, -N(RN6RN7) , - (C1-C6) alkyl-N (RN6RN7) , or
Figure imgf000030_0001
, wherein RN4 and RNs are independently -H or
-(C1-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (C1-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (C1-C6) alkoxy, -C (0) (C1-C6) alkyl, or -C(O)H; each RA is independently - (C1-C6) alkoxy, - (C1-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (C1-C6) alkoxy, -C (0) (C1-C6) alkyl, -C(O)OH, -CN, - (C1-C6) haloalkoxy,
- (C1-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (C1-C6) alkyl-N (RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (C1-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (C1-C6) alkoxy, -C (0) (C1-C6) alkyl, or -C(O)H; Docket 05-869-WO n i s 0 , 1 , 2 , 3 , or 4 ; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) ,
- ( Ci-C6 ) al kyl -N ( RNI ORNI I ) , or -C ( O) N (RNi0RNii ) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
In another embodiment, the invention comprises compounds of formula (IV), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, RI, n, and p are as defined in formula (IV) .
In another embodiment, the invention comprises compounds of formula (IV), wherein Docket 05-869-WO
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (C1-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (C1-C6) alkyl, or -C(O)H; L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) -, -N (RN4) - (Ci-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C (0) N (RN6RN7) , wherein RN4 and RNs are independently -H or -(Ci-C6) alkyl, Docket 05-869-WO wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H; and RA, RB, RI, n, and p are as defined in formula (IV) .
In another embodiment, the invention comprises compounds of formula (IV), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C(O)N(R114)-,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 Docket 05-869-WO substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (IV) .
In another embodiment, the invention comprises compounds of formula (V) ,
Figure imgf000034_0001
(V) or a pharmaceutically acceptable salt thereof, wherein Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl; Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3), Docket 05-869-WO
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S (O)2-, -N (RN4) -, -N (R114) C (0) -, -C (0) N (RN4) -, -S (O) 2N (RN4) -, -N (RN4) S (O) 2-, - (CI-C6) alkyl-0-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (R114) -, -N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (RN4) C (0) -, -N (R114) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (R114) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N (RN4) -, -C(0)N(RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl -N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N (RN5) - (CI-C6) alkyl-, -N (RN4) C (0) O- (CI-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (O) 0-,
- (Ci-C6) alkyl-N (RN4) C (O) O- (Ci-C6) alkyl-, -OC (O)N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N (RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4) - (Ci-C6) alkyl-, Docket 05-869-WO wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C(O) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (0) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7), - (Ci-C6) alkyl-N(RN6RN7) , or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) ,
- ( Ci -C6 ) al kyl -N ( RNI ORNI I ) , or -C ( 0 ) N ( RNI ORNI I ) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4. Docket 05-869-WO
In another embodiment, the invention comprises compounds of formula (V) , wherein,
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (C1-C6) alkoxy, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (C1-C6) alkoxy, -C (0) (C1-C6) alkyl, -C(O)OH, -CN,
- (C1-C6) haloalkoxy, - (C1-C6) haloalkyl, -halogen, -OH, - (C1-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (C1-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (C1-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (C1-C6JaIkOXy, -C(O) (C1-C6) alkyl, or -C(O)H; and L, RA, RB, R1, n, and p are as defined in formula (V) .
In another embodiment, the invention comprises compounds of formula (V) , wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (C1-C6JaIkOXy, -C (0) (C1-C6) alkyl, -C(O)OH, -CN,
- (C1-C6) haloalkoxy, - (C1-C6) haloalkyl, -halogen, Docket 05-869-WO
-OH, - ( Ci-C6 ) al kyl -OH, -NO2 , -N (RN2RN3 ) ,
- ( C1-C6 ) al kyl -N (RN2RN3 ) , or -C ( 0) N (RN2RN3 ) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-0-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(Ru4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (R114) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C (0) N (RN6RN7) , wherein RN4 and RNs are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and RA, RB, RI, n, and p are as defined in formula (V) .
In another embodiment, the invention comprises compounds of formula (V) , wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, Docket 05-869-WO wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (C1-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N(RN4) -, -N (RN4) - (Ci-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (C1-C6) alkyl, or -C(O)H; Docket 05-869-WO
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (V) .
In another embodiment, the invention comprises compounds of formula (VI),
Figure imgf000040_0001
(VI) or a pharmaceutically acceptable salt thereof, wherein Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl;
Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (RN4) C (0) -, -C (0) N (RN4) -, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (CI-C6) alkyl-O-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-N (RN4) -, -N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4)-, -C(0)N(RN4)- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N (RN5)- (CI-C6) alkyl-, -N (RN4) C (0) 0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC(O)N(RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N (RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4)- (CI-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C (0) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (0) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7) , - (Ci-C6) alkyl-N (RN6RN7) , or
Figure imgf000041_0001
, wherein RN4 and RN5 are independently -H or -(Ci-C6) alkyl, Docket 05-869-WO wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) ,
- ( Ci -C6 ) al kyl -N ( RNI ORNI I ) , or -C ( 0 ) N ( RNI ORNI I ) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
In another embodiment, the invention comprises compounds of formula (VI), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, Docket 05-869-WO
-C ( O) ( Ci-C6 ) al kyl , -C ( O) OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, Ri, n, and p are as defined in formula (VI) .
In another embodiment, the invention comprises compounds of formula (VI), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H; and RA, RB, RI, n, and p are as defined in formula (VI) .
In another embodiment, the invention comprises compounds of formula (VI), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, Docket 05-869-WO
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-0-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C (0) N (RN6RN7) , wherein RN4 and RNs are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VI) .
In another embodiment, the invention comprises compounds of formula (VI), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently Docket 05-869-WO
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is - (Ci-C6) alkyl-O-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7) , wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, or -C(O) (Ci-C6) alkyl;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VI) .
In another embodiment, the invention comprises compounds of formula (VI), wherein
Y is a bond, phenyl, or pyridyl;
L is - (Ci-C6) alkyl-O-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, Docket 05-869-WO
-C ( O) ( Ci-C6 ) al kyl , -C ( O) OH, -halogen ,
Figure imgf000047_0001
) t wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C(O) (Ci-C6) alkoxy, or -C (0) (Ci-C6) alkyl;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VI) .
In another embodiment, the invention comprises compounds of formula (VII) ,
Figure imgf000047_0002
(VII) or a pharmaceutically acceptable salt thereof, wherein Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl; Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, Docket 05-869-WO
-C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (R114) C (0) -, -C(O)N(R114)-, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (C1-C6) alkyl-0-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) -, -N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (R114) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N (R114) -, -C(0)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (0) N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (R114) -, -S (0) 2N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) S (0) 2N (R115) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N (RN5)- (CI-C6) alkyl-, -N (RN4) C (0) 0- (CI-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC (O)N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N(RN4) -, or
- (Ci-C6) alkyl-OC (O)N (R114) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl, Docket 05-869-WO
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C(O) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (0) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7), - (Ci-C6) alkyl-N(RN6RN7) , or -C(O)N(RN6RN7), wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) , -(Ci-C6) alkyl-N (RNIORNII), or -C (0) N (RNIORNII) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, Docket 05-869-WO pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, Ri, n, and p are as defined in formula (VII) .
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently Docket 05-869-WO
-H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C(O)N(R114)-,
- (Ci-C6) alkyl-0-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and RA, RB, RI, n, and p are as defined in formula (VII) .
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently Docket 05-869-WO
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (C1-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VII) . Docket 05-869-WO
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (C1-C6) alkoxy, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (C1-C6) alkoxy, -C (0) (C1-C6) alkyl, -C(O)OH, -CN,
- (C1-C6) haloalkoxy, - (C1-C6) haloalkyl, -halogen, -OH, - (C1-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (C1-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (C1-C6JaIkOXy, -C(O) (C1-C6) alkyl, or -C(O)H;
L is - (C1-C6) alkyl-O-, - (C1-C6) alkyl-O- (C1-C6) alkyl-,
- (C1-C6) alkyl-S-, - (C1-C6) alkyl-S- (C1-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (C1-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (C1-C6) alkoxy, -C (0) (C1-C6) alkyl, -C(O)OH, -halogen,
Figure imgf000053_0001
t wherein RN6 and RN7 are each independently -H,
- (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C(O) (C1-C6) alkoxy, or -C (0) (C1-C6) alkyl; R1 is -H, - (C1-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VII) . Docket 05-869-WO
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, phenyl, or pyridyl;
L is - (Ci-C6) alkyl-O-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen,
-N (RN6RN7) , wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C(O) (Ci-C6) alkoxy, or -C (0) (Ci-C6) alkyl;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VII) .
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, and
L is - (Ci-C6) alkyl-O- (Ci-C6) alkyl-, or
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -halogen,
-N(RN6RN7) , wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, allyl, propargyl, acetyl, or -C (0) (Ci-C6) alkoxy;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VII) . Docket 05-869-WO
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is pyridyl, and
L is - (Ci-C6) alkyl-O- or - (Ci-C6) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y; Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VII) .
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is a bond, and
L is - (C1-C6) alkyl-O- (C1-C6) alkyl-, or - (C1-C6) alkyl-S- (C1-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (C1-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (C1-C6) alkoxy,
-C (0) (C1-C6) alkyl, -halogen,
Figure imgf000055_0001
t wherein RN6 and RN7 are each independently -H, - (C1-C6) alkyl, allyl, propargyl, acetyl, or -C (0) (C1-C6) alkoxy; R1 is H; and RA, RB, n, and p are as defined in formula (VII) .
In another embodiment, the invention comprises compounds of formula (VII), wherein
Y is pyridyl, and
L is - (C1-C6) alkyl-O- or - (C1-C6) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y;
R1 is H; and RA, RB, n, and p are as defined in formula (VII) . Docket 05-869-WO
In another embodiment, the invention comprises compounds of formula (VIII) ,
Figure imgf000056_0001
(VIII) or a pharmaceutically acceptable salt thereof, wherein Ri is -H, - (Ci-C6) alkyl, - (Ci-C6) alkyl-phenyl, or
- (C3-C6) alkenyl;
Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3), or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(R114)-, -N(RN4)C(O)-, -C(O)N(R114)-, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (CI-C6) alkyl-O-, -0- (Ci-C6) alkyl-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2-,
-S (O)2- (Ci-C6) alkyl-, - (Ci-C6) alkyl-S (O)2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (R114) -, -N (R114) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4)-, -C(0)N(RN4)- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (O)N(RN5)- (CI-C6) alkyl-, -N (RN4) C (0) 0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC(O)N(RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N (RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4)- (CI-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C (0) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (0) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7) , - (Ci-C6) alkyl-N (RN6RN7) , or
Figure imgf000057_0001
, wherein RN4 and RNs are independently -H or -(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, Docket 05-869-WO
- ( C2-C6 ) al kynyl ,
-C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNI0RNII) , -(Ci-C6) alkyl-N (RNIORNII), or -C (0) N (RNIORNII) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, Docket 05-869-WO
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (O) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H; and L, RA, RB, Ri, n, and p are as defined in formula (VIII) . In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H;
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or Docket 05-869-WO
- ( Ci-C6 ) al kyl -N (RN4 ) - ( Ci-C6 ) al kyl - , wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and RA, RB, Ri, n, and p are as defined in formula (VIII) .
In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N (RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, Docket 05-869-WO
-C(O) (Ci-C6) alkyl, or -C(O)H; L is -0-, -S-, -N(RN4)-, -N(RN4)C(0)-, -C(O)N(R114)-,
- (Ci-C6) alkyl-0-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VIII) .
In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl, Docket 05-869-WO
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
L is - (Ci-C6) alkyl-O-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen,
Figure imgf000062_0001
t wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C(O) (Ci-C6) alkoxy, or -C (0) (Ci-C6) alkyl;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VIII) .
In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is a bond, phenyl, or pyridyl;
L is - (Ci-C6) alkyl-O-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -halogen, Docket 05-869-WO
-N ( RN6RN7 ) , wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl,
-C (0) (Ci-C6) alkoxy, or -C (0) (Ci-C6) alkyl; Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VIII) . In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is a bond, and
L is - (Ci-C6) alkyl-O- (Ci-C6) alkyl-, or
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -halogen,
-N(RN6RN7) , wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, allyl, propargyl, acetyl, or -C (0) (Ci-C6) alkoxy;
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VIII) .
In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is pyridyl, and
L is - (Ci-C6) alkyl-O- or - (Ci-C6) alkyl-S- , wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y; Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl; and RA, RB, n, and p are as defined in formula (VIII) .
In another embodiment, the present invention comprises compounds of formula (VIII), wherein Docket 05-869-WO
Y i s a bond, and
L i s - ( Ci -C6 ) al kyl -0- ( Ci -C6 ) al kyl - , or
- ( Ci -C6 ) al kyl - S - ( Ci -C6 ) al kyl - , wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -halogen,
-N(RN6RN7) , wherein RN6 and RN7 are each independently -H, - (Ci-C6) alkyl, allyl, propargyl, acetyl, or -C (0) (Ci-C6) alkoxy; Ri is H; and RA, RB, n, and p are as defined in formula (VIII) .
In another embodiment, the invention comprises compounds of formula (VIII), wherein
Y is pyridyl, and
L is - (Ci-C6) alkyl-O- or - (Ci-C6) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y;
Ri is H; and RA, RB, n, and p are as defined in formula (VIII) .
In another aspect, the invention includes synthetic intermediates that are useful in making the compounds of the invention .
In another aspect, the invention provides methods of preparing the compounds of the invention and the intermediates used in those methods.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula
(I) or a pharmaceutically acceptable salt thereof and at least Docket 05-869-WO one pharmaceutically acceptable solvent, carrier, adjuvant, or excipient .
In another aspect, the invention provides a methods of treating Type I diabetes, Type II diabetes, and Syndrome X
(consisting of such abnormalities as obesity, dyslipidemia, hypercoagulation, hypertension, insulin resistance and leading to heart disease and diabetes) , comprising administering either a pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula
(I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
The compounds of the invention inhibit PTP-IB, and therefore, are useful in the treating or controlling other PTP-IB mediated diseases, including controlling or treating Type 2 diabetes, improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof.
In another aspect, the invention encompasses a method of inhibiting PTP-IB comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention encompasses a method of treating cancer comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound or salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
In another aspect, the invention encompasses a method of treating neurodegenerative diseases comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound or salt of formula (I), or a Docket 05-869-WO pharmaceutical composition comprising a compound or salt of formula ( I ) .
In another aspect, the invention provides a method of treating immunological disease comprising administering either a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
In another aspect, the invention provides a method of treating bleeding disorders comprising administering either a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
The invention also provides methods of using PTP-IB inhibitors of formula (I) for improving the cardiovascular or cerebrovascular risk profile in patients experiencing or subject to type II diabetes (non-insulin-dependent diabetes mellitus) or Syndrome X, preferably in patients experiencing or subject to human type II diabetes. These methods may also be characterized as the reduction of risk factors for heart disease, stroke, or heart attack in patients experiencing or subject to type II diabetes or Syndrome X.
The invention also provides methods and compositions for combination therapy of Type I diabetes, Type II diabetes, and Syndrome X. In the following table, Table 1, methods for using a pharmacological combination of one or more PTP-IB inhibitor and one or more combination agent are described for the treatment of Type II diabetes or Syndrome X in a patient in need of such treatment. In the following embodiments, such treatments comprise administration of the inventive compounds of formula (I) as disclosed herein either concomitantly, simultaneously, or together with a therapeutically-effective Docket 05-869-WO amount of said additional compounds and medicaments. In the case of combination therapy methods involving insulins as the associated agent, the methods are for the treatment of Type I or Type II diabetes in a patient in need of such treatment.
Table 1
Figure imgf000067_0001
Docket 05-869-WO
Figure imgf000068_0001
Docket 05-869-WO
Figure imgf000069_0001
Docket 05-869-WO
Insulins useful with the methods and combinations of this invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combinations of intermediate and rapid acting insulins.
Rapid acting commercially available insulin products include HUMALOG® Brand Lispro Injection (rDNA origin); HUMULIN® Regular Human Injection, USP [rDNA origin]; HUMULIN® Regular U- 500 Concentrated Human Injection, USP [rDNA origin] ; REGULAR ILETIN® II (insulin injection, USP, purified pork) available from Eli Lilly and Co.; and the NOVALIN® Human Insulin Injection and VENOSULIN® BR Buffered Regular Human Injection, each available from Novo Nordisk Pharmaceuticals.
Commercially available intermediate acting insulins useful with this invention include, but are not limited to, the HUMULIN® L brand LENTE® human insulin [rDNA origin] zinc suspension, HUMULIN® N NPH human insulin [rDNA origin] isophane suspension, LENTE® ILETIN. RTM. II insulin zinc suspension, USP, purified pork, and NPH ILETIN® II isophane insulin suspension, USP, purified pork, available from Eli Lilly and Company, LANTUS® insulin glargine [rDNA origin] injection, available from Aventis Pharmaceuticals, and the NOVOLIN L Lente® human insulin zinc suspension (recombinant DNA origin) , and NOVOLIN® N NPH human insulin isophane suspension (recombinant DNA origin) products available from Novo Nordisk Pharmaceuticals, Inc, Princeton N.J.
Also useful with the methods and formulations of this invention are intermediate and rapid acting insulin combinations, such as the HUMALOG® Mix 75/25 (75% Insulin Lispro Protamine Suspension and 25% Insulin Lispro Injection), HUMULIN® 50/50 (50% Human Insulin Isophane Suspension and 50% Human Insulin Injection) and HUMULIN® 70/30 (70% Human Insulin Docket 05-869-WO
Isophane Suspension and 30% Human Insulin Injection), each available from Eli Lilly and Company. Also useful are the NOVALIN® 70/30 (70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection) line of combination products available from Novo Nordisk Pharmaceuticals.
A commercially available long acting insulin for use with this invention is the HUMULIN® U Ultralente® human insulin [rDNA origin] extended zinc suspension, available from Eli Lilly and Company.
Also useful in the methods of this invention are inhaled insulin products, such as the EXUBERA® inhaled insulin product developed by Pfizer Inc. and Aventis SA.
Each of these insulin products can be administered as directed by a medical professional using administrations, dosages and regimens known in the art, such as those published for each product in the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics Company, Inc. at Montvale, N.J., the relevant sections of which are incorporated herein by reference.
Pharmaceutical Formulations
The compounds of general Formula (I) may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula (I) and a pharmaceutically acceptable carrier. One or more compounds of Docket 05-869-WO general Formula (I) may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula (I) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, Docket 05-869-WO calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Formulations for oral use may also be presented as lozenges .
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions Docket 05-869-WO may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring, and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol . Among Docket 05-869-WO the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides . In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the present invention may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene Docket 05-869-WO glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of Docket 05-869-WO the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, Docket 05-869-WO polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) . The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, Docket 05-869-WO time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water. Preferred non-human animals include domesticated animals.
Definitions
The term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl .
The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing the designated number of carbon atoms and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1- heptenyl, and 3-decenyl. Docket 05-869-WO
The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing the designated number of carbon atoms and containing at least one carbon- carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthalene and biphenyl . Preferred examples of aryl groups include phenyl, naphthyl, and anthracenyl . More preferred aryl groups are phenyl and naphthyl. Most preferred is phenyl.
The term "cycloalkyl" refers to a cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The terms "halogen" or "halo" indicate fluorine, chlorine, bromine, and iodine.
The term "haloalkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy .
The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl . Docket 05-869-WO
The term "heterocycloalkyl" refers to a ring or ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloalkyl ring is optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, 1 , 2 , 3, 4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl . Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, and pyrrolidinonyl .
The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thienyl, 5, 6, 7, 8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl .
The compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers . In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can Docket 05-869-WO be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.
When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E- configurations. Likewise, all tautomeric forms are also intended to be included. The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well- established literature methods known to those of ordinary skill in the art.
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 Docket 05-869-WO 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, 1999) .
Compounds herein are named using ACD/ChemSketch version 8.17 (commercially available from Advanced Chemistry Development, Inc., Toronto, ON, Canada).
Methods of Preparation
Compounds of the invention can be generally prepared according to the methods outlined in Scheme A. RA, RB, n and p are as defined in formula (I) . Variable L represents a linker, and Z represents 0, S, or NR, where R is H or any functionality which does not interefer with the required reactivity outlined below; protecting groups are designated by P. X represents a halogen or leaving group such as tosylate, triflate and the like, which are familiar to those skilled in the art. The following scheme is a representation of a specific example to illustrate the general synthetic methods. Those skilled in the art will recognize that the regiochemistry of the products in the following scheme can be readily adjusted without modification of the particular synthetic steps by substitution of the appropriate starting materials. For example, substitution of 3-bromo-α- bromoacetophenone for 4-bromo-α-bromoacetophenone in the initial synthetic step would impart a meta- regiochemistry between the halogen and thiazole in Al, and ultimately a meta- regiochemistry between the thaizole and dibenzofuran in the final product, A5. Docket 05-869-WO
Figure imgf000084_0001
Scheme A
To begin the synthesis, a dehydrative cyclization reaction between 4-halo-α-bromoacetophenone and for example, 2, 2-dimethylpropionic acid thiocarbamoylmethyl ester yields a thiazole of structure Al, where R' is t-butyl . R' may be any group which will not interfere with the subsequently required reactivity, such as phenyl, n-alkyl, s-alkyl, t-alkyl, and the like. Further, Al and 4-dibenzofuranylboronic acid are coupled according to standard Suzuki palladium catalyzed conditions, involving Pd (PPh3) 4 and a base, such as Na2CO3 t0 yield A2. This conversion of may also be performed via palladium catalysis utilizing organozinc (Negishi) , organomagnesium (Kumada) , or organotin (Stille) reactants with aryl halides with suitably protected starting materials if chemical incompatibilities would exist otherwise. The haloarene may be an iodo- , bromo- , or chloroarene. The palladium source may be, for example, Pd (PPh3) 4, Pd2(dba)3, Pd(OAc)2, PdCl2 (PPh3) 2, PdCl2 (MeCN) 2, PdCl2(PhCN)2, PdCl2 (dppf), PdCl2 (dppp) , PdCl2 (dppe) , PdCl2(COD), Pd (PCy3) 2, or Pd(tBu3P)2, all of which are available commercially from either Aldrich Chemical (Milwaukee, WI) or Strem Chemical (Newburyport, MA) . In particular, those skilled in the art will recognize that alternative palladium Docket 05-869-WO catalysts may be prepared from P0I2 (dba) 3 in situ by the addition of a ligand source, such as dppf, dppe, dppp, PCy3,
P(o-tol)3, P(2-furyl)3, BINAP, P (tBu3) 2 (biphenyl) , and N- heterocyclic carbenes, such as Arduengo's carbene, N, N' - bis (2, 6-diisopropylphenyl) imidazol-2-ylidene, or N, N' - bis (2 , 4 , 6-trimethylphenyl) imidazolidin-2-ylidene, and the like.
Following deprotection of A2 by hydrolysis under basic conditions, to yield A3, A4 is prepared by treatment of A3 with a nucleophilic activation and reaction agent such as PPh3Br2, PBr3, POBr3, or PPh3 and CBr4. The benzyl chloride may be prepared anagously with PPh3Cl2, POCl3, PCl5, or PPh3 and CCl4. Likewise, the benzyl iodide may be prepared using PPh3I2.
A5 can be prepared by two final steps; first, alkylation of a thiol, alcohol, or amine in the presence of a base with A4, then deprotection of the carboxylic acid. For example, an ester protecting group may be hydrolyzed under basic conditions to yield the carboxylic acid. In scheme A, L represents a linker, and Z represents 0, S, or NR, where R is H or any functionality which does not interefer with the required reactivity. The thiol, alcohol, or amine necessarily includes an appropriately protected carboxylic acid. Such bases include, but are not limited to, Na2CO3, K2CO3, Cs2CO3, triethylamine, diethylisopropylamine, NaOH, and KOH. Catalysts may be added to facilitate the reaction, including KI, n-Bu4NI, and the like. Appropriate thiols, alcohols, and amines for preparation of compounds of the present invention include, but are not limited to, BOC-protected amino acid esters, such as, alkyl N-BOC-Cys, alkyl N-BOC-Ser, alkyl N- BOC-Thr, alkyl N-BOC-His, alkyl N-BOC-Lys, alkyl N-BOC-Tyr, alkyl N-BOC homoserine, alkyl N-BOC homocysteine; straight and branched alkyl thiols, alcohols, and amines such as alkyl Docket 05-869-WO mercaptoacetates, alkyl 2-mercaptopropanoates, alkyl 3- mercaptopropanoates, alkyl hydroxyacetates, alkyl 2- hydroxypropanoates, alkyl 3-hydroxypropanoates, alkyl glycinates, alkyl β-alaninates, alkyl alinates, alkyl ω- aminoalkanoates, alkyl ω-mercaptoalkanoates, alkyl ω- hydroxyalkanoates, and the like.
Example 1
Figure imgf000086_0001
2-tert-butoxycarbonylamino-3- [2- (3-dibenzofuran-4-yl-phenyl) - thiazol-4-ylmethylsulfanyl] -propionic acid
Figure imgf000086_0002
Preparation of 2- (3-bromo-phenyl) -thiazole-4-carboxylic acid ethyl ester
A solution of 3-bromo-thiobenzamide (6.4 g, 29.6 mmol) and 3-bromo-2-oxo-propionic acid ethyl ester (6.4 g, 33.1 mmol) in ethanol (50 mL, 0.6 M) is refluxed for 16 hours. After evaporation of the solvent, the residue is purified by flash chromatography (15% ethyl acetate in heptane) to give 2-
(3-bromo-phenyl) -thiazole-4-carboxylic acid ethyl ester (7.3 g, 79%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.18-8.16
(m, 2 H), 7.89 (dd, J1 = 1.8 Hz, J2 = 1.0 Hz, 1 H) , 7.56 (dd, J1 = 1.8 Hz, J2 = 1.0 Hz, 1 H), 7.31 (t, J = 7.9 Hz, 1 H), 4.44
(q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H).
Example Ib Docket 05-869-WO
Figure imgf000087_0001
Preparation of [2- (bromo-phenyl) -thiazol-4-yl] -methanol
A solution of 2- (3-bromo-phenyl) -thiazole-4-carboxylic acid ethyl ester (6.0 g, 19.2 mmol) in THF (40 mL, 0.3 M) is cooled to 0 0C. Lithium aluminum hydride (LiAlH4) (1 M in THF; 17.2 mL, 17.2 mmol) is added dropwise over 5 minutes. After stirring for 30 minutes, the solution is diluted with ethyl acetate (40 mL) , saturated aq. NaCl (15 mL) and methanol (40 mL) . MgSO4 is added and the solution is filtered and concentrated. Purification by flash chromatography (15-25% ethyl acetate in heptane) gives [2- (bromo-phenyl) -thiazol-4- yl] -methanol (4.1 g, 79%) as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.10 (t, J = 1.9 Hz, 1 H), 7.82 (dd, J1 = 1.9 Hz, J2 = 1.0 Hz, 1 H) , 7.53 (dd, J1 = 1.9 Hz, J2 = 1.0 Hz, 1 H), 7.29 (t, J = 7.9 Hz, 1 H), 7.20 (s, 1 H), 4.82 (d, J = 5.9 Hz, 2 H)
Figure imgf000087_0002
Preparation of [2- (3-dibenzofuran-4-yl-phenyl) -thiazol-4-yl] ■ methanol
A solution of [2- (bromo-phenyl) -thiazol-4-yl] -methanol (2.0 g, 7.4 mmol), 4-dibromobenzene boronic acid (1.9 g, 9.0 mmol), and tetrakistriphenylphosphine palladium (Pd (Ph3) 4) (0.2 g, 0.2 mmol) in DME (18 mL, 0.4M) is treated with 2M
Na2CO3 (4.5 mL, 9.0 mmol) . The reaction mixture is heated to Docket 05-869-WO
90 0C for 8 hours, cooled to room temperature, and the solution is diluted with H2O (20 mL) . The organics are extracted with ethyl acetate (2 x 50 mL) . Purification by flash chromatography (40% ethyl acetate in heptane) affords [2- (3- dibenzofuran-4-yl-phenyl) -thiazol-4-yl ] -methanol (2.5 g, 96%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.42 (t, J = 1.8 Hz, 1 H), 8.00-7.94 (m, 4 H), 7.65 (dd, J1 = 7.5 Hz, J2 = 1.2 Hz, 1 H), 7.61-7.56 (m, 2 H), 7.48-7.41 (m, 2 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.19 (s, 1 H), 4.84 (d, J = 5.8 Hz, 2 H)
Example Id
Figure imgf000088_0001
Preparation of 2-tert-butoxycarbonylamino-3- [2- (3- dibenzofuran-4-yl-phenyl) -thiazol-4-ylmethylsulfanyl] - propionic acid methyl ester
A solution of [2- (3-dibenzofuran-4-yl-phenyl) -thiazol-4- yl] -methanol (0.20 g, 0.56 mmol) , 2- tert-butoxycarbonylamino- 3-mercapto-propionic acid methyl ester (0.26 g, 1.1 mmol), 1, 1' - (azodicarbonyl) dipiperidine (0.25 g, 1.2 mmol), and imidazole (0.07 g, 1.2 mmol) in dichloromethane (7 mL, 0.1 M) is treated with trimethylphosphine (1 M in THF; 1.1 mL, 1.1 mmol) . After stirring for 2 hours at room temperature, the solution is diluted with heptane (10 mL) and the precipitate is removed by filtration. The filtrate is concentrated and purified by flash chromatography (25% ethyl acetate in heptane) to afford 2- tert-butoxycarbonylamino-3- [2- (3- dibenzofuran-4-yl-phenyl) -thiazol-4-ylmethylsulfanyl] - propionic acid methyl ester (0.27 g, 84%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz) 8.43 (t, J = 1.8 Hz, 1 H), 8.04- Docket 05-869-WO
7.94 (m, 4 H), 7.67 (dd, J1 = 7.5 Hz, J2 = 1.2 Hz, 1 H), 7.61-
7.57 (m, 2 H), 7.49-7.43 (m, 2 H), 7.37 (t, J = 7.5 Hz, 1 H),
7.16 (s, 1 H), 5.86 (d, J = 7.9 Hz, 1 H), 4.66-4.61 (m, 1 H), 3.94 (d, J = 3.8 Hz, 2 H), 3.71 (s, 3 H), 3.06-2.98 (m, 2 H), 1.41 (s, 9 H)
Example Ie
Figure imgf000089_0001
Preparation of 2-tert-butoxycarbonylamino-3- [2- (3- dibenzofuran-4-yl-phenyl) -thiazol-4-ylmethylsulfanyl] - propionic acid
A solution of 2- tert-butoxycarbonylamino-3- [2- (3- dibenzofuran-4-yl-phenyl) -thiazol-4-ylmethylsulfanyl] - propionic acid methyl ester (0.26 g, 0.45 mmol) in THF (5 mL) and methanol (1 mL) (0.1 M) is treated with 2 M NaOH (1.3 mL, 2.3 mmol) at 0 0C. The solution is stirred for 2 hours and then acidified with 2N HCl to a pH of 3. The organics are extracted with ethyl acetate (2 x 20 mL) and dried over MgSO4. Purification by flash chromatography (5% methanol in dichloromethane) affords 2- tert-butoxycarbonylamino-3- [2- (3- dibenzofuran-4-yl-phenyl) -thiazol-4-ylmethylsulfanyl] - propionic acid (0.18 g, 71%) as a white foam. mp 115-116 0C; Rf 0.36 (15% methanol in dichloromethane) 1H NMR (DMSO, 300 MHz) δ 8.37 (m, 1 H), 8.21-8.17 (m, 2 H), 8.01-7.97 (m, 2 H), 7.77-7.71 (m, 2 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.59-7.49 (m, 3 H), 7.42 (t, J = 7.6 Hz, 1 H), 4.00-3.94 (m, 1 H), 3.89 (s, 2 H), 2.97 (dd, J1 = 13.4 Hz, J2 = 4.5 Hz, 1 H), 2.82 (dd, J1 = Docket 05-869-WO
13.4 Hz, J2 = 7.0 Hz, 1 H) , 1.35 (s, 9 H) ESI-LCMS m/z calcd for C30H28N2O5S2 : 560.7; found 561.3 (M+l) + .
Example 2
Figure imgf000090_0001
Preparation of 5- [2- (3-dibenzofuran-4-yl-phenyl) -thiazol-4- ylmethoxy] -nicotinic acid (Compound 2)
The title compound (alternatively named 5-{[2-(3- dibenzo [b, d] furan-4-ylphenyl) -1, 3-thiazol-4- yl] methoxyjnicotinic acid) is prepared in a manner analogous to that set forth above in Example 1, except 5-hydroxy- nicotinic acid methyl ester is used instead of 2-tert- butoxycarbonylamino-3-mercapto-propionic acid methyl ester in step 4 to give, after saponification using the conditions outlined in step 5, 5- [2- (3-dibenzofuran-4-yl-phenyl) -thiazol- 4-ylmethoxy] -nicotinic acid . mp 268-270 0C; Rf 0.20 (15% methanol in dichloromethane) 1H NMR (DMSO, 300 MHz) δ 8.67 (s, 1 H), 8.61 (s, 1 H), 8.40 (s, 1 H), 8.20 (d, J = 7.6 Hz, 2 H), 8.03-7.90 (m, 4 H), 7.77-7.67 (m, 3 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 1 H), 5.41 (s, 2 H) ESI-LCMS m/z calcd for C28H18N2O4S : 478.5; found 479.3 (M+l) + .
Example 3 Docket 05-869-WO
Figure imgf000091_0001
Preparation of 3- [2- (3-dibenzofuran-4-yl-phenyl) -thiazol-4- ylmethylsulfanyl ] -propionic acid (Compound 3)
The title compound (alternatively named 3-({[2-(3- dibenzo [b, d] furan-4-ylphenyl) -1, 3-thiazol-4- yl ] methyl } thio) propanoic acid) is prepared in a manner analogous to that set forth above in Example 1, except 3- mercapto-propionic acid methyl ester was used instead of 2- tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester in step 4 to give, after saponification using the conditions outlined in step 5, 3- [2- (3-dibenzofuran-4-yl- phenyl) -thiazol-4-ylmethylsulfanyl ] -propionic acid. mp 70-80
O C; Rf 0.31 (5% methanol in dichloromethane) 1H NMR (DMSO, 300 MHz) δ 8.38 (m, 1 H), 8.21-8.17 (m, 2 H), 8.02-7.97 (m, 2 H), 7.77-7.71 (m, 2 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.58 (s, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 1 H), 3.92
(s, 2 H), 2.73 (t, J = 6.8 Hz, 2 H), 2.56 (t, J = 6.8 Hz, 2 H). ESI-LCMS m/z calcd for C25H19NO3S2 : 445.5; found 446.3
(M+l)+.
Figure imgf000091_0002
Docket 05-869-WO
Preparation of 2-tert-butoxycarbonylamino-3- [2- (4- dibenzofuran-4-yl-phenyl) -thiazol-4-ylmethylsulfanyl] - propionic acid
The title compound is prepared in a manner analogous to that set forth above in Example 1, except 4-bromo- thiobenzamide was used instead of 3-bromo-thiobenzamide in step 1 to give 2- (4-bromo-phenyl) -thiazole-4-carboxylic acid ethyl ester. This compound is then submitted to the conditions described in steps 2-5 to afford 2-tert- butoxycarbonylamino-3- [2- (4-dibenzofuran-4-yl-phenyl) -thiazol- 4-ylmethylsulfanyl] -propionic acid, mp 125-135 0C; Rf 0.21
(10% methanol in dichloromethane) 1H NMR (DMSO, 300 MHz) δ 8.20-8.15 (m, 2 H), 8.09 (d, J = 8.7 Hz, 2 H), 8.03 (d, J = 8.7 Hz, 2 H), 7.76-7.72 (m, 2 H), 7.56 (s, 1 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 1 H), 4.08-4.04 (m, 1 H), 3.91 (s, 2 H), 3.00 (dd, J1 = 13.4 Hz, J2 = 4.4 Hz, 1 H), 2.83
(dd, J1 = 13.4 Hz, J2 = 7.9 Hz, 1 H), 1.38 (s, 9 H). ESI-LCMS m/z calcd for C30H28N2O5S2 : 560.7; found 561.3 (M+l) + .
Example 5
The following compounds may be prepared essentially according to the procedures outlined in Scheme A and described in the above examples.
Figure imgf000092_0001
Docket 05-869-WO
Figure imgf000093_0001
Docket 05-869-WO
BIOLOGY EXAMPLES Example 6
Method for measuring PTP-IB activity
The test compounds are evaluated for their in vitro inhibitory activity against recombinant human PTP-IB with phosphotyrosyl dodecapeptide TRDI(P)YETD(P)Y(P)YRK. This corresponds to the 1142-1153 insulin receptor kinase regulatory domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues; IR-triphosphopeptide as a source of substrate. Enzyme reaction progression is monitored via the release of inorganic phosphate as detected by the malachite green - ammonium molybdate method for the phosphopeptide .
Preferred compounds of the invention exhibit IC5O values of less than 10 μM; more preferred compounds of the invention exhibit IC50 values of less than 1 μM. Particularly preferred compounds exhibit IC5O values of less than 300 nM.
It is understood that the foregoing detailed description and accompanying Examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined by the appended claims. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. Docket 05-869-WO
Example 7
Results of PTP-IB activity testing
Figure imgf000095_0001
It is understood that the foregoing detailed description and accompanying Examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined by the appended claims. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

Docket 05-869-WOWhat we claim i s :
1 . A compound of the formula
Figure imgf000096_0001
or a pharmaceutically acceptable salt thereof, wherein X1 is 0, S, or N (RN1) , wherein RN1 is -H or - (Ci-C6) alkyl; X2 is CH or N; R1 is -H, - (C1-C6) alkyl, - (C1-C6) alkyl-phenyl, or
- (C3-C6) alkenyl;
Y is a bond, -aryl-, or -heteroaryl-, wherein the aryl or the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (C1-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (C1-C6JaIkOXy, -C(O) (C1-C6) alkyl, -C(O)OH, -CN,
- (C1-C6) haloalkoxy, - (C1-C6) haloalkyl, -halogen, -OH, - (C1-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (C1-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (C1-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (C1-C6JaIkOXy, -C (0) (C1-C6) alkyl, or -C(O)H;
L is -0-, -S-, -S(O)2-, -N(RN4)-, -N (R114) C (0) -, -C(O)N(R114)-, -S(O)2N(RN4)-, -N(RN4)S(O)2-, - (C1-C6) alkyl-O-, -0- (C1-C6) alkyl-, - (C1-C6) alkyl-O- (C1-C6) alkyl-,
- (C1-C6) alkyl-S-, -S- (C1-C6) alkyl-,
- (C1-C6) alkyl-S- (C1-C6) alkyl-, - (C1-C6) alkyl-S (O)2-,
-S (O)2- (C1-C6) alkyl-, - (C1-C6) alkyl-S (O)2- (C1-C6) alkyl-,
- (C1-C6) alkyl-N (R114) -, -N (R114) - (C1-C6) alkyl-, Docket 05-869-WO
- (Ci-C6) alkyl-N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) -, -N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4) -, -C(0)N(RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-C (O)N(RN4)- (CI-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) -, -S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S (0) 2N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2-, -N (RN4) S (0) 2- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2- (Ci-C6) alkyl-, -N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) -,
- (Ci-C6) alkyl-N (RN4) S (0) 2N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) -,
- (Ci-C6) alkyl-N (RN4) C (0) N (RN5) - (Ci-C6) alkyl-, -N (RN4) C (0) 0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-N (RN4) C (0) 0-,
- (Ci-C6) alkyl-N (RN4) C (0) 0- (Ci-C6) alkyl-, -OC (O)N (RN4) - (Ci-C6) alkyl-,
- (Ci-C6) alkyl-OC (O)N(RN4) -, or
- (Ci-C6) alkyl-OC (O)N (RN4) - (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy,
-C(O) (Ci-C6) alkyl, -C(O)OH, - (Ci-C6) alkyl-C (0) OH,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -N(RN6RN7) , - (Ci-C6) alkyl-N (RN6RN7) , or
Figure imgf000097_0001
, wherein RN4 and RN5 are independently -H or
-(Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H, Docket 05-869-WO
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H;
A is -aryl- or -heteroaryl-; each RA is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N(RN8RN9),
- (Ci-C6) alkyl-N(RN8RN9) , or -C (0) N (RN8RN9) , wherein RN8 and RN9 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; n is 0, 1, 2, 3, or 4;
B is aryl- or heteroaryl-; each RB is independently - (Ci-C6) alkoxy, - (Ci-C6) alkyl,
- (C2-C6) alkenyl, - (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -CN, - (Ci-C6) haloalkoxy,
- (Ci-C6) haloalkyl, -halogen, -OH, -NO2, -N (RNi0RNii) ,
- ( Ci -C6 ) al kyl -N ( RNI ORNI I ) , or -C ( 0 ) N ( RNI ORNI I ) , wherein RNi0 and RNn are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H; and p is 0, 1, 2, 3, or 4.
2. A compound according to claim 1, wherein
A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl.
3. A compound according to claim 2, wherein
B is phenyl, naphthyl, furanyl, thienyl, benzothienyl, Docket 05-869-WO pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, lH-indazolyl, or benzopyrazolyl .
4. A compound according to claim 3, wherein
Y is a bond, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoindoyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, -C(O)OH, -CN,
- (Ci-C6) haloalkoxy, - (Ci-C6) haloalkyl, -halogen, -OH, - (Ci-C6) alkyl-OH, -NO2, -N(RN2RN3),
- (Ci-C6) alkyl-N(RN2RN3) , or -C (0) N (RN2RN3) , wherein RN2 and RN3 are each independently -H, - (Ci-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C(O) (Ci-C6) alkyl, or -C(O)H.
5. A compound according to claim 4, wherein
L is -0-, -S-, -N(RN4)-, -N(RN4)C(O)-, -C (0) N (RN4) -,
- (Ci-C6) alkyl-O-, -0- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, -S- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S- (Ci-C6) alkyl-,
-(Ci-C6) alkyl-N(RN4)-, -N (RN4) - (CI-C6) alkyl-, or Docket 05-869-WO
- ( Ci-C6 ) al kyl -N (RN4 ) - ( Ci-C6 ) al kyl - , wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkoxy, - (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7), or -C(O)N(RN6RN7) , wherein RN4 and RN5 are independently -H or
- (Ci-C6) alkyl, wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C(O) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, or -C(O)H.
6. A compound according to claim 5, wherein
Ri is -H, - (Ci-C6) alkyl, benzyl, or allyl.
7. A compound according to claim 6, having the formula,
Figure imgf000100_0001
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, having the formula,
Figure imgf000100_0002
Docket 05-869-WO or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8, having the formula,
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 9, having the formula,
Figure imgf000101_0002
or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 10, having the formula,
Figure imgf000101_0003
or a pharmaceutically acceptable salt thereof, Docket 05-869-WO
12. A compound according to claim 11, wherein
L is - (Ci-C6) alkyl-O-, - (Ci-C6) alkyl-O- (Ci-C6) alkyl-,
- (Ci-C6) alkyl-S-, - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -C(O)OH, -halogen, -N(RN6RN7) , wherein RN6 and RN7 are each independently -H,
- (Ci-C6) alkyl, - (C2-C6) alkenyl,
- (C2-C6) alkynyl, -C (0) (Ci-C6) alkoxy, or -C (0) (C1-C6) alkyl.
13. A compound according to claim 12, wherein
Y is a bond, phenyl, or pyridyl .
14. A compound according to claim 13, having the formula,
Figure imgf000102_0001
or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 14, wherein Y is a bond, and
L is - (Ci-C6) alkyl-O- (Ci-C6) alkyl-, or - (Ci-C6) alkyl-S- (Ci-C6) alkyl-, Docket 05-869-WO wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy,
-C (0) (Ci-C6) alkyl, -halogen,
Figure imgf000103_0001
t wherein RN6 and RN7 are each independently -H, - (Ci-C6) alkyl, allyl, propargyl, acetyl, or -C (0) (Ci-C6) alkoxy.
16. A compound according to claim 14, wherein
Y is pyridyl, and
L is - (Ci-C6) alkyl-O- or - (Ci-C6) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y.
17. A compound according to claim 15, wherein Ri is H.
18. A compound according to claim 16, wherein Ri is H.
19. A compound according to claim 13, having the formula,
Figure imgf000103_0002
or a pharmaceutically acceptable salt thereof,
20. A compound according to claim 19, wherein Y is a bond, and L is - (Ci-C6) alkyl-O- (Ci-C6) alkyl-, or Docket 05-869-WO
- ( Ci -C6 ) al kyl - S - ( Ci -C6 ) al kyl - , wherein the alkyl portion of each of the above are optionally substituted with 1, 2, 3, or 4 substituents that are independently
- (Ci-C6) alkyl, - (Ci-C6) alkoxy, -C (0) (Ci-C6) alkoxy, -C (0) (Ci-C6) alkyl, -halogen,
-N(RN6RN7) , wherein RN6 and RN7 are each independently -H, - (Ci-C6) alkyl, allyl, propargyl, acetyl, or -C (0) (Ci-C6) alkoxy.
21. A compound according to claim 19, wherein
Y is pyridyl, and
L is - (Ci-C6) alkyl-O- or - (Ci-C6) alkyl-S-, wherein, the alkyl terminus is attached to the thiazole ring and the oxygen or sulfur terminus is attached to Y.
22. A compound according to claim 20, wherein Ri is H.
23. A compound according to claim 21, wherein Ri is H.
24. A compound according to claim 1 which is
N- ( tert-butoxycarbonyl) -5- { [2- (3-dibenzo [b, d] furan-4- ylphenyl) -1, 3-thiazol-4-yl] methyl } cysteine;
5-{ [2- (3-dibenzo [b, d] furan-4-ylphenyl) -1, 3-thiazol-4- yl ] methoxy} nicotinic acid;
3- ( { [2- (3-dibenzo [b, d] furan-4-ylphenyl) -1, 3-thiazol-
4-yl] methyl } thio) propanoic acid; or
N- (tert-butoxycarbonyl) -S- { [2- (4-dibenzo [b, d] furan-4- ylphenyl) -1 , 3-thiazol-4-yl ] methyl } cysteine .
25. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable solvent, carrier, adjuvant or excipient. Docket 05-869-WO
26. A method of treating syndrome X, obesity, diabetes, immunological disease, bleeding disorders, or cancer comprising administering a pharmaceutically acceptable amount of a compound of claim 1 to a patient in need of such treatment .
27. A method of treating syndrome X, obesity, diabetes, immunological disease, bleeding disorders, or cancer comprising administering a pharmaceutical composition claim 25 to a patient in need of such treatment.
28. A method of treating Type II diabetes comprising administering a pharmaceutically acceptable amount of a compound of claim 1 to a patient in need of such treatment.
29. A method of treating Type II diabetes comprising administering a pharmaceutical composition claim 25 to a patient in need of such treatment.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors

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