EP1928455A1 - Anilinopyrazole derivatives useful for the treatment of diabetes - Google Patents

Anilinopyrazole derivatives useful for the treatment of diabetes

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Publication number
EP1928455A1
EP1928455A1 EP06802675A EP06802675A EP1928455A1 EP 1928455 A1 EP1928455 A1 EP 1928455A1 EP 06802675 A EP06802675 A EP 06802675A EP 06802675 A EP06802675 A EP 06802675A EP 1928455 A1 EP1928455 A1 EP 1928455A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
mmol
alkyl
halo
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06802675A
Other languages
German (de)
French (fr)
Inventor
Derek Lowe
Tatiana Shelekhin
Gan Wang
Xin Ma
Christiana Iwuagwu
Shihong Ying
Steven Magnuson
Joachim Rudolph
Johannes Koebberling
Josef Pernerstorfer
Thomas Mueller
Michael Brands
Dirk Heimbach
Niels Lindner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Healthcare LLC
Original Assignee
Bayer Healthcare LLC
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Filing date
Publication date
Application filed by Bayer Healthcare LLC filed Critical Bayer Healthcare LLC
Publication of EP1928455A1 publication Critical patent/EP1928455A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to anilinopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.
  • Type 1 diabetes or insulin dependent diabetes mellitus (IDDM) arises when patients lack insulin-producing beta-cells in their pancreatic glands.
  • IDDM insulin dependent diabetes mellitus
  • Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM) occurs in patients with impaired beta-cell function and alterations in insulin action.
  • the current treatment for type 1 diabetic patients is injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin.
  • the drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin. Over time, almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.
  • new therapies to treat type 2 diabetes are needed.
  • new treatments to retain normal (glucose-dependent) insulin secretion are needed.
  • Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion (i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose); low primary and secondary failure rates; and preservation of islet cell function.
  • the compounds of this invention are believed to provide such benefits.
  • the invention provides anilinopyrazole derivatives of formula (I)
  • R is H or (Ci-C 2 )alkyl; R 1 is H,
  • (C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo, (C 1 -C 3 )haloalkyl, or phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
  • (C 1 -C 6 )alkyl optionally substituted with one (Q-GOalkoxy, (C 3 -C 6 )cycloalkyl (Q-C ⁇ alkoxy,
  • R 2 is H, halo, (C r C 6 )alkyl
  • R 3 represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
  • R 4 Is (Q-GOalkyl, (C 3 -C 6 )cycloalkyl,
  • n 0, 1, 2, or 3;
  • X is CO 2 R 8 , CONR 5 R 6 , or SO 2 NHR 7 ;
  • R 5 is H
  • R 6 is H or (Ci-C 6 )alkyl
  • R 7 is H or methyl
  • R 8 is H, or
  • the invention relates to a compound of the above first embodiment having the structure
  • R is H or (C 1 -C 2 ⁇ IkVl; R 1 is H,
  • (C 1 -C 6 )alkyl optionally substituted with one (CrC 4 )alkoxy, (C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )OIlCyI, CF 3 , and halo, (CrC 3 )haloalkyl, or phenyl optionally substituted with up to two substituents selected from the group consisting of halo,
  • R 2 is H, halo
  • R 3 represents optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R 3 are selected from the group consisting of (C 1 -C 4 JaIkOXy, (C 3 -C 6 )cycloalkoxy (C 1 -C 3 )haloalkoxy, (d-C 6 )alkyl,
  • R 1 is other than H or methyl
  • R 4 is (Ci-C ⁇ alkyl
  • X is CO 2 R 8 , CONR 5 R 6 , or SO 2 NHR 7 ;
  • R 5 is H
  • R 6 is H or (Ci-Qs)alkyl
  • R 7 is H or methyl
  • R 8 is H, or (Ci-COalkyl, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the above first embodiment having the structure
  • R is H or (Ci-QOalkyl;
  • R 1 is H, (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )OIkOXy, (C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (CrC 3 )alkyl, CF 3 , and halo, or (C 1 -C 3 )haloalkyl,
  • R 2 is H, phenyl, 1,3-benzodioxolane, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of
  • R represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
  • R 4 is (Ci-C ⁇ alkyl, (C 3 -C 6 )cycloalkyl,
  • n 0, 1, 2, or 3;
  • X is CO 2 R 8 .
  • R 8 is H, or
  • the invention relates to a compound of the above first embodiment having the structure
  • R is H or (Ci-C 2 )alkyl;
  • R 1 is phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
  • (Ci-C 6 )alkyl optionally substituted with one (C 1 -C-OaIkOXy, (C 3 -C 6 )cycloalkyl (C 1 -CeOaTkOXy,
  • R 2 is H
  • R 3 represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
  • (Ci-C 6 )alkyl optionally substituted with one (Q-GOalkoxy, (C 3 -C 6 )cycloalkyl, and (Q-C ⁇ haloalkyl, halo, cyano,
  • R 4 is (Q-GOalkyl
  • n 0, 1, 2, or 3;
  • X is CO 2 R 8 .
  • R 8 is H, or (Ci-C ⁇ alkyl, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the above fourth embodiment having the structure
  • R is H or (C r C 2 )alkyl
  • R 1 is phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
  • (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C ⁇ aIkOXy, (C 3 -C 6 )cycloalkyl (C ! -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy
  • R 2 is H, or
  • R 3 represents optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R are selected from the group consisting of (Ci-CUJalkoxy, (C 3 -C 6 )cycloalkoxy (Ci-C 3 )haloalkoxy,
  • R 4 is (CrC 4 )alkyl
  • n 0, 1, or 2
  • X is CO 2 R 8 .
  • R 8 is H, or (C r C 4 )alkyl, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the above fifth embodiment having the structure
  • R is H or (Q-C 2 )alkyl
  • R 1 is phenyl substituted in meta-position with one substituent selected from the group consisting of halo,
  • (CrC 6 )alkyl optionally substituted with one (Q-GOalkoxy, (C 1 -C 6 )alkoxy, and (C 3 ⁇ C 6 )cycloalkoxy
  • R 2 is H
  • R 3 represents optionally substituted pyridine, optionally substituted pyi ⁇ dazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R 3 are selected from the group consisting of
  • (C 1 -C 6 )alkyl optionally substituted with one (Q-GOalkoxy, (C 3 -C 6 )cycloalkyl, (d-C 3 )haloalkyl, halo, and cyano,
  • R 4 is (Ci-C 4 )alkyl
  • n 0, I, or 2
  • X is CO 2 R 8 .
  • R 8 is H, or
  • the invention relates to a compound of the above first embodiment having the formula (I) wherein R is H;
  • R 1 is methyl, ethyl, tert-butyl or cyclopropyl, or phenyl optionally substituted with one substituent selected from the group consisting of
  • R 2 is H, phenyl, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of
  • R 3 represents pyridine, pyrimidine, or pyrazine, optionally substituted with up to two substituents selected from
  • R 4 is (C 1 -C 4 )alkyl
  • n 0, I, or 2;
  • X is CO 2 R 8 .
  • R 8 is H, or
  • halo means F, Br, Cl, and I.
  • (Ci-C 4 )alkyl means a linear or branched saturated hydrocarbon radical having from 1 to 4 C atoms, 1 to 6 C atoms, 2 to 6 C atoms, respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
  • (C 3 -C 6 )alkenyl means a linear or branched unsaturated hydrocarbon radical containing a double bond and from 3 to 6 carbon atoms.
  • the double bond may be between any two available carbon atoms in the chain.
  • groups include, allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like.
  • (C 3 -C 6 )alkynyl means a linear or branched unsaturated hydrocarbon radical containing a triple bond and from 3 to 6 carbon atoms.
  • the triple bond may be between any two available carbon atoms in the chain.
  • Such groups include, propargyl, 2- butynyl, l-methyl-2-butynyl, 3-hexynyl, and the like.
  • (C 3 -C 6 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • (Ci-C 3 )alkoxy means a linear or branched saturated hydrocarbon radical having from 1 to 3 C atoms, 1 to 4 C atoms, or 1 to 6 C atoms, respectively, said radical being attached to an O atom.
  • the O atom is the atom through which the alkoxy substituent is attached to the rest of the molecule.
  • groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • (C 3 -C 6 )cycloalkoxy includes cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
  • (Ci-C 3 )haloalkoxy and “(C 2 -C 3 )haloalkoxy” mean a (Ci-C 3 )alkoxy group or a (C 2 -C 3 )alkoxy group, respectively, substituted on C with at least one halogen atom.
  • Such groups include trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloroethoxy, 3-chloropropoxy, l-fluoro-2,2,-dichloroethoxy, and the like.
  • (C 1 -C 3 )haloalkyl and "(C 2 -C 3 )haloalkyl” mean a (d-C 3 )alkyl group or (C 2 -C 3 )alkyl group substituted on C with at least one halogen atom.
  • groups include trifluoromethyl, difluoroethyl, l-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4-bromohexyl, and the like.
  • C(O) means a radical in which the C atom bears a doubly bonded oxygen, (an oxo substituent) and in which there remains two additional binding sites, that is, represents a radical of the formula:
  • (C r C 4 )acyl means a (C 1 -C 4 )alkyl radical substituted on the C of a C(O) group.
  • the C of the C(O) is the group is also the atom through which the substituent is attached to the rest of the molecule.
  • Such groups include, but are not limited to, acetyl (CH 3 C(O)-), n-propanoyl (CH 3 CH 2 C(O)-), isobutanoyl ((CH 3 ) 2 CHC(O)-), and the like.
  • the formula "NR 8 R 8 means that each of the two possible R 8 groups attached to the
  • N atom is selected independently from the other so that they may be the same or they may be different.
  • (Q-QOalkylthio) and “(C r C 6 )alkylthio” mean a linear or branched saturated hydrocarbon radical having from 1 to 3 C atoms, or 1 to 6 C atoms, respectively, said radical being attached to an S atom.
  • the S atom is the atom through which the alkylthio substituent is attached to the rest of the molecule.
  • SO 2 (C 1 -C 3 )alkyl means a linear or branched saturated hydrocarbon radical having from 1 to 3 C atoms, said radical being attached to the S atom of the SO 2 group.
  • the S atom of the SO 2 group is the atom through which the SO 2 (Ci-C 3 )alkyl substituent is attached to the rest of the molecule.
  • Such groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and isopropylsulfonyl, and the like.
  • 6-membered carbocyclic ring means a partially unsaturated ring containing C atoms fused to the pyrazole ring to form a tetrahydroindazole ring system.
  • the ring may be optionally substituted with (Ci-C 6 )alkyl groups at any available position, up to a total of about 6 C atoms.
  • 5- or 6-membered heterocycles means a saturated 5- or 6-membered ring containing up to two heteroatoms selected from a group consisting of N, O, and S.
  • Such rings include, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, and the like.
  • 5- or 6-membered heteroaryl ring means a unsaturated 5- or 6-membered aromatic ring containing up to 3 atoms independently selected from a group consisting of N,
  • Such rings include, but not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiophene, furane, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, and the like.
  • tetrahydronaphthyl means bicyclic ring radicals of the formulae ' respectively.
  • the radical is attached to the rest of the molecule at any available carbon of the phenyl ring.
  • the substituent may be attached at any available carbon atom.
  • optionally substituted means that the moiety so modified may have from none to up to at least the highest number of substituents indicated.
  • Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable.
  • each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.
  • Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.
  • stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.
  • Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2- hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicylic, galactaric, and galacturonic acid, and combinations thereof. Tautomers of the compounds of the invention are encompassed by the present invention. Thus,
  • the protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
  • the present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability, and release time ⁇ see, e.g.,
  • Major drug biotransformation reactions include iV-dealkylation, 0-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation, and acetylation (see, e.g., Goodman and Gilman's The
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.
  • Reaction Scheme A illustrates the general method for the preparation of compounds of Formula (Ia), namely, Formula (I) where R is H.
  • An aminopyrazole of Formula (III) is coupled with either a 2-bromo, 2-iodo, or 2-[(trifluoromethyl)sulfonyl]oxy benzoic acid, benzoic ester, benzoic acid amide, or benzenesulfonamide of Formula (IV), using Ullmann- type conditions (copper (II) acetate in DMF, heated in a sealed tube for 16 h) or a 2- bromobenzoic ester, benzoic acid amide, or benzenesulfonamide of Formula (IV) using Buchwald-type conditions (cesium carbonate, BINAP and Pd 2 (dba) 3 in anhydrous toluene, heated to 110 0 C for 16 h under argon).
  • Reaction Scheme B illustrates a general method for conversion of compounds of Formula (Ib) into other Formula (Ia) compounds having at least one R 4 substituent, by reaction of the halogen-containing (Ib) under Suzuki coupling conditions [e.g., a palladium catalyst such as Pd(dppf)Cl 2 , and a boronic acid (V)].
  • Suzuki coupling conditions e.g., a palladium catalyst such as Pd(dppf)Cl 2 , and a boronic acid (V)].
  • Reaction Scheme C outlines a general method for the preparation of other Formula (Ia) compounds from compounds of Formula (Id), which is Formula (I) where R 2 is bromo or iodo.
  • a bromine or iodine is introduced to the compound of Formula (Ic) (Formula (I) where R 2 is H) and the resulting Formula (Id) compound is allowed to undergo a Suzuki reaction with a boronic acid R 2 B(OH) 2 .
  • Formula (Ia) compounds may be prepared containing a variety of R 2 and R 4 substituents as shown in Reaction Scheme D.
  • Reaction Scheme D For example, coupling a dibromobenzoic acid, dibromobenzoic ester, or dibromobenzenesulfonamide of Formula (IVa) with a pyrazole of Formula (HIa) provides an intermediate of Formula (Ie).
  • Suzuki reaction of (Ie) with a boronic acid derivative gives (If) which can be brominated or iodinated to give (Id).
  • (Id) can be converted to the Formula (Ia) compounds via another Suzuki reaction.
  • the reaction is conducted in the presence of a base such as LiNMe 2 or K 2 CO 3 .
  • JVyV-dibenzylsulfonamide compound of Formula (Ir) is prepared as described in Reaction Scheme A and can be de-benzylated with sulfuric acid to give the compound of Formula (Is).
  • the compounds of Formula (I) where R is (Ci-C 2 )alkyl are prepared by iV-alkylation of the corresponding Formula (Ia) compounds where R is H, using standard conditions such as those shown in Reaction Scheme I.
  • Such conditions include an alkylating agent such as iodomethane, and a base such as sodium hydride, and the reaction is carried out in inert solvent such as DMF.
  • 5-Aminopyrazoles 5-Aminopyrazole starting materials of Formula (III) are either commercially available or can be prepared as shown in Reaction Schemes K, Kl, L, or M.
  • R 20 is H, (C 1 -C 4 ) alkyl ( lllc ) ( llld )
  • Suitable boronic acid esters include R 2 B(OR') 2 where R' is a lower alkyl group, or two R' groups may form a ring
  • Reaction Scheme M illustrates how the aminopyrazole of Formula (Ilia) may be converted to other aminopyrazoles of Formula (III) by bromination and Suzuki or Stille coupling reactions to introduce an R 2 group other than H.
  • the product of the Stille reaction (HIc) can also be reduced, for example by hydrogenation, to give the saturated compound of Formula (Illd).
  • Hydrazine starting materials of Formula (II) are either commercially available or, in the case of heteroaryl hydrazines of Formula (Ha) where R 3 is optionally substituted heteroaryl, can be prepared by routes described in Reaction Scheme Nl and N2. Reaction Scheme Nl
  • a substituted aniline is converted into a diazonium salt intermediate which is subsequently reduced using tin(II)chloride as the reductant.
  • Hvdrazones Hydrazone starting materials of Formula (lib) are either commercially available or, can be prepared as shown in Reaction Scheme O.
  • 2-Bromo, 2-iodo, and/or 2-r(trifluoromethyl)sulfonyl1oxy benzoic acid derivatives The 2-bromo, 2-iodo, and/or 2-[(trifluoromethyl)sulfonyl]oxy benzoic acid derivatives used in the coupling reactions with 5-aminopyrazoles were either commercially available or prepared by straightforward means well known in the art.
  • CDI carbonyl diimidazole Celite ® brand of diatomaceous earth filtering agent registered trademark of
  • DOWEX ® 66 Dowex hydroxide, weakly basic anion, macroporous, 25-50 mesh dppf 1 , 1' -bis(diphenylphosphino)ferrocene
  • Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification.
  • concentration under reduced pressure refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius ( 0 C).
  • Thin layer chromatography TLC was performed on EM Science pre-coated glass-backed silica gel 60 A F-254 250 ⁇ m plates. Column chromatography (flash chromatography) was performed on a Biotage system using 32-63 micron, 60 A, silica gel pre-packed cartridges.
  • Electron impact mass spectra were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source was maintained at 250 0 C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • HPLC retention times indicated for the specific examples in this invention are either recorded directly under the above HPLC ES-MS conditions, shown in the subsequent tables as (A) and (B), or recorded under one of the following methods:
  • 3-Hydrazino-4-methylpyridine hydrochloride (628 mg, 3.93 mmol) (step 1) and 3,3- dimethyl-2-oxobutanenitrile (532 mg, 4.25 mmol) were dissolved in ethanol (5 mL) in a sealed tube and heated at ⁇ 80 0 C for 15 h. The flask was then cooled to rt, opened, and the solvent was removed under reduced pressure. The crude residue was treated with water, and basified by slow addition of concentrated aq. NaOH solution (ice bath used since highly exothermic). The product was extracted with DCM (3x), the combined organic layers were dried over Na 2 SO 4 and concentrated to give the product as an oil (758 mg, 77 %).
  • ES-MS m/z 231.2 (MH + ); HPLC RT (min) 1.33 ⁇ method (A) ⁇ .
  • Step 3 Preparation of methyl 2- ⁇ r3-teit-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- yll amino I -5-methoxybenzoate
  • step 2 3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- amine (259 mg, 0.56 mmol) (step 2) and methyl 2-bromo-5-methoxybenzoate (114.8 mg, 0.47 mmol) were combined in an oven-dried pressure tube.
  • BESfAP (93.4 mg, 0.094 mmol), Pd 2 dba 3 (85.8 mg, 0.094 mmol), and powdery cesium carbonate (pre-dried in a high vacuum oven) (458 mg, 1.41 mmol) were added subsequently, followed by toluene (2 mL).
  • the pressure tube was sealed and the reaction mixture heated at 80 0 C for 16 h.
  • Step 4 Preparation of 2- ⁇ r3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-yllamino ⁇ -5- methoxybenzoic acid
  • Methyl 2- ⁇ [3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-yl]amino ⁇ -5- methoxybenzoate (83 mg, 0.21 mmol) (step 3) was dissolved in THF (3.O mL), and a solution of LiOH-H 2 O (26.5 mg, 0.63 mmol) in water (1.0 mL) was added, followed by a small amount of MeOH to homogenize the mixture. After stirring for 15 h at rt at 40 0 C, the reaction mixture was cooled, the organic solvent removed under reduced pressure and the aq layer acidified by addition of 2N HCl.
  • Step 2 Preparation of l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH-pyrazol-5-amine
  • Step 3 Preparation of methyl 2- ⁇ ri-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH-pyrazol-5-yll amino ⁇ -5-methylbenzoate
  • the mixture was cooled to rt, filtered through a Celite plug using ethyl acetate as eluent, concentrated to dryness, and subjected to column chromatography purification using a gradient elution from 10% to 20% EtOAc in hexane to afford 1.62 g (67%) of the desired product.
  • Step 4 Preparation of methyl 2- ⁇ r4-bromo-l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH- pyrazol-5-yll amino I -5-methylbenzoate
  • Step 5 Preparation of methyl 2-(ri-(3,6-dimethylpyrazin-2-yl)-3-ethyl-4-pyridin-3-yl-lH- pyrazol-5-yll amino ⁇ -5-methylbenzoate
  • Step 6 Preparation of 2- ⁇ ri-(3,6-dimethylpyrazin-2-yl)-3-ethyl-4-pyridin-3-yl-lH-pyrazol- 5-vHamino
  • Step 4 Preparation of methyl 5-(trifluoromethoxy)-2- ⁇ r(trifluoromethyl)sulfonvnoxy ⁇ benzoate
  • Step 5 Preparation of methyl 2- ⁇ r3-ethyl-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-vHamino ⁇ - 5-(trifruoromethoxy)benzoate
  • Step 6 Preparation of methyl 2- ⁇ r4-bromo-3-ethyl-l-f3-methylpyridin-2-yl)-lH-pyrazol-5- yll amino ⁇ -5-(trifluorometlioxy)benzoate
  • Step 7 Preparation of 2- ⁇ r3-ethyl-4-(6-methoxypyridin-3-yl)-l-(3-methylpyridin-2-yl)-lH- pyrazol-5-yll amino ⁇ -5-(trifluoromethoxy)benzoic acid
  • Step 3 Preparation of 5-Bromo-2-r3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5- ylaminol-benzoic acid methyl ester
  • Step 5 Preparation of 2-r4-Bromo-3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5- ylaminol-5-cvclopropyl-benzoic acid methyl ester
  • Step 7 Preparation of 5-Cyclopropyl-2-r3-cvclopropyl-4-(6-methoxy-pyridin-3-yl)-l-(3- methyl-pyridin-2-yl)-lH-pyrazol-5-ylaminol-benzoic acid
  • Step 1 Synthesis of 2-r3-(3-Ethylphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-ylaminol- 5-fluorobenzoic acid methyl ester
  • Step 2 Preparation of 2-r3-(3-Ethylphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5- ylaminol-5-fluorobenzoic acid
  • Step 1 Preparation of l-(3,6-Dimethylpyrazm-2-yl)-3-(3-ethylphenyl)-lH- ⁇ yrazol-5-amine
  • Step 2 Preparation of 2-ri-C3,6-Dimethylpyrazin-2-yl)-3-( ' 3-ethylphenyl)-lH-Pyrazol-5- ylaminol -benzoic acid methyl ester
  • the mixture was cooled to rt, filtered through a Celite plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 30% to 100% acetonitrile in water to afford 72 mg (45%) of the desired product.
  • Step 3 Preparation of l-r2-(3,6-Dimethylpyrazin-2-yl)-3-(3-ethylphenyl)-lH-pyrazol-5- ylaminol -benzoic acid
  • 3,5-Dimethylpyridine N-oxide (10.0 g, 81.2 mmol) was consecutively treated with concentrated nitric acid (10.1 mL) and concentrated sulfuric acid (43.3 mL). The resulting mixture was stirred at 110 0 C for 1.5 h. After cooling to room temperature, the mixture was poured into ice water and the pH was adjusted to 12 by addition of solid potassium hydroxide. The resulting precipitate was collected by filtration. The mother liquor was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and the solvents were evaporated off. The residue was combined with the solid obtained by filtration yielding 3,5-dimethyl-4-nitropyridine N-oxide (7.5 g, 50%) which was used for the next step without further purification.
  • 3,5-Dimethyl-4 ⁇ nitropyridine (3.78 g, 21.4 mmol) was dissolved in hydrazine monohydrate (75 mL) and the resulting solution was stirred at 100 0 C for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl actetate (100 mL). The solution was washed with a mixture of brine and sodium hydroxide solution, dried over MgSO 4 and concentrated under reduced pressure yielding 4-hydrazino-3,4-dimethyl pyridine (2.2 g, 75%).
  • Step 2 Preparation of l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol ⁇ 5-amine
  • Step 3 Preparation of methyl 2- ⁇ ri-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)- lH-pyrazol-5-y ⁇ amino Ibenzoate
  • Step 4 Preparation of 2-ri-(3,5-dimethylpyridin-4-yl)-3-(3-ethvbhenyl)-lH-pyrazol-5- yliaminobenzoic acid hydrochloride
  • Step 1 Preparation of methyl 2- ⁇ [l-( ' 3,5-dimethylpyridm-4-yl)-3-(3-ethylphenyl)- lH-pyrazol-5-yl1arnino)-5-fluorobenzoate
  • Step 2 Preparation of 2-ri-(3.5-dimethylpyridin-4-yl)-3-(3-ethylphenylVlH-pyrazol-5- vnamino-5-fluorobenzoic acid hydrochloride
  • Step 1 Preparation of 3-(3-ethylphenyl)-l-(3-trifluoromemylpyridin-2-yl)-lH-pyrazol-5- amine
  • Step 2 Preparation of 5-bromo-2-r3-f3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)-lH- PVrazol-5-ylaminol-benzoic acid methyl ester
  • Step 3 Preparation of 5-cvclopropyl-2-r3-(3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)- lH-pyrazol-5-ylaminoi-benzoic acid methyl ester
  • Step 4 Preparation of 5-cyclopropyl-2-r3-(3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)- lH-pyrazol-5-ylaminol-benzoic acid
  • Step 1 Preparation of 2-r3-ethyl-4-(2-methoxyphenyl)-l-(3-methylpyridin-2-yl)-lH- pyrazol-5-ylaminol-5-trifluoromethoxy-benzoic acid methyl ester
  • Step 2 Preparation of 243-ethyl-4-(2-memoxyphenylM-(3-methyl ⁇ yridm-2-yl)-lH- pyrazol-5-ylaminol -5-trifluoromethoxy-benzoic acid
  • Step 1 Preparation of l-(3-ethylphenyl)-3,3-dimercaptoprop-2-en-l-one
  • the aqueous phase was acidified with IN sulfuric acid while cooled in an ice bath and it was extracted three times with tert-butylmethylether. The organic extracts were dried over NaCl and evaporated to dryness in vacuo. This material was used in the next step without further purification.
  • Step 2 Preparation of ethyl 2- ⁇ r3-(3-ethylphenyl)-3-oxopropanethiovHamino
  • the reaction mixture consists of two major components. One was ethyl 2-aminobenzoate and the other component contained a mixture of tautomers of ethyl 2-
  • Step 3 Preparation of ethyl 2- ⁇ r3-(3-ethylphenyl)-l-(2-methylquinolin-4-yl)-lH-pyrazol-5- yliamino Ibenzoate
  • Step 4 Preparation of 2- ⁇ r3-(3-ethylphenyl)-l-(2-methylquinolin-4-yl)-lH-pyrazol-5-yl1 amino I benzoic acid hydrochloride
  • Step 1 Preparation of 3,3-dimercapto-l-phenylprop-2-en-l-one
  • the aqueous phase was acidified with IN sulfuric acid in an ice bath and then extracted three times with tert-butylmethylether. The combined organic extracts were dried over NaCl and evaporated to dryness in vacuo. This material (21 g) was used in the following step without further purification.
  • Step 2 Preparation of ethyl 2-r(3 ⁇ oxo ⁇ 3-phenylpropanethioyl)aminolbenzoate
  • Step 3 Preparation of ethyl 2- ⁇ ri-(3,5-dichloropyridin-4-yl) ⁇ 3-phenyl-lH-pyrazol-5-yll amino jbenzoate
  • Step 4 Preparation of 2- ⁇ ri-(3,5-dichloropyridin-4-yl)-3-phenyl-lH-pyrazol-5-yl1amino ⁇ benzoic acid hydrochloride
  • Step 2 Preparation of tert-butyl 2-cvano-3-(3-isopropoxyphenyl)-3-oxopropanoate
  • Step 4 Preparation of l-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol- 5-amine
  • Step 5 Preparation of methyl 2- ⁇ ri-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)- 1 H-p yrazol-5- yll amino ⁇ -5-methylbenzoate
  • Step 6 Preparation of 2-ri-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol- 5-yl1amino-5-methylbenzoic acid hydrochloride
  • 3-isopropylbenzoic acid was prepared following a known literature procedure from 1-bromo 3-isoproylbenzene (Smith, J.G.; Turle, R.A.; /. Org. Chem. 1972, 37, 126-131).
  • Step 4 Preparation of 2- ⁇ r3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)-lH-pyrazol- 5-vnamino
  • Step 1 Preparation of di-tert-butyl l-(4-methyl-3-thienyl)hydrazine-l,2-dicarboxylate
  • Step 4 Preparation of methyl 2- ⁇ r3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5- yll amino ⁇ -4-fluorobenzoate
  • Step 5 Preparation of 2-i r3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol- 5-vnamino
  • Step 1 Preparation of tert-butyl 2-cvano-3-(2-ethylpyridm-4-yl) ⁇ 3-oxopropanoate
  • Step 3 Preparation of methyl 2-i r3-f2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH- pyrazol-5-vH amino ⁇ -5-methylbenzoate
  • Step 4 Preparation of 2- ⁇ r3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH-pyrazol- 5-vHarnino
  • the compounds of the present invention may be employed in the treatment of diabetes, including both type 1 and type 2 diabetes (non-insulin dependent diabetes mellitus). Such treatment may also delay the onset of diabetes and diabetic complications.
  • the compounds may be used to prevent subjects with impaired glucose tolerance from proceeding to develop type 2 diabetes.
  • Other diseases and conditions that may be treated or prevented using compounds of the invention in methods of the invention include: Maturity- Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40, 1994); Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11:299, 1994); impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999); impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796, 1991); gestational diabetes (Metzger, Diabetes, 40:197, 1991); and metabolic syndrome X.
  • MODY Maturity- Onset Diabetes of
  • the compounds of the present invention may also be effective in such disorders as obesity, and in the treatment of atherosclerotic disease, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease, and hypertension), cerebrovascular disease and peripheral vessel disease.
  • the compounds of the present invention may also be useful for treating physiological disorders related to, for example, cell differentiation to produce lipid accumulating cells, regulation of insulin sensitivity and blood glucose levels, (which are involved in, for example, abnormal pancreatic beta-cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that are stimulatory to beta-cells), macrophage differentiation which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, reduction in the pancreatic beta-cell mass, insulin secretion, tissue sensitivity to insulin, liposarcoma cell growth, polycystic ovarian disease, chronic anovulation, hyperandrogenism, progesterone production, steroidogenesis, redox potential and oxidative stress in cells, nitric oxide synthase (NOS) production, increased gamma glutamyl trans
  • Compounds of the invention may also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999).
  • Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.
  • Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, ⁇ -adrenergic agents, ⁇ -interferon and drugs used to treat HIV infection.
  • the compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diabetes and related disorders.
  • the methods and compounds described herein may be used, partially or completely, in combination therapy.
  • the compounds of the invention may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, ⁇ -glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs.
  • Such therapies may be administered prior to, concurrently with or following administration of the compounds of the invention.
  • Insulin includes both long and short acting forms and formulations of insulin.
  • PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof.
  • PPAR agonist may include agonists of PPAR- ⁇ , PPAR- ⁇ , PPAR- ⁇ or any combination of two or three of the subunits of PPAR.
  • PPAR agonists include, for example, rosiglitazone and pioglitazone.
  • Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide, ⁇ -glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of the invention include acarbose, miglitol and voglibose.
  • Insulin sensitizers that may be useful in treating diabetes include thiazolidinediones and non-thiazolidinediones.
  • Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of the invention include metformin, such as Glucophage and Glucophage XR.
  • Insulin secretagogues that may be useful in treating diabetes when administered with a compound of the invention include sulfonylurea and non-sulfonylurea drugs: GLP-I, GIP, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide.
  • GLP-I includes derivatives of GLP-I with longer half-lives than native GLP-I, such as, for example, fatty-acid derivatized GLP-I and exendin.
  • compounds of the invention are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta-cells to the insulin secretagogue.
  • Anti-obesity drugs include ⁇ -3 agonists, CB-I antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical).
  • Compounds of the invention may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives.
  • Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, ⁇ -blockers and ACE inhibitors.
  • Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with an insulin sensitizer and an anti- obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
  • subject includes mammals (e.g., humans and animals).
  • treatment includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
  • combination therapy means the administration of two or more therapeutic agents to treat a diabetic condition and/or disorder.
  • administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent.
  • administration encompasses use of each type of therapeutic agent in a sequential manner.
  • terapéuticaally effective means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
  • pharmaceutically acceptable means that the subject item is appropriate for use in a pharmaceutical product. Based on well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.
  • a unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day.
  • the daily dosage for administration by injection may be from about 0.01 to about 200 mg/kg.
  • the daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight.
  • the transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds described herein may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
  • the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and
  • Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, 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 such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or ⁇ -propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose.
  • Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2- dimethyl-l,l-dioxolane ⁇ 4-methanol, ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin,
  • Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2- alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, al
  • compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorb
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art ⁇ see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized,
  • compositions for its intended route of administration include: acidifying agents, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.
  • acidifying agents for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid
  • alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.
  • adsorbents e.g., powdered cellulose and activated charcoal
  • aerosol propellants e.g., carbon dioxide, CCl 2 F 2 , F 2 ClC-CClF 2 and CClF 3
  • air displacement agents e.g., nitrogen and argon
  • antifungal preservatives e.g., benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • antimicrobial preservatives e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • antioxidants e.g., ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, but
  • clarifying agents e.g., bentonite
  • emulsifying agents but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate
  • encapsulating agents e.g., gelatin and cellulose acetate phthalate
  • flavorants e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants e.g., glycerin, propylene glycol and sorbitol
  • levigating agents e.g., mineral oil and glycerin
  • oils e.g., arachis oil, mineral oil, olive oil, peanut
  • the compounds described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-obesity, or with known antidiabetic or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof.
  • An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried.
  • An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.
  • Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art ⁇ see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20 th edition, 2000). The following examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.
  • a capsule formula is prepared from: Compound of this invention 10 mg
  • the components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.
  • a tablet is prepared from:
  • Compound of this invention 25 mg Cellulose, microcrystalline 200 mg
  • aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • a mg/mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary.
  • the solution is diluted for administration with sterile 5% dextrose and is administered as an IV infusion.
  • Intramuscular suspension The following intramuscular suspension is prepared:
  • Compound of this invention 50 ⁇ g/mL
  • the suspension is administered intramuscularly.
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing the active ingredient.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art.
  • in vitro, ex vivo, and in vivo assays that are well known in the art.
  • the following assays may be used.
  • Insulin secretion of dispersed rat islets mediated by a number of compounds of the present invention was measured as follows. Islets of Langerhans, isolated from male Sprague-Dawley rats (200-250 g), were digested using collagenase. The dispersed islet cells were treated with trypsin, seeded into 96 V-bottom plates, and pelleted. The cells were then cultured overnight in media with or without compounds of this invention. The media was aspirated, and the cells were pre-incubated with Krebs-Ringer-HEPES buffer containing 3 niM glucose for 30 minutes at 37°C.
  • the pre-incubation buffer was removed, and the cells were incubated at 37°C with Krebs-Ringer-HEPES buffer containing the appropriate glucose concentration (e.g., 8 mM) with or without compounds for an appropriate time.
  • the appropriate glucose concentration e.g. 8 mM
  • an appropriate concentration of GLP-I or forskolin was also included.
  • a portion of the supernatant was removed and its insulin content was measured by SPA. The results were expressed as "fold over control" (FOC), in accordance with standard practice in the field.
  • Compounds of Formula (T) of the current invention are also useful for identifying their associated biological target(s) (e.g., nucleic acids, peptides, polypeptides, proteins, carbohydrates, lipids, or other molecules) effecting the functional response of insulin secretion.
  • biological target(s) e.g., nucleic acids, peptides, polypeptides, proteins, carbohydrates, lipids, or other molecules
  • targets, or protein molecules that are modulated by the compounds of present invention can be identified by several means.
  • one such method of target identification can be accomplished, by photoaffinity labeling techniques well-known in the art.
  • compounds of Formula (I) that contain a photoactive group, such as a benzoylphenyl group are prepared and additionally labeled with a radioactive isotope such as tritium.
  • pancreatic beta-cell lysate homogenate or any biological sample, such as a sample obtained from an organism (e.g., mammal) or from components (e.g., cells, biological tissue or fluid) of an organism, cell line or tissue culture sample; or the sample may be a sample derived from a patient including, but are not limited to, tissue or cells therefrom) containing the suspected target(s), incubated for a period of time sufficient to effect association of the probe molecule with the target protein, then the mixture is irradiated with light at the wavelength of the photoactive group of the probe molecule.
  • any biological sample such as a sample obtained from an organism (e.g., mammal) or from components (e.g., cells, biological tissue or fluid) of an organism, cell line or tissue culture sample; or the sample may be a sample derived from a patient including, but are not limited to, tissue or cells therefrom
  • the mixture is irradiated with light at the wavelength of the photoactive group of the probe molecule.
  • the protein and probe molecule that become covalently bound as a result of the irradiation is then purified using standard methods, facilitated by the radioactivity of probe/target complex as a means to differentiate it from the rest of the lysate mixture.
  • Identification of the purified protein (the probe/target complex) is then conducted using methods well described in the art ⁇ see, e.g., Dorman, et al., Tibtech. 18:64-77, 2000).
  • Another method using the compounds of Formula (I) to identify the biological target effecting the functional response of insulin secretion is the so called drug "pull-down" experiments (see, e.g., Graves, et al., Rec. Prog. Horm. Res. 58:1-24, 2003).
  • Formula (I) compounds containing functional groups that are suitable for chemical coupling may be coupled to a commercially available polymer (resins) containing a suitably reactive linker group.
  • a commercially available polymer resins
  • the polymeric beads containing immobilized Formula (I) compound may then be used as bait for appropriate pancreatic beta-cell tissue lysates, by allowing the polymer beads to come in contact with the lysate, incubating for a period of time sufficient for the target proteins to form a complex with the polymer, removing the unbound protein material from the polymer, and cleaving of the bound protein from the polymer.
  • purified protein target(s) of interest may then be identified by mass spectrometric analysis using techniques well know in the art ⁇ see, e.g., Kim, et al., Biochem. MoI. Biol. 36:299-304, 2003.

Abstract

The present invention relates to anilinopyrazole compounds of formula (1) in which R3 represents an aromatic 5- or 6-membered heteroaromatic ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted, X represents a carboxylic acid, ester or amide, or sulfonamide, and the remaining groups are as defined in the text. It also relates to pharmaceutical compositions containing these materials and, and methods for treating diabetes and related disorders using these materials.

Description

Anilinopyrazole Derivatives Usfeful for the Treatment of Diabetes
Field
The present invention relates to anilinopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.
Background
Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups. Type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action. The current treatment for type 1 diabetic patients is injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin. Over time, almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.
Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion (i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose); low primary and secondary failure rates; and preservation of islet cell function. The compounds of this invention are believed to provide such benefits.
Description of the Invention In a first embodiment, the invention provides anilinopyrazole derivatives of formula (I)
wherein
R is H or (Ci-C2)alkyl; R1 is H,
(Ci-C6)alkyl optionally substituted with one (C1-C4)alkoxy,
(C3-C6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C1-C3)alkyl, CF3, and halo, (C1-C3)haloalkyl, or phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
(C1-C6)alkyl optionally substituted with one (Q-GOalkoxy, (C3-C6)cycloalkyl (Q-C^alkoxy,
(C3-C6)cycloalkoxy (C1-C3)haloalkyl, (C1-C3)ImIOaIkOXy, cyano, nitro, and
(Q-GOacyl,
R2 is H, halo, (CrC6)alkyl,
(C3-C6)cycloalkyl,
(d-Cs^aloalkyl, or phenyl, 1,3-benzodioxolane, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of (Ci-C4)alkyl optionally substituted with halogen and/or one (Q-GOalkoxy (C3-C6)cycloalkyl, (d-C4)alkoxy (C3-C6)cycloalkoxy, halo, (C1-C3)IIaIOaIkOXy, cyano,
(Q-GOacyl, and benzoyl,
R3 represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
(Q-GOalkoxy, (C3-C6)cycloalkoxy (C1-C3)haloalkoxy,
(Q-C^alkyl optionally substituted with one (C1-C^aIkOXy, (C3-C6)cycloalkyl, (Ci-C3)haloalkyl, halo, and cyano, with the provisos that a) when R3 is unsubstituted pyridyl and R and R2 are H and X is CO2H, then R1 is other than H or methyl, b) when R3 is unsubstituted 2-pyridyl and R and R2 are H and X is CO2H and n is 2 and both R4 groups are F, then R1 is other than ethyl, and c) when R3 is 6-methyl-2-pyridyl or 4,6-dimethyl-2-pyridyl and R and R2 are H and X is CO2H, then R1 is other than methyl,
R4 Is (Q-GOalkyl, (C3-C6)cycloalkyl,
(CrC3)alkoxy, (C1-C3)haloalkyl, (Ci-C3)haloalkoxy, or halo,
n = 0, 1, 2, or 3;
X is CO2R8, CONR5R6, or SO2NHR7;
R5 is H,
(Ci-C4)alkyl, or
SO2-phenyl, said phenyl being optionally substituted with up to two substituents selected from the group consisting of halo
(Q-C^alkyl optionally substituted with one (Q-GOalkoxy, (Ci-C4)alkoxy, (CrC3)haloalkyl, and (C1-C3)haloalkoxy,
R6 is H or (Ci-C6)alkyl;
R7 is H or methyl; and
R8 is H, or
(Q-GOalkyl, or a pharmaceutically acceptable salt thereof.
In a second embodiment, the invention relates to a compound of the above first embodiment having the structure
(I) wherein
R is H or (C1-C2^IkVl; R1 is H,
(C1-C6)alkyl optionally substituted with one (CrC4)alkoxy, (C3-C6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C1-C3)OIlCyI, CF3, and halo, (CrC3)haloalkyl, or phenyl optionally substituted with up to two substituents selected from the group consisting of halo,
(Ci-C4)alkyl optionally substituted with one (C1-C4)OIkOXy,
(C3-C6)cycloalkyl
(Ci-C4)alkoxy, (C3-C6)cycloalkoxy
(CrC3)haloalkyl,
(C1-C3)haloalkoxy, cyano, nitro, and (C1-C4)OCyI,
R2 is H, halo,
(Ci-Q)alkyl, (C3-C6)cycloalkyl,
(Ci-C3)haloalkyl, pyridyl optionally substituted with up to two substituents selected from the group consisting of
(C1-C3)alkoxy, (C3-C6)cycloalkoxy,
(C1-C3)ImIOaIkOXy, (CrC3)haloalkyl, halo, and (Ci-Cύalkyl; pyrimidyl, optionally substituted with (Ci-C4)alkyl or (Q-GOalkoxy, or phenyl optionally substituted with up to two substituents selected from the group consisting of (Ci-GOalkyl, (C3-C6)cycloalkyl, (Ci-C4)alkoxy, (C3-C6)cycloalkoxy, halo, (CrC3)haloalkoxy,
(CrC4)acyl, and benzoyl,
R3 represents optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R3 are selected from the group consisting of (C1-C4JaIkOXy, (C3-C6)cycloalkoxy (C1-C3)haloalkoxy, (d-C6)alkyl,
(C3-C6)cycloalkyl, and (Ci-C3)haloalkyl, and the number of said optional substituents on R3 is 0, 1, or 2, with the provisos that a) when R3 is unsubstituted pyridyl and R and R2 are H and X is CO2H, then
R1 is other than H or methyl, b) when R3 is unsubstituted 2-pyridyl and R and R2 are H and X is CO2H and n is 2 and both R4 groups are F, then R1 is other than ethyl, and c) when R3 is 6-methyl-2-pyridyl or 4,6-dimethyl-2~pyridyl and R and R2 are H and X is CO2H, then R1 is other than methyl,
R4 is (Ci-Cύalkyl,
(C3-C6)cycloalkyl, (CrC3)alkoxy, (Ci-C3)haloalkyl,
(Q-C^haloalkoxy, or halo, n = 0, 1, 2, or 3;
X is CO2R8, CONR5R6, or SO2NHR7;
R5 is H,
(Ci-Cøalkyl, or
SO2-phenyl, said phenyl being optionally substituted with up to two substituents selected from the group consisting of halo (Q-C^alkyl optionally substituted with one (Q-GOalkoxy,
(Ci-C4)alkoxy,
(Ci-C3)haloalkyl, and
(C!-C3)haloalkoxy,
R6 is H or (Ci-Qs)alkyl;
R7 is H or methyl; and
R8 is H, or (Ci-COalkyl, or a pharmaceutically acceptable salt thereof.
In a third embodiment, the invention relates to a compound of the above first embodiment having the structure
(I) wherein
R is H or (Ci-QOalkyl; R1 is H, (C1-C6)alkyl optionally substituted with one (C1-C4)OIkOXy, (C3-C6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (CrC3)alkyl, CF3, and halo, or (C1-C3)haloalkyl,
R2 is H, phenyl, 1,3-benzodioxolane, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of
(Q-GOalkyl optionally substituted with halogen and/or one (Q-GOalkoxy (C3-C6)cycloalkyl, (CrC4)alkoxy
(C3-C6)cycloalkoxy, halo,
(C1-C3)haloalkoxy, cyano, (d-C4)acyl, and benzoyl,
R represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
(Ci-C4)alkoxy, (C3-C6)cycloalkoxy (Ci-C3)haloalkoxy,
(CrC6)alkyl optionally substituted with one (Q-GOalkoxy, (C3-C6)cycloalkyl, and
(C1-C3)haloalkyl, halo, cyano, with the provisos that a) when R3 is unsubstituted pyridyl and R and R2 are H and X is CO2H, then R1 is other than H or methyl, b) when R3 is unsubstituted 2-pyridyl and R and R2 are H and X is CO2H and n is 2 and both R4 groups are F, then R1 is other than ethyl, and c) when R3 is 6-methyl-2-pyridyl or 4,6-dimethyl-2-pyridyl and R and R2 are H and X is CO2H, then R1 is other than methyl,
R4 is (Ci-Cύalkyl, (C3-C6)cycloalkyl,
(C1-C3)alkoxy, (C1-C3)haloalkyl, (Ci-C3)haloalkoxy, or halo,
n = 0, 1, 2, or 3;
X is CO2R8, and
R8 is H, or
(Ci-GOalkyl, or a pharmaceutically acceptable salt thereof.
In a fourth embodiment, the invention relates to a compound of the above first embodiment having the structure
(I) wherein
R is H or (Ci-C2)alkyl; R1 is phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
(Ci-C6)alkyl optionally substituted with one (C1-C-OaIkOXy, (C3-C6)cycloalkyl (C1-CeOaTkOXy,
(C3-C6)cycloalkoxy (Ci-C3)haloalkyl, (C!-C3)lialoalkoxy, cyano, nitro, and (Q-GOacyl,
R2 is H,
(C1-C6)alkyl, or (C3-C6)cycloalkyl,
R3 represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
(C1-C^aIkOXy, (C3-C6)cycloalkoxy
(C1-C3)haloalkoxy,
(Ci-C6)alkyl optionally substituted with one (Q-GOalkoxy, (C3-C6)cycloalkyl, and (Q-C^haloalkyl, halo, cyano,
R4 is (Q-GOalkyl,
(C3-C6)cycloalkyl, (Q-C3)alkoxy,
(Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, or halo,
n = 0, 1, 2, or 3;
X is CO2R8, and
R8 is H, or (Ci-Cύalkyl, or a pharmaceutically acceptable salt thereof.
In a fifth embodiment, the invention relates to a compound of the above fourth embodiment having the structure
(I) wherein
R is H or (CrC2)alkyl;
R1 is phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
(C1-C6)alkyl optionally substituted with one (C1-C^aIkOXy, (C3-C6)cycloalkyl (C!-C6)alkoxy, (C3-C6)cycloalkoxy
(C1-C3)haloalkyl, (CrC3)haloalkoxy, cyano, nitro, and (Ci-C4)BCyI,
R2 is H, or
(C1-C6)alkyl,
R3 represents optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R are selected from the group consisting of (Ci-CUJalkoxy, (C3-C6)cycloalkoxy (Ci-C3)haloalkoxy,
(C1-C6^IkVl optionally substituted with one (Q-GOalkoxy, (C3-C6)cycloalkyl, (C1-C3)haloalkyl, halo, and cyano,
R4 is (CrC4)alkyl,
(C3-C6)cycloalkyl, (CrC3)alkoxy,
(CrC3)haloalkyl, (Ci-C3)haloalkoxy, or halo,
n = 0, 1, or 2,
X is CO2R8, and
R8 is H, or (CrC4)alkyl, or a pharmaceutically acceptable salt thereof.
In a sixth embodiment, the invention relates to a compound of the above fifth embodiment having the structure
0) wherein
R is H or (Q-C2)alkyl;
R1 is phenyl substituted in meta-position with one substituent selected from the group consisting of halo,
(CrC6)alkyl optionally substituted with one (Q-GOalkoxy, (C1-C6)alkoxy, and (C3~C6)cycloalkoxy
R2 is H,
R3 represents optionally substituted pyridine, optionally substituted pyiϊdazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R3 are selected from the group consisting of
(Ci-C4)alkoxy, (C3-C6)cycloalkoxy
(C1-C3)haloalkoxy,
(C1-C6)alkyl optionally substituted with one (Q-GOalkoxy, (C3-C6)cycloalkyl, (d-C3)haloalkyl, halo, and cyano,
R4 is (Ci-C4)alkyl,
(CrC3)alkoxy, (C1-C3)haloalkyl,
(Ci-C3)haloalkoxy, or halo,
n = 0, I, or 2,
X is CO2R8, and
R8 is H, or
(d-C4)alkyl, or a pharmaceutically acceptable salt thereof.
In a seventh embodiment the invention relates to a compound of the above first embodiment having the formula (I) wherein R is H;
R1 is methyl, ethyl, tert-butyl or cyclopropyl, or phenyl optionally substituted with one substituent selected from the group consisting of
(Q-C^alkyl optionally substituted with one (C1-C4)RIkOXy, (C1-C6)OIkOXy, (C3-C6)cycloalkoxy (Ci-C3)haloalkyl,
(Ci-C3)haloalkoxy, and cyano,
R2 is H, phenyl, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of
(Ci-Gύalkyl, (C3-C6)cycloalkyl,
(Ci-GOalkoxy halo,
(C i -C3)haloalkoxy, cyano, and (Ci-C4)SCyI,
R3 represents pyridine, pyrimidine, or pyrazine, optionally substituted with up to two substituents selected from
(Q-GOalkoxy,
(Q-C6)alkyl optionally substituted with one (C1-GOaIkOXy,
(C3-C6)cycloalkyl, (Q-C3)haloalkyl, halo, and cyano, with the provisos that a) when R3 is unsubstituted pyridyl and R and R2 are H and X is CO2H, then R1 is other than H or methyl, b) when R3 is unsubstituted 2-pyridyl and R and R2 are H and X is CO2H and n is 2 and both R4 groups are F, then R1 is other than ethyl, and c) when R3 is 6-methyl-2-pyridyl or 4,6-dimethyl-2-pyridyl and R and R2 are H and X is CO2H, then R1 is other than methyl,
R4 is (C1-C4)alkyl,
(C!-C3)alkoxy,
(C1-C3)haloalkyl,
(C1-C3)haloalkoxy, or halo,
n = 0, I, or 2;
X is CO2R8, and
R8 is H, or
(C1-C4OaIkVl, or a pharmaceutically acceptable salt thereof.
Definitions
The terms identified below, if used, have the following meaning throughout: The term "halo" means F, Br, Cl, and I.
The terms "(Ci-C4)alkyl," "(C1-C6)alkyl," and "(C2-C6)alkyl" mean a linear or branched saturated hydrocarbon radical having from 1 to 4 C atoms, 1 to 6 C atoms, 2 to 6 C atoms, respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. The term "(C3-C6)alkenyl" means a linear or branched unsaturated hydrocarbon radical containing a double bond and from 3 to 6 carbon atoms. The double bond may be between any two available carbon atoms in the chain. Such groups include, allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like. The term "(C3-C6)alkynyl" means a linear or branched unsaturated hydrocarbon radical containing a triple bond and from 3 to 6 carbon atoms. The triple bond may be between any two available carbon atoms in the chain. Such groups include, propargyl, 2- butynyl, l-methyl-2-butynyl, 3-hexynyl, and the like.
The term "(C3-C6)cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The terms "(Ci-C3)alkoxy," "(Q-GOalkoxy," and "(CrC6)alkoxy" mean a linear or branched saturated hydrocarbon radical having from 1 to 3 C atoms, 1 to 4 C atoms, or 1 to 6 C atoms, respectively, said radical being attached to an O atom. The O atom is the atom through which the alkoxy substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.
The term "(C3-C6)cycloalkoxy" includes cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
The terms "(Ci-C3)haloalkoxy" and "(C2-C3)haloalkoxy" mean a (Ci-C3)alkoxy group or a (C2-C3)alkoxy group, respectively, substituted on C with at least one halogen atom. Such groups include trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloroethoxy, 3-chloropropoxy, l-fluoro-2,2,-dichloroethoxy, and the like.
The terms "(C1-C3)haloalkyl" and "(C2-C3)haloalkyl" mean a (d-C3)alkyl group or (C2-C3)alkyl group substituted on C with at least one halogen atom. Such groups include trifluoromethyl, difluoroethyl, l-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4-bromohexyl, and the like.
The formula C(O) means a radical in which the C atom bears a doubly bonded oxygen, (an oxo substituent) and in which there remains two additional binding sites, that is, represents a radical of the formula:
O ^C-\ The term "(CrC4)acyl" means a (C1-C4)alkyl radical substituted on the C of a C(O) group. The C of the C(O) is the group is also the atom through which the substituent is attached to the rest of the molecule. Such groups include, but are not limited to, acetyl (CH3C(O)-), n-propanoyl (CH3CH2C(O)-), isobutanoyl ((CH3)2CHC(O)-), and the like. The formula "NR8R8" means that each of the two possible R8 groups attached to the
N atom is selected independently from the other so that they may be the same or they may be different.
The terms "(Q-QOalkylthio" and "(CrC6)alkylthio" mean a linear or branched saturated hydrocarbon radical having from 1 to 3 C atoms, or 1 to 6 C atoms, respectively, said radical being attached to an S atom. The S atom is the atom through which the alkylthio substituent is attached to the rest of the molecule. Such groups
The term "SO2(C1-C3)alkyl" means a linear or branched saturated hydrocarbon radical having from 1 to 3 C atoms, said radical being attached to the S atom of the SO2 group. The S atom of the SO2 group is the atom through which the SO2(Ci-C3)alkyl substituent is attached to the rest of the molecule. Such groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and isopropylsulfonyl, and the like.
The term "6-membered carbocyclic ring" means a partially unsaturated ring containing C atoms fused to the pyrazole ring to form a tetrahydroindazole ring system. The ring may be optionally substituted with (Ci-C6)alkyl groups at any available position, up to a total of about 6 C atoms.
The term "5- or 6-membered heterocycles" means a saturated 5- or 6-membered ring containing up to two heteroatoms selected from a group consisting of N, O, and S. Such rings include, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, and the like.
The term "5- or 6-membered heteroaryl ring" means a unsaturated 5- or 6-membered aromatic ring containing up to 3 atoms independently selected from a group consisting of N,
O, and S. Such rings include, but not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiophene, furane, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, and the like.
The terms "tetrahydronaphthyl," "indanyl," "benzodioxolyl," or "benzodioxanyl" mean bicyclic ring radicals of the formulae ' respectively. The radical is attached to the rest of the molecule at any available carbon of the phenyl ring. Where the radical is optionally substituted, the substituent may be attached at any available carbon atom. The term "optionally substituted" means that the moiety so modified may have from none to up to at least the highest number of substituents indicated. Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. When there are two or more substituents on any moiety, each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.
Alternative Forms of Compounds of the Invention
Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.
The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above. Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Examples of organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2- hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicylic, galactaric, and galacturonic acid, and combinations thereof. Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.
The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
The present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability, and release time {see, e.g.,
"Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995), which is hereby incorporated by reference). Commonly used prodrugs are designed to take advantage of the major drug biotransformation reactions, and are also to be considered within the scope of the invention.
Major drug biotransformation reactions include iV-dealkylation, 0-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation, and acetylation (see, e.g., Goodman and Gilman's The
Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which is hereby incorporated by reference).
A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.
General Preparative Methods
In general, the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.
Reaction Scheme A illustrates the general method for the preparation of compounds of Formula (Ia), namely, Formula (I) where R is H. An aminopyrazole of Formula (III) is coupled with either a 2-bromo, 2-iodo, or 2-[(trifluoromethyl)sulfonyl]oxy benzoic acid, benzoic ester, benzoic acid amide, or benzenesulfonamide of Formula (IV), using Ullmann- type conditions (copper (II) acetate in DMF, heated in a sealed tube for 16 h) or a 2- bromobenzoic ester, benzoic acid amide, or benzenesulfonamide of Formula (IV) using Buchwald-type conditions (cesium carbonate, BINAP and Pd2(dba)3 in anhydrous toluene, heated to 110 0C for 16 h under argon).
Reaction Scheme A
SO2N(Bn)2
(IV)
Reaction Scheme B illustrates a general method for conversion of compounds of Formula (Ib) into other Formula (Ia) compounds having at least one R4 substituent, by reaction of the halogen-containing (Ib) under Suzuki coupling conditions [e.g., a palladium catalyst such as Pd(dppf)Cl2, and a boronic acid (V)]. Reaction Scheme B
(Ib) X = CO2R8 (V) (Ia)
CONR5R6 SO2N(Bn)2 n = 1 ,2 or 3 p = 0,1 or 2
Reaction Scheme C outlines a general method for the preparation of other Formula (Ia) compounds from compounds of Formula (Id), which is Formula (I) where R2 is bromo or iodo. In this scheme, a bromine or iodine is introduced to the compound of Formula (Ic) (Formula (I) where R2 is H) and the resulting Formula (Id) compound is allowed to undergo a Suzuki reaction with a boronic acid R2B(OH)2.
Reaction Scheme C
X = CO2Rb C COONNRR;5R6 SO2N(Bn)2
By combining the methods of Reaction Schemes A, B, and C, Formula (Ia) compounds may be prepared containing a variety of R2 and R4 substituents as shown in Reaction Scheme D. For example, coupling a dibromobenzoic acid, dibromobenzoic ester, or dibromobenzenesulfonamide of Formula (IVa) with a pyrazole of Formula (HIa) provides an intermediate of Formula (Ie). Suzuki reaction of (Ie) with a boronic acid derivative gives (If) which can be brominated or iodinated to give (Id). Finally, (Id) can be converted to the Formula (Ia) compounds via another Suzuki reaction. Reaction Scheme D
Buchwald-type coupling
(HIa) (IVa) (Ie): (I), R2 = H
X = CO2R8, CONR5R6 SO2N(Bn)2, or SO2NHMe
Other compounds of Formula (I) where R is iodo (Formula Ig) or fluoro (Formula Ih) may be prepared from Formula (If) compounds as shown in Reaction Scheme E, by iodination with NIS or fluorination with Selectfluor® (a commercially available reagent), respectively.
Reaction Scheme E
(Ih)
Compounds of Formula (I) in which R4 is an amino group NR >53rR>60 or imidazole can be prepared by a special sequence outlined in Reaction Scheme F. Reaction Scheme F
Ij): R4 = 4-F; X = CO2R8 (Ik): R4 = NR5Rb or imidazol-1 -yl X = CO2R8
In this sequence, a 4-fluoro group on the phenyl ring can be displaced by an R4 group, where R4 = NR5R6 or an imidazolyl, in an aromatic nucleophilic substitution reaction. The reaction is conducted in the presence of a base such as LiNMe2 or K2CO3.
Compounds of Formula (I) where X is C(O)NR >5 Rr>6 can be prepared by the route described in Reaction Scheme G.
Reaction Scheme G
(Im): (I), X = CO2R8 R5R6NH (lo): (I), X = CONR5R6 hydrolysis
(In): (I), X = CO2H (Ip): (I), X = CONHSO2Ar
An ester compound of Formula (Im) is hydrolyzed to the acid compound of Formula (In) usually in mild aqueous base. Formula (In) can then be converted to amides of Formula
(Io) by reaction with an amine R5R6NH and a coupling agent, or with an optionally substituted phenyl sulfonamide ArSO2NH2 and a coupling agent, to give the acyl sulfonamide of Formula (Ip). Reaction Scheme H outlines the general method for preparation of Formula (I) compounds in which X = SO2NHR7 and R7 is H.
Reaction Scheme H
(Ir): (I), X = SO2N(Bn)2 (Is): (I), X = SO2NH2
The JVyV-dibenzylsulfonamide compound of Formula (Ir) is prepared as described in Reaction Scheme A and can be de-benzylated with sulfuric acid to give the compound of Formula (Is).
Reaction Scheme I
The compounds of Formula (I) where R is (Ci-C2)alkyl are prepared by iV-alkylation of the corresponding Formula (Ia) compounds where R is H, using standard conditions such as those shown in Reaction Scheme I. Such conditions include an alkylating agent such as iodomethane, and a base such as sodium hydride, and the reaction is carried out in inert solvent such as DMF.
Reaction Scheme J
(Ia) Reaction Scheme J outlines an approach to compounds Ia starting with addition of carbondisulfide to arylacetophenones (R2 =H). Exchange of one sulfur with anthranilic acid produces thioamides which can be cyclized with hydrazines to yield compounds (Ia).
Synthesis of Intermediates
Intermediates are either commercially available, or are prepared by standard methods known in the art and/or by analogy to one of the procedures shown below.
5-Aminopyrazoles 5-Aminopyrazole starting materials of Formula (III) are either commercially available or can be prepared as shown in Reaction Schemes K, Kl, L, or M.
Reaction Scheme K
(VII) (VIII) (lib) (III)
In Reaction Scheme K, condensation of an optionally substituted acetonitrile with an appropriately substituted ester (VII), and base, gives the cyanoketone (VIII). If the cyanoketone (VIII) is commercially available, this step is omitted. Esters of Formula (VII) where R1 is an optionally substituted phenyl, can be prepared, if necessary, from the corresponding bromo compound of Formula R^Br, for example, by reaction with BuLi and CO2 to form an acid of Formula R^COOH, which can be esterified to (VII). The compound of formula (VIII) is then allowed to react with a substituted hydrazine of Formula (II) to give the desired aminopyrazole (III).
Reaction Scheme Kl
pjoptsub
(MIe)
The compounds of formula (HIe), where R is an optionally substituted phenyl and R is H of the corresponding formula (III), can also be prepared by the route described in Reaction Scheme Kl, from commercially available phenylketones.
Reaction Scheme L
In Reaction Scheme L, acetonitrile is allowed to condense to the enaminonitrile (IX), then react with the hydrazine (II) or hydrazone (lib), to form (EIa) ((EI) where R2 = H]).
Reaction Scheme M
R20 is H, (C1-C4) alkyl (lllc) (llld)
*Suitable boronic acid esters include R2B(OR')2 where R' is a lower alkyl group, or two R' groups may form a ring
and trimeric boronic acid esters such as
Reaction Scheme M illustrates how the aminopyrazole of Formula (Ilia) may be converted to other aminopyrazoles of Formula (III) by bromination and Suzuki or Stille coupling reactions to introduce an R2 group other than H. The product of the Stille reaction (HIc) can also be reduced, for example by hydrogenation, to give the saturated compound of Formula (Illd).
Examples of preparations of aminopyrazoles are shown in the descriptions of Examples 1, 3, 4, 5, 6, 7, 82, 102, 104, and 162, below.
Hydrazines
Hydrazine starting materials of Formula (II) are either commercially available or, in the case of heteroaryl hydrazines of Formula (Ha) where R3 is optionally substituted heteroaryl, can be prepared by routes described in Reaction Scheme Nl and N2. Reaction Scheme Nl
Ropt sub = an optional (Ha), [(II), R3 = optionally substituted heteroaryl] substituent = Heteroaryl
A substituted aniline is converted into a diazonium salt intermediate which is subsequently reduced using tin(II)chloride as the reductant.
Reaction Scheme N2
Ropt sub = an optional (Ha) substituent = Heteroaryl halo = Br or Cl
Hvdrazones Hydrazone starting materials of Formula (lib) are either commercially available or, can be prepared as shown in Reaction Scheme O.
Reaction Scheme O
R0P* sub = an optional (lib) substituent
I Het. I = heteroaryl Examples of preparations of heteroaryl hydrazines and hydrazones are shown in the descriptions of Example 1, 3, 6, and 7, below.
2-Bromo, 2-iodo, and/or 2-r(trifluoromethyl)sulfonyl1oxy benzoic acid derivatives The 2-bromo, 2-iodo, and/or 2-[(trifluoromethyl)sulfonyl]oxy benzoic acid derivatives used in the coupling reactions with 5-aminopyrazoles were either commercially available or prepared by straightforward means well known in the art.
Specific Examples of the Invention The following specific examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.
Abbreviations and Acronyms
When any of the following abbreviations is used in this disclosure, it has the meaning listed below: abs absolute
Ac acetyl
AcOH acetic acid amu atomic mass unit aq. Aqueous
Ar aryl
BINAP 2,2' -Bis(diphenylρhosphino)- 1,1' -binaphthyl
Bn benzyl
B oc t-butoxycarbonyl br broad
BTMAICl2 benzyltrimethylammonium dichloriodate
Bu butyl
CDCl3 deuterochloroform
CDI carbonyl diimidazole Celite® brand of diatomaceous earth filtering agent, registered trademark of
Celite Corporation
CI-MS chemical ionization mass spectroscopy cone concentrated d doublet
DCM dichloromethane dd doublet of doublet ddd doublet of doublet of doublet
DMAP 4-(N,N-dimethyl)amino pyridine
DMF ΛζiV-dimethyl formamide
DMSO dimethylsulfoxide
DMSO-J6 dimethylsulfoxide-<i,5
DOWEX® 66 Dowex hydroxide, weakly basic anion, macroporous, 25-50 mesh dppf 1 , 1' -bis(diphenylphosphino)ferrocene
EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EI electron impact ionization
EI- MS electron impact - mass spectrometry equiv equivalent
ES - MS electrospray mass spectrometry
Et ethyl
Et2O diethyl ether
Et3N triethylamine
EtOAc ethyl acetate
EtOH ethanol g gram
GC-MS gas chromatography - mass spectrometry h hour(s)
Hex hexanes
1H NMR proton nuclear magnetic resonance
HOAT 1 -hydroxy-7-aza-benzotriazole
HOBT 1 -hydroxybenzotriazole
HPLC high-performance liquid chromatography
HPLC ES-MS high-performance liquid chromatography-electrospray mass spectroscopy
KOtBu potassium tert-butoxide
L liter LC-MS liquid chromatography / mass spectroscopy
LDA lithium diisopropylamide
LiOH lithium hydroxide m multiplet
M molar ra/z mass over charge
Me methyl
MeOH methanol mg milligram
MHZ megahertz min minute(s) mL milliliter mmol millimole mol mole mp melting point
MS mass spectrometry
N normal
NaOAc sodium acetate
NBS iV-bromosuccinimide
NIS JV-iodosuccinimide
NMM 4-methylmorpholine
NMR nuclear magnetic resonance
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2 palladium acetate
Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
Pd/C palladium on carbon
Pd(dppf)Cl2 [ 1 , 1 ' -bis (diphenylphosphino)ferrocene] dichloropalladium(II)
Ph phenyl ppm parts per million
Pr propyl prep preparative psi pounds per square inch q quartet qt quintet
Rf TLC retention factor
RP-HPLC reverse phase HPLC rt room temperature
RT retention time (HPLC)
S singlet sat. saturated
TBAF tetrabutylarnnionium fluoride
TBDMS fert-butyldimethylsilyl
TBDMSCl tert-butyldimethylsilyl chloride
TBS ferf-butyldimethylsilyl
TFA trifluoroacetic acid
TfO [(tiϊfluoromethyl)sulfonyl]oxy
THF tetrahydrofuran
TLC thin layer chromatography
TMS tetramethylsilane
TsOH p-toluenesulfonic acid v/v volume per unit volume vol volume w/w weight per unit weight
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
General Experimental Methods
Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentration under reduced pressure" refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (0C). Thin layer chromatography (TLC) was performed on EM Science pre-coated glass-backed silica gel 60 A F-254 250 μm plates. Column chromatography (flash chromatography) was performed on a Biotage system using 32-63 micron, 60 A, silica gel pre-packed cartridges. Purification using preparative re versed-phase HPLC chromatography were accomplished using a Gilson 215 system, typically using a YMC Pro-C18 AS-342 (150 x 20 mm LD.) column. Typically, the mobile phase used was a mixture of H2O (A) and acetonitrile (B). The water could be mixed or not with 0.1% TFA. A typical gradient was:
Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 μM coating; 30 m x 0.25 mm). The ion source was maintained at 2500C and spectra were scanned from 50-800 amu at 2 sec per scan.
High pressure liquid chromatography-electrospray mass spectra (HPLC ES-MS) were obtained using either a:
(A) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C- 18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
Or
(B) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a Waters Sunfire C18 column (2.1 x 30 mm, 3.5uM), a Gilson autosampler and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total ran time was 6.5 minutes.
HPLC retention times indicated for the specific examples in this invention are either recorded directly under the above HPLC ES-MS conditions, shown in the subsequent tables as (A) and (B), or recorded under one of the following methods:
Method (C): GSS-HPPSK2
Instrument: HP 1100 with DAD-detection; column: Kromasil RP- 18, 60 mm x 2.1 mm, 3.5 μm; eluent A: 5 mL HClO4 (70%)/L water, eluent B: acetonitrile; gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 6.5 min 90%B, 6.7 min 2% B, 7.5 min 2% B; flow: 0.75 mL/min; oven: 3O0C; UV-detection: 210 nm.
Method (D): GSS-HPPSLK2 Instrument: HP 1100 with DAD-detection; column: Kromasil RP-18, 60 mm x 2.1 mm, 3.5 μm; eluent A: 5 mL HClO4 (70%)/L water, eluent B: acetonitrile; gradient: 0 min 2 %B, 0.5 min 2%B, 4.5 min 90%B, 9 min 90%B, 9.2 min 2% B, 10 min 2% B; flow: 0.75 mL/min; oven: 30 0C; UV-detection: 210 nm.
Method (E): GSS-HPPSLLK2
Instrument: HP 1100 with DAD-detection; column: Kromasil RP-18, 60 mm x 2.1 mm, 3.5 μm; eluent A: 5 mL HClO4 (70%)/L water, eluent B: acetonitrile; gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 15 min 90%B, 15.2 min 2% B, 16 min 2% B; flow: 0.75 mL/min; oven: 30 0C; UV-detection: 210 nm.
Method (F): MHZ-Zl-HYD-I
Instrument MS: Micromass ZQ; with HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 Ll water + 0.5 mL 50% formic acid in water, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid in water; gradient: 0.0 min 90%A -> 2.5 min 30% A -> 3.0 min 5% A -» 4.5 min 5% A; flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; oven: 50 0C; UV-detection: 210 nm.
Method (G): MHZ-Z2-HYD-1 Instrument MS: Micromass ZQ; with HPLC: HP 1100 Series; UV DAD; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 L water + 0.5 mL 50% formic acid in water, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid in water; gradient: 0.0 min 90%A -» 2.5 min 30%A -» 3.0 min 5%A -> 4.5 min 5%A; flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; oven: 50 0C; UV-detection: 210 nm.
Method (H): MHZ-Q-HYD-I
Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 L water + 0.5 mL 50% formic acid in water, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid in water; gradient: 0.0 min 90%A -> 2.5 min 30%A -> 3.0 min 5%A -_> 4.5 min 5%A; flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; oven: 50 0C; UV-detection: 210 nm.
Method (I): MHZ-Z2-GEM-1 Instrument: Micromass ZQ with HPLC: HP 1100 Series; column: Phenomenex Gemini 3μ 30 mm x 3 mm; eluent A: 1 L water + 0.5 mL 50% formic acid in water, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid in water; gradient: 0.0 min 90%A -> 2.5 min 30%A -> 3.0 min 5%A -> 4.5 min 5%A; flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; oven: 50 0C; UV-detection: 210 nm. Method (J): MHZ-Q-GEM-I
Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; eluent A: 1 L water + 0.5 mL 50% formic acid in water, eluent B: 1 L acetonitril + 0.5 mL 50% formic acid in water; gradient: 0.0 min 90% A -> 2.5 min 30%A -> 3.0 min 5%A -> 4.5 min 5%A; flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; oven: 50 0C; UV-detection: 208-400 nm.
Methode (K): MHZ-P-GOLD-I
Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; column: Thermo Hypersil GOLD 3μ 2Ox 4mm; eluent A: 1 L water + 0.5mL 50% formic acid in water, eluent B: 1 L acetonitril + 0.5 mL 50% formic acid in water; gradient: 0.0 min 100%A -> 0.2 min 100%A -> 2.9 min 30%A -> 3.1 min 10%A -»5.5 min 10%A; oven: 50 0C; flow: 0.8 mL/min; UV-detection: 210 nm. Routine one-dimensional NMR spectroscopy was performed on 300/400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.49 ppm for DMSO-Jg , 1.93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CD2Cl2 and 7.26 ppm for CDCl3 for 1H spectra, and 39.5 ppm for OMSO-d6 , 1.3 ppm for CD3CN, 49.0 ppm for CD3OD, 53.8 ppm for CD2Cl2 and 77.0 ppm for CDCl3 for 13C spectra.
Example 1
Preparation of 2-{r3-tert-butyI-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-vnamino}-5- methoxybenzoic acid
Step 1: Preparation of 3-hydrazino-4-methylpyridine hydrochloride
To a solution of 37% aq HCl/water (1:1) (9 mL) was added 4-methylpyridin-3-amine (1.00 g, 9.25 mmol), and the mixture was cooled to 0 0C. An ice-cold solution of NaNO2 (638 mg, 9.25 mmol) in water (4.5 mL) was added dropwise to the first solution, and the temperature was maintained at 0 0C during the addition. The reaction mixture was then stirred for 10 min at ~ 0 0C until it turned into a thick bright orange-colored homogeneous paste. SnCl2 (3.16 g, 16.6 mmol) was dissolved in 37% aq HCl (6 mL), the solution was cooled to 0 0C, and then added to the above diazonium salt solution over several minutes while maintaining the temperature at 0 0C. The reaction mixture was then warmed to 20 0C by using a water bath and allowed to stand until no further precipitation occurred. The precipitate was collected by filtration, washed with a small amount of cold water, and dried under high vacuum. The crude product (628 mg, 43%) was used in the next step without further purification. ES-MS m/z 124.1 (MH+); HPLC RT (min) 0.80 {method (A)}.
Step 2: Preparation of 3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-amine
3-Hydrazino-4-methylpyridine hydrochloride (628 mg, 3.93 mmol) (step 1) and 3,3- dimethyl-2-oxobutanenitrile (532 mg, 4.25 mmol) were dissolved in ethanol (5 mL) in a sealed tube and heated at ~ 80 0C for 15 h. The flask was then cooled to rt, opened, and the solvent was removed under reduced pressure. The crude residue was treated with water, and basified by slow addition of concentrated aq. NaOH solution (ice bath used since highly exothermic). The product was extracted with DCM (3x), the combined organic layers were dried over Na2SO4 and concentrated to give the product as an oil (758 mg, 77 %). ES-MS m/z 231.2 (MH+); HPLC RT (min) 1.33 {method (A)}.
Step 3: Preparation of methyl 2-{r3-teit-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- yll amino I -5-methoxybenzoate
Under a nitrogen atmosphere, 3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- amine (259 mg, 0.56 mmol) (step 2) and methyl 2-bromo-5-methoxybenzoate (114.8 mg, 0.47 mmol) were combined in an oven-dried pressure tube. BESfAP (93.4 mg, 0.094 mmol), Pd2dba3 (85.8 mg, 0.094 mmol), and powdery cesium carbonate (pre-dried in a high vacuum oven) (458 mg, 1.41 mmol) were added subsequently, followed by toluene (2 mL). The pressure tube was sealed and the reaction mixture heated at 80 0C for 16 h. The mixture was cooled to rt, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient elution with 5 to 10% EtOAc in hexane to give the product as an oil (89 mg, 48%). 1H NMR (400 MHz, CD3CN) δ 9.00 (s, IH), 8.48 (d, IH), 8.44 (s, IH), 7.39 (d, IH), 7.32 (d, IH), 7.18 (d, IH), 7.09 (dd, IH), 6.23 (s, IH), 3.79 (s, 3H), 3.76 (s, 3H), 2.19 (s, 3H), 1.36 (s, 9H); ES-MS ni/z 395.2 (MH+); HPLC RT (min) 3.04 {method (A)}.
Step 4: Preparation of 2-{r3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-yllamino}-5- methoxybenzoic acid
Methyl 2-{[3-tert-butyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-yl]amino}-5- methoxybenzoate (83 mg, 0.21 mmol) (step 3) was dissolved in THF (3.O mL), and a solution of LiOH-H2O (26.5 mg, 0.63 mmol) in water (1.0 mL) was added, followed by a small amount of MeOH to homogenize the mixture. After stirring for 15 h at rt at 40 0C, the reaction mixture was cooled, the organic solvent removed under reduced pressure and the aq layer acidified by addition of 2N HCl. The mixture was extracted with EtOAc (2x), and the combined organic layers dried over Na2SO4 and concentrated to give a colorless solid. This solid was washed with a small amount of acetonitrile and dried under high vacuum to afford 48 mg (60%) of the product. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, IH), 8.51 (d, IH), 7.58 (d, IH), 7.44 (d, IH), 7.24 (d, IH), 7.12 (dd, IH), 6.24 (s, IH), 3.77 (s, 3H), 2.23 (s, 3H), 1.39 (s, 9H); ES-MS m/z 381.2 (MH+); HPLC RT (min) 2.72 {method (A)}.
Example 2
Preparation of 2-{r3-tert-butyl-l-(4-methvIpyridin-3-yI)-lH-pyrazoI-5-ynamϊno} benzoic acid
The product was obtained by using the same sequence as described for Example 1 with the difference that in step 3 methyl 2-bromo~5-methoxybenzoate was used as the starting material and Pd(OAc)2 was used instead of Pd2dba3 (equimolar amount). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, 2H), 7.92 (dd, IH), 7.44 (m, 2H), 7.23 (d, IH), 6.81 (t, IH), 6.32 (s, IH), 2.20 (s, 3H), 1.40 (s, 9H); ES-MS m/z 351.2 (MH+); HPLC RT (min) 2.74 {method (A)}. Example 3
Preparation of 5-chIoro-2-{r3-ethvI-l-(4-methvIpyridin-3-yl)-4-pyridin-3-yl-lH- pyrazoI-5-vπamino}benzoic acid
Step 1. Preparation of diphenylmethanone (4-methylpyridin-3-yl)hydrazone
A mixture of 3-bromo-4-methyl-pyridine (10 g, 58 mmol), benzophenone hydrazone (12.5 g, 64 mmol), sodium t-butoxide (7.8 g, 81 mmol), and Xantphos (67 mg, 0.12 mmol) in toluene (80 niL) was degassed for 15 min by passing nitrogen through. To this was added Pd(OAc)2 (26 mg, 0.12 mmol) and this mixture was heated at 850C overnight. It was cooled to rt and diluted with ethyl acetate (150 mL). The organic layer was washed with water (2 X 150 mL), then brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with methanol (50 mL) and filtered. The solid was washed with methanol (25 mL) and dried under vacuum to give the desired product N- benzhydrylidene-N'-(4-methyl-pyridin-3-yl)-hydrazine as brown solid (10 g, 91%). H NMR (300 MHz, CDCl3) δ 8.70 (br s, 1 H), 7.90 (d, 1 H), 7.65 - 7.30 (m, 11 H), 7.0 (d, 1 H), 1.90 (s, 3 H) LC-MS m/z 288.1 (MH+), HPLC RT (min) 2.45 {method (A)}.
Step 2. Preparation of 3-ethyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-arnine
To a suspension of 3-oxo-pentanenitrile (8.7 g, 90 mmol), diphenylmethanone (4- methylpyridin-3-yl)hydrazone (14.3 g, 50 mmol) in ethanol (170 mL), p-toluenesulfonic acid monohydrate (57 g, 300 mmol) in ethanol (170 mL) was added and it was heated at reflux overnight. The reaction mixture was cooled to rt and the solvent was removed under vacuum. Sat. aq. NaHCO3 solution (300 mL) was added and the aqueous layer was basified slowly with solid NaHCO3 to pH 9. The basic aqueous layer was extracted with dichloromethane (2 X 100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography (20-40% EtOAc/hexane) to give 3-ethyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-amine as brown solid (0.7 g, 7%). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, 1 H), 8.35 (s, 1 H), 7.40 (d, 1 H), 5.30 (s, 1 H), 5.05 (br s, 2 H), 2.40 (q, 2 H), 2.05 (s, 3 H), 1.10 (t, 3 H). LC-MS m/z 203.2 (MH+), HPLC RT (min) 1.05 {method (A)}.
Step 3. Preparation of methyl 5-chloro-2-{r3-ethyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- yll amino } benzoate
To a solution of 3-ethyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-amine (750 mg, 3.71 mmol), 2-bromo-5-chloro-benzoic acid methyl ester (925 mg, 3.71 mmol), BINAP (230 mg, 0.37 mmol), Pd2(dba)3 (203 mg, 0.22 mmol) in toluene (50 mL) was added Cs2CO3 (1687 mg, 5.19 mmol). The resulting reaction mixture was degassed for 15 min by passing nitrogen through and then heated at 118 °C overnight. The mixture was cooled to rt, diluted with ethyl acetate (300 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (20-40% EtOAc/hexane) separated the mixture to give the product methyl 5-chloro-2-{[3-ethyl-l-(4- methylpyridin-3-yl)-lH-pyrazol-5-yl]amino}benzoate as a light yellow solid (480 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 9.2 (br s, 1 H), 8.45 (d, 2 H), 7.8 (s, 1 H), 7.45 (d, 1 H), 7.35 (d, 1 H), 7.0 (d, 1 H), 6.3 (s, 1 H), 3.7 (s, 3 H), 2.6 (q, 2 H), 2.1 (s, 3 H), 1.1 (t, 3 H). LC-MS m/z 371.1 (MH+), HPLC RT (min) 3.20 {method (A)}. Step 4. Preparation of methyl 2-{ r4-bromo-3~emyl-l~(4-methyrpyridin-3-yl)-lH-pyrazol- 5-yll amino } -5-chlorobenzoate
To a solution of methyl 5-chloro-2-{[3-ethyl-l-(4-methylpyridin~3~yl)-lH-pyrazol-5- yl]amino}benzoate (500 mg, 1.35 mmol) in dichloromethane (20 mL) at - 5 0C in an ice bath, l,3-dibromo-5,5-dimethylhydantoin (192 mg, 0.67 mmol) was added slowly. The reaction mixture was allowed to warm to it in 2 h. The organic layer was washed with sat.
NaHCO3 (2 X 50 mL), followed by 10% sodium thiosulfate (2 X 50 mL), then brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the desired product methyl 2-{ [4- biOmo-3-ethyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-yl]amino}-5-chloro-benzoate as light yellow oil (400 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 9.0 (br s, 1 H), 8.8 (s, 1 H), 8.6 (d,
1 H), 7.7 (d, 1 H), 7.4 (m, 2 H), 6.5 (d, 2 H), 3.8 (s, 3 H), 2.6 (q, 2 H), 2.1 (s, 3 H), 1.1 (t, 3
H). LC-MS m/z 451.0 (MH+), HPLC RT (min) 3.60 {method (A)}.
Step 5. Preparation of 5-chloro-2-(r3-ethyl-l-(4-methylpyridin-3-yl)-4-pyridin-3-yl-lH- pyrazol-5-yll amino Ibenzoic acid
To a solution of methyl 2-{[4-bromo-3-ethyl-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- yl] amino} -5-chlorobenzoate (200 mg, 0.44 mmol) and 3-pyridineboronic acid (164 mg, 1.33 mmol) in DMF (5 mL) in a 10 mL microwave reactor tube was added 2N Na2CO3 (1.0 mL) and Pd(PPh3)4 (31 mg, 0.03 mmol). It was degassed for 10 min by passing nitrogen through. The reaction was performed in a microwave reactor at 150 0C for 15 min. The resulting reaction mixture was cooled to rt, filtered, and diluted with methanol, then separated by prep HPLC. The prep HPLC fractions were evaporated in vacuo. The solid was dissolved in ethyl acetate (5 mL) and sat. aq. Na2CO3 (2 mL) was added. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired product 5-chloro-2-{[3- ethyl-l-(4-methylpyridin-3-yl)-4-pyridin-3-yl-lH-pyrazol-5-yl]amino}benzoic acid as white solid (50 mg, 26%). 1H NMR (300 MHz, CDCl3) 6 8.45 - 8.35 (m, 5 H), 7.70 - 7.25 (m, 4 H), 6.80 (d, 1 H), 6.20 (d, 1 H), 2.70 (q, 2 H), 2.20 (s, 3 H), 1.10 (t, 3 H). LC-MS m/z 434.1 (MH+), HPLC RT (min) 2.22 {method (A)}.
Example 4
Preparation of 5-chIoro-2-{r3-ethyI-4-(6-methoxypyridin-3-yI)-l-pyridin-2-yl-lH- pyrazol-5-yπamino}benzoic acid
Step 1. Preparation of 3-ethyl-l-pyridin-2-yl-lH-pyrazol-5-amine
To a 100 mL 3-neck round-bottom flask fitted with argon inlet, septum and addition funnel was added 2-hydrazinopyridine (5.8 g, 59 mmol), 3-oxo-pentanenitrile (6.5 g, 59 rnriiol), acetic acid (7.1 g, 119 mmol) and ethanol (15 mL). It was heated at reflux overnight. The reaction mixture was cooled to rt and the solvent was removed in vacuo.
Ethyl acetate (150 mL) was added and the organic layer was washed with sat. NaHCO3 (100 mL), water (100 mL), and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20-40% EtOAc/hexane). The product 3-ethyl-l-pyridin-2-yl-lH-pyrazol-5-amine was obtained as yellow solid (2.7 g,
24%); 1H NMR (300 MHz, CDCl3) 6 8.30 (d, 2 H), 7.90 (t, 1 H), 7.80 (d, 1 H), 7.20 (d, 1 H),
6.70 (br s, 2 H), 5.25 (s, 1 H), 2.40 (q, 2 H), 1.20 (t, 3 H). LC-MS m/z 189.2 (MH+), HPLC
RT (min) 1.81 {method (A)}. Step 2. Preparation methyl 5-chloro-2-r(3-ethyl-l-pyridin-2-yl-lH-pyrazol-5-yl)amino1 benzoate
To a solution of 3-ethyl-l-pyridin-2-yl-lH-pyrazol-5-amine (300 mg, 1.59 mmol), 2- bromo-5-chloro-benzoic acid methyl ester (596 mg, 2.39 mmol), BINAP (99 mg, 0.16 mmol), Pd2(dba)3 (175 mg, 0.19 mmol) in toluene (60 mL) was added Cs2CO3 (725 mg, 2.23 mmol). The resulting reaction mixture was degassed for 15 min under nitrogen and then heated at 118 0C overnight. The mixture was then cooled to rt, diluted with ethyl acetate (300 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (20-40% EtOAc/hexane) separated the mixture to give the desired product methyl 5-chloro-2-[(3-ethyl-l-pyridin-2-yl- lH-pyrazol-5-yl)amino]benzoate as light yellow solid (100 mg, 18%). 1H NMR (300 MHz, CDCl3) δ 8.50 (d, 1 H), 8.0 (m, 1 H), 7.80 (m, 2 H), 7.60-7.50 (m, 2 H), 7.30 (d, 1 H), 6.25 (s, 1 H), 3.90 (s, 3 H), 2.60 (q, 2 H), 1.20 (t, 3 H). LC-MS m/z 357.2 (MH+), HPLC RT (min) 4.13 { method (A) } .
Step 3. Preparation of methyl 2-r(4-bromo-3-ethyl-l-pyridin-2-yl-lH-pyrazol-5-yl)amino1- 5-chlorobenzoate
To a solution of methyl 5-chloro-2-[(3-ethyl-l-pyridin-2-yl-lH-pyrazol-5- yl)amino]benzoate (100 mg, 0.28 mmol) in dichloromethane (5 mL) at - 5 0C (ice bath), 1,3- dibromo-5,5-dimethylhydantoin (40 mg, 0.14 mmol) was added slowly. It was allowed to warm to rt over 2 h. The organic layer was washed with sat. aq. NaHCO3 (2 X 10 mL), followed by 10% sodium thiosulfate (2 X 10 mL), then brine (10 mL), dried over Na2SO4 and concentrated in vacuo to give the desired product methyl 2-[(4-bromo-3-ethyl-l-pyridin- 2-yl-lH-pyrazol-5-yl)amino]-5-chlorobenzoate as light yellow oil (50 mg, 41%). 1H NMR (300 MHz, CDCl3) δ 8.4 (d, 1 H), 8.0 (m, 1 H), 7.80 (m, 1 H), 7.5 (d, 1 H), 7.30 (t, 1 H), 6.70 (d, 1 H), 3.90 (s, 3 H), 2.60 (q, 2 H), 1.20 (t, 3 H). LC-MS m/z 437.0 (MH+), HPLC RT (min) 4.45 {method (A)}.
Step 4. Preparation of 5-chloro-2-{ r3-ethyl-4-(6-methoxypyridm-3-yl)-l-pyridm-2~yl~lH- pyrazol-5-vnamino|benzoic acid
To a solution of methyl 2-[(4-bromo-3-emyl-l-pyridin-2-yl~lH-pyrazol-5~yl)amino]- 5-chlorobenzoate (50 mg, 0.11 mmol) and 2-methoxy-5-pyridineboronic acid (52 mg, 0.34 mmol) in DMF (1.5 mL) in a 10 mL microwave reactor tube was added 2N Na2CO3 (0.3 mL) and Pd(PPh3)4 (8 mg, 0.01 mmol). It was degassed for 10 min by passing nitrogen through reaction mixture. The reaction was performed in microwave reactor at 150 °C for
15 min. It was cooled to it and filtered and diluted with methanol, then separated by prep HPLC. The prep HPLC fraction was evaporated in vacuo. The solid was dissolved in ethyl acetate (5 mL) and sat. Na2CO3 (2 mL) was added. The organic layer was separated and dried over Na2SO4, evaporated the solvent to give the desired product 5-chloro-2-{[3-ethyl-
4-(6-methoxypyridin-3-yl)-l-pyridin-2-yl-lH-pyrazol-5-yl]amino}benzoic acid as white solid (7.4 mg, 14.3%). 1H NMR (300 MHz, CDCl3) 6 10.80 (br s, 1 H), 8.35 (d, 1 H), 8.10 (s, 1 H), 7.95 - 7.60 (m, 4 H), 7.30 (t, 1 H), 7.0 (d, 1 H), 6.8 (d, 1 H), 6.40 (d, 1 H), 3.80 (s, 3
H), 2.70 (q, 2 H), 1.20 (t, 3 H). LC-MS m/z 450.1 (MH+), HPLC RT (min) 3.48 {method
(A)}.
Example 5 Preparation of 5-chIoro-2-{r3-ethyl-4-(6-methoxypyridin-3-yI)-l-pyridin-4-yl-lH- pyrazoI-5-yIlaminolbenzoic acid
Step 1. Preparation of 3 -ethyl- 1 -p yridin-4-yl-lH-pyrazol-5-amine
To a 100 mL 3 -neck round-bottom flask fitted with argon inlet, septum and addition funnel was added 4-hydrazinopyridine (7.3 g, 67 mmol), 3-oxo-pentanenitrile (6.5 g, 67 mmol), acetic acid (8.03 g, 133.8 mmol) and ethanol (35 mL). It was heated at reflux overnight. The reaction mixture was cooled to rt and the solvent was evaporated, ethyl acetate (150 mL) was added and the organic layer was washed with sat. NaHCO3 (100 mL), water (100 mL), and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20-40% EtOAc/hexane). The product
3-ethyl-l-pyridin-4-yl-lH-pyrazol-5~amine was obtained as yellow solid (5.0 g, 40%); 1H
NMR (300 MHz, CDCl3) 6 8.50 (d, 2 H), 7.65 (d, 2 H), 5.60 (br s, 2 H), 5.40 (s, 1 H), 2.40
(q, 2 H), 1.05 (t, 3 H). LC-MS tn/z 189.1 (MH+), HPLC RT (min) 1.09 {method (A)}.
Step 2. Preparation of methyl 5-chloro-2-F(3-ethyl-l-pyridin-4-yl-lH-pyrazol-5-yl)arninol benzoate
To a solution of 3-ethyl-l-pyridin-4-yl-lH-pyrazol-5-amine (5.4 g, 28.7 mmol), 2-
Bromo-5-chloro-benzoic acid methyl ester (8.6 g, 34.4 mmol), BINAP (1.7 g, 2.87 mmol), Pd2(dba)3 (1.5 g, 1.7 mmol) in toluene (100 mL) was added Cs2CO3 (13 g, 40 mmol). The resulting reaction mixture was degassed for 15 min by passing nitrogen through and then heated at 118 °C overnight. The mixture was then cooled to rt, diluted with ethyl acetate and washed with water. The organic layer was then dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (20-40% EtOAc/hexane) separated the mixture to give the desired product methyl 5-chloro-2-[(3-ethyl-l-pyridin-4-yl-lH-pyrazol- 5-yl)amino] benzoate as light yellow solid (8.0 g, 78%). 1H NMR (300 MHz, CDCl3) δ 9.30 (br s, 1 H), 8.60 (d, 2 H), 7.80 (s, 1 H), 7.60 (d, 2 H), 7.40 (d, 1 H), 6.70 (d, 1 H), 6.40 (s, 1 H), 3.80 (s, 3 H), 2.50 (q, 2 H), 1.20 (t, 3 H). LC-MS in/z 357.1 (MH+), HPLC RT (min) 2.75 {method (A)}.
Step 3. Preparation of methyl 2-r(4-bromo-3-ethyl-l-pyridin-4-yl-lH-pyrazol-5-yl)aminol- 5-chlorobenzoate
To a solution of methyl 5-chloro-2-[(3-ethyl-l-pyridin-4-yl-lH-pyrazol-5-yl)amino] benzoate (3.0 g, 8.4 mmol) in dichloromethane (50 niL) at - 5 0C (ice bath), 1,3-dibromo- 5,5-dimethylhydantoin (1.2 g, 4.2 mmol) was added slowly. It was allowed to warm to rt over 2 h. The organic layer was washed with sat. NaHCO3 (2 X 20 mL), followed by 10% sodium thiosulfate (2 X 20 mL), then brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give the desired product methyl 2-[(4-bromo-3-ethyl-l-pyridin-4-yl-lH-pyrazol-5- yl)amino]-5-chlorobenzoate as light yellow oil (2.3 g, 63%). 1H NMR (300 MHz, CDCl3) δ 9.30 (br s, 1 H), 8.60 (d, 2 H), 7.80 (s, 1 H), 7.60 (d, 2 H), 7.40 (d, 1 H), 6.40 (d, 1 H), 3.80 (s, 3 H), 2.50 (q, 2 H), 1.20 (t, 3 H). LC-MS m/z 437.0 (MH+), HPLC RT (min) 3.07 {method (A)}.
Step 4. Preparation of 5-chloro-2-{r3-ethyl-4-f6-methoxypyridin-3-yl)-l-pyridin-4-yl-lH- pyrazol-5-vn amino I benzoic acid
To a solution of methyl 2-[(4-bromo-3-ethyl-l-pyridin-4-yl-lH-pyrazol-5-yl)arnino]- 5-chlorobenzoate (0.3 g, 0.7 mmol) and 2-methoxy-5-pyridineboronic acid (315 mg, 2 mmol) in DMF (3 mL) in a 10 mL microwave reactor tube was added 2N Na2CO3 (0.6 mL) and Pd(PPh3)4 (47 mg, 0.04 mmol). It was degassed for 10 min by passing nitrogen through. The reaction was performed in microwave reactor at 150 0C for 15 min. It was cooled to rt and filtered and diluted with methanol, then separated by prep HPLC. The prep HPLC fraction was evaporated in vacuo. The solid was dissolved in ethyl acetate (10 mL) and sat. Na2CO3 (4 mL) was added. The organic layer was separated and dried over Na2SO4, evaporated the solvent to give the desired product 5-chloro-2-{[3-ethyl-4-(6- methoxypyridin-3-yl)-l-pyridin-4-yl-lH-pyrazol-5-yl]amino {benzoic acid as white solid (101 mg, 32.6%). 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1 H), 8.60 (d, 2 H), 8.20 (s, 1 H), 7.80 (d, 2 H), 7.70 (s, 1 H), 7.20 (d, 1 H), 6.80 (d, 1 H), 6.30 (d, 1 H), 3.80 (s, 3 H), 2.70 (q, 2 H), 1.20 (t, 3 H). LC-MS m/z 450.2 (MH+), HPLC RT (min) 2.68 {method (A)}.
Example 6
Preparation of 2-{ri-(3,6-dimethylpyrazin-2-yI)-3-ethyI-4-pyridin-3-yl-lH-pyrazol-5- yllamino}-5-methyIbenzoic acid
Step 1: Preparation of 3-hvdrazino-2,5-dimethyrpyrazine
The mixture of 3-chloro-2,5-dimethylpyrazine (5.00 g, 35 mol) and hydrazine hydrate (17.53 g, 350 mol) was heated at 120 0C for 30 min. The mixture was cooled to it and diluted with hexane. The resulting solid was filtered, washed with hexane and dried under vacuum to afford 2.60 g (53%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1 H), 5.68 (s, 1 H), 3.99 (s, 2 H), 2.38 (s, 3 H), 2.31 (s, 3 H) ; ES-MS m/z 139.0 (MH+); HPLC RT (min) 1.12 {method (A)}.
Step 2: Preparation of l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH-pyrazol-5-amine
To a solution of 3-hydrazino-2,5-dimethylpyrazine (2.00 g, 14.47 mmol) in ethanol (40 mL) was added 3-oxo-pentanenitrile (2.53 g, 26.05 mmol) and a catalytic amount of cone. HCl. The resulting mixture was then heated at 1000C overnight. The reaction mixture was cooled to rt and concentrated to dryness. The residue was dissolved in EtOAc and washed with sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 10% hexane/EtOAc to afford 2.54 g (45%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.39 (s, 1 H), 5.47 (s, 1 H), 2.57 (s, 3 H), 2.55 (q, 2 H), 2.53 (s, 3 H), 1.15 (s, 3 H); ES-MS m/z 218.2 (MH+); HPLC RT (min) 1.31 {method (A)}.
Step 3: Preparation of methyl 2-{ri-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH-pyrazol-5-yll amino } -5-methylbenzoate
To a dried flask was added l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH-pyrazol-5-amine (1.48 g, 6.81 mmol), 2-iodo-5-methyl-benzoic acid methyl ester (1.79 g, 6.48 rnmol), Pd2(dba)3 (356.4 mg, 0.39 mmol), BINAP ( 404.0 mg, 0.65 mmol) and Cs2CO3 (3.17 g, 9.73 mmol). The flask was degassed followed by addition of toluene (50 mL), and the mixture was then heated at 120 0C for 20 h. The mixture was cooled to rt, filtered through a Celite plug using ethyl acetate as eluent, concentrated to dryness, and subjected to column chromatography purification using a gradient elution from 10% to 20% EtOAc in hexane to afford 1.62 g (67%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 10.50 (s, 1 H), 8.42 (s, 1 H), 7.75 (d, 1 H), 7.37 (d, 1 H), 7.29 (dd, 1 H), 6.23 (s, 1 H), 3.87 (s, 3 H), 2.70 (s, 3 H), 2.69 (q, 2 H), 2.59 (s, 3 H), 2.26 (s, 3 H), 1.32 (t, 3H); ES-MS m/z 366.2 (MH+); HPLC RT (min) 3.92 {method (A)}.
Step 4: Preparation of methyl 2-{ r4-bromo-l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH- pyrazol-5-yll amino I -5-methylbenzoate
To a cold solution of methyl 2-{ [l-(3,6-dimethylpyrazm-2-yl)-3-ethyl-lH~pyrazol-5- yl] amino} -5-methylbenzoate (1.62 g, 4.43 mmol) in DCM (30 mL) was slowly added 1,3- dibromo-5,5-dimethylhydantoin in DCM (20 mL) and the resulting mixture was stirred for 1 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, 10% sodium thiosufate solution and brine. The organic layer was dried and concentrated and the residue was purified by column chromatography eluting with 6% EtOAc in hexane to afford 1.65 g (84%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 9.71 (s, 1 H), 8.37 (s, 1 H), 7.67 (d, 1 H), 7.15 (dd, 1 H), 6.57 (d, 1 H), 3.88 (s, 3 H), 2.74 (q, 2 H), 2.55 (d, 6 H), 2.22 (s, 3 H), 1.34 (t, 3 H); ES-MS m/z 444.0 (MH+); HPLC RT (min) 4.20 {method (A)}.
Step 5: Preparation of methyl 2-(ri-(3,6-dimethylpyrazin-2-yl)-3-ethyl-4-pyridin-3-yl-lH- pyrazol-5-yll amino } -5-methylbenzoate
To a solution of methyl 2-{[4-bromo-l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-lH- pyrazol-5-yl] amino} -5-methylbenzoate (300 mg, 0.68 mmol) in toluene (6 mL) was added dioxane (2 mL), 3-pyridineboronic acid (165 mg, 1.35 mmol),), and 2 N K2CO3 (2 mL, 4.00 mmol). The flask was degassed with N2 followed by addition of Pd(PPh3)4 (59.3 mg, 0.081 mmol) and the mixture was then heated to 100 0C for 18 h. The mixture was cooled to rt, filtered through a Celite plug using EtOAc as eluent, concentrated to dryness, and subjected to purification by column chromatography on silica gel using a gradient elution from 6% to 10% EtOAc in hexanes to afford 82 mg (27%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 9.94 (s, 1 H), 8.52 (d, 1 H), 8.37 (s, 1 H), 8.32 (dd, 1 H), 7.83 (m, 1 H), 7.55 (s, 1 H), 7.35 (m, 1 H), 6.84 (dd, 1 H), 6.40 (d, 1 H), 3.88 (s, 3 H), 2.84 (q, 2 H), 2.60 (d, 6 H), 2.08 (s, 3 H), 1.26 (t, 3 H) ; ES-MS m/z 443.2 (MH+); HPLC RT (min) 2.63 {method (A)}.
Step 6: Preparation of 2-{ri-(3,6-dimethylpyrazin-2-yl)-3-ethyl-4-pyridin-3-yl-lH-pyrazol- 5-vHamino|-5-methylbenzoic acid
To a solution of methyl 2-{[l-(3,6-dimethylpyrazin-2-yl)-3-ethyl-4-ρyridin-3-yl-lH- pyrazol-5-yl] amino} -5-methylbenzoate (67 mg, 0.15 mmol) in methanol (4 mL) was added IN NaOH (ImL) and the mixture was then heated at 50 0C for 18 h. The reaction mixture was cooled to rt, concentrated and the pH of the solution was adjusted to 5 by addition of 10% phosphoric acid solution and the resulting solid was filtered, washed with water and dried under vacuum to give 50 mg (77%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.54 (s, 1 H), 8.39 (s, 1 H), 8.33 (d, 1 H), 7.87 (m, 1 H), 7.59 (d, 1 H), 7.38 (dd, 1 H), 6.84 (dd, 1 H), 6.40 (d, 1 H), 2.84 (q, 2 H), 2.60 (d, 6 H), 2.11 (s, 3 H), 1.28 (t, 3 H) ; ES-MS m/z 429.2 (MH+); HPLC RT (min) 2.40 {method (A) } .
Example 7
Preparation of 2-{r3-ethyI-4-(6-methoxypyridin-3-yI)-l-(3-methyIpyridin-2-yI)-lH- pyrazol-5-vnamino}-5-(trifluoromethoxy)benzoic acid
Step 1: Preparation of diphenylmethanone (3-methylpyridin-2-yl)hydrazone
A mixture of 2-bromo-3 -methyl pyridine (10.76 g, 62.55 mmol), benzophenone hydrazone (11.16 g, 56.87 mmol) and Xantphos (1.65 g, 2.84 mmol) in toluene (100 mL) was degassed by passing nitrogen through for 0.5 h. To the mixture was added sodium t-butoxide (13.12 g, 136.48 mmol) followed by Pd(OAc)2 (0.64 g, 2.84 mmol) and the mixture was stirred at 950C overnight. Some red solid was observed. The reaction mixture was concentrated to a third of its original volume. The red solid formed was collected by filtration, washed with hexanes, then dried under vacuum to give the desired compound (10.20 g, 62.4%). 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.96 (IH, d, J = 8 Hz), 7.90 (lH,s), 7.66-6.76 (1 IH, m), 6.79-6.76 (IH, t, J = 4.5 Hz), 2.20 (3H,S); LC-MS m/z 288.1 (MH+), HPLC RT (min) 2.38 {method (A)}.
Step 2: Preparation of 3-ethyl-l-(3-methylpyridm-2-ylHH-pyrazol-5-amine
3-Oxo-pentanenitrile (4.87 g, 26.10 mmol) and diphenylmethanone (3-methyl pyridin-2-yl)hydrazone (5.00 g, 17.40 mmol) were dissolved in anhydrous EtOH (150 mL). TsOH (3.31 g, 17.4 mmol) and cone. HCl (14.29 mL, 174.0 mmol) were added to the solution. The mixture was heated at reflux overnight. Additional 3-oxo-pentanenitrile (4.87 g, 26.10 mmol) was added. The mixture was refluxed another 24 h. EtOAc was added. The resulting mixture was basified by slow addition of sat. Na2CO3. The organic layer was dried over MgSO4 and then concentrated. Column chromatography purification (25% EtOAc/ hexane) afforded the title compound as a light yellow oil (1.5 g, 42.6%). 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.34 (IH, d, J = 2.8 Hz), 7.86-7.84 (IH, d, J = 9.6 Hz), 7.39-7.36 (IH, t, J =4.5 Hz), 5.46 (IH, S), 2.58-2.52 (2H, q, J = 6.0 Hz), 2.30 (3H, s), 1.26-1.23 (3H, t, J = 4.2 Hz); LC-MS m/z 203.1 (MH+), HPLC RT (min) 1.07 {method (A)}.
Step 3: Preparation of methyl 2-hvdroxy-5-(trifluoromethoxy)benzoate
Concentrated sulfuric acid (1.0 mL) was carefully added to a solution of 2-hydroxy- 5-trifluoromethoxy-benzoic acid (11.0 g, 49.52 mmol) in methanol (150 mL). The mixture was refluxed overnight. Additional sulfuric acid (1.0 mL) was added and the mixture was refluxed for another 3 days. The mixture was cooled to rt, concentrated and purified by a silica gel plug eluting with hexanes. After concentrating the desired fractions, colorless oil was obtained as pure product (11.4 g, 97.8%). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (IH, s), 7.61 (IH, s), 7.44-7.46 (IH, d, J = 8.0 Hz), 7.01-7.03 (IH, d, J = 8.0 Hz), 3.88 (3H, s); LC-MS m/z 234.9 [(M-H)-], HPLC RT (min) 5.05 {method (A)}.
Step 4: Preparation of methyl 5-(trifluoromethoxy)-2-{r(trifluoromethyl)sulfonvnoxy} benzoate
A solution of methyl 2-hydroxy-5-(trifluoromethoxy)benzoate (1.50 g, 6.35 mmol) in dry pyridine (20.0 mL) was cooled to -12 0C in an ice/acetone bath. Trifluoromethane- sulfonic anhydride (2.17 mL, 12.70 mmol) was added. The cooling bath was removed and the pink solution was stirred for 2 h. The mixture was then poured into water and extracted with DCM. The organic layer was dried over MgSO4. Column chromatography purification eluting with hexanes afforded the title compound as a colorless oil (1.30 g, 55.6%). 1H NMR (400 MHz, DMSOd6) δ 7.90 (IH, s), 7.81-7.78 (IH, d, J = 12.0 Hz), 7.69-7.67 (IH, d, J = 8.0 Hz), 3.87 (3H, s).
Step 5: Preparation of methyl 2-{ r3-ethyl-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-vHamino}- 5-(trifruoromethoxy)benzoate
To a mixture of 3-ethyl-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-amine (643mg, 3.18 mmol), methyl 5-(trifluoromethoxy)-2-{ [(trifluoromethyl)sulfonyl]oxy} benzoate (1.29 g, 3.50 mmol) in toluene (5.0 mL) were added BINAP (198 mg, 318 umol), Pd(OAc)2 (43 mg, 191 umol), and cesium carbonate (1.45 g, 4.45 mmol). The suspension was degassed for 10 min. and then heated at 1000C overnight. After it was cooled to rt, the mixture was concentrated to dryness. Column chromatography purification (eluting with hexanes then 10 % EtOAc/hexanes) afforded the title compound ( 1.0 g, 74.9%). 1H NMR (400 MHz, acetone-d6) δ 10.96 (IH, s), 8.47-8.46 (IH, d, J = 6.4 Hz), 7.86-7.83 (IH, d, J = 10.0 Hz), 7.80 (lH,s), 7.63-7.61 (IH, d, J = 9.6 Hz),7.47-7.44 (IH, d, J = 12.0 Hz), 7.36-7.33 (IH, dd, J = 7.6 Hz and 4.8 Hz), 6.31 (IH, s), 3.94 (3H, s), 2.71-2.65 (2H, q, J = 7.6 Hz), 2.50 (3H, s), 1.32-1.28 (3H, t, 6.8 Hz) ; LC-MS m/z 421.2 (MH+), HPLC RT (min) 4.01 {method (A)}.
Step 6: Preparation of methyl 2-{r4-bromo-3-ethyl-l-f3-methylpyridin-2-yl)-lH-pyrazol-5- yll amino } -5-(trifluorometlioxy)benzoate
To a solution of methyl 2-f r3-ethyl-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-yll amino ) -5-f trifruoromethoxy)benzoate (950 mg, 2.26 mmol) in DCM (10.0 mL) at 0-5 °C was slowly added l,3-dibromo-5,5-dimethylhydantoin (323 mg, 1.13 mmol). The resulting mixture was stirred for 2 h. It was then washed with sat. sodium bicarbonate twice, followed by 10% sodium thiosulfate twice and brine once. The organic layer was dried over MgSO4 and then concentrated. The residue was dried under vacuum. The titled compound was obtained as an off-white solid (900 mg, 79.8%). 1H NMR (400 MHz, acetone-d6) δ 10.01 (lH,s), 8.38-8.36 (IH, d, J = 6.4 Hz), 7.84-7.82 (IH, d, J = 9.2 Hz), 7.76 (IH, s), 7.42-7.40 (IH, d, J = 9.2 Hz), 7.37-7.34 (IH, dd, J = 7.6 Hz & 4.8 Hz), 6.87-6.84 (IH, d, J = 9.2 Hz), 3.94 (3H, s), 1.34-1.30 (3H, t, J = 7.6 Hz); LC-MS m/z 499.1 & 501.0 (MH+), HPLC RT (min) 4.31 {method (A)}.
Step 7: Preparation of 2-{ r3-ethyl-4-(6-methoxypyridin-3-yl)-l-(3-methylpyridin-2-yl)-lH- pyrazol-5-yll amino } -5-(trifluoromethoxy)benzoic acid
To a degassed solution of methyl 2-{[4-bromo-3-ethyl-l-(3-methylpyridin-2-yl)-lH- pyrazol-5-yl] amino }-5-(trifluoromethoxy)benzoate (100 mg, 0.2 mmol) and 6- methoxypyridine-3-boronic acid (91.90 mg, 0.60 mmol) in DMF (2 mL), 2N sodium carbonate (0.50 mL, 1.00 mmol) was added followed by Pd(PPh3)4 (13.89 mg, 0.012 mmol). The mixture was heated in a microwave reactor at 15O0C for 15 min. Reverse phase HPLC purification afforded pure product (15.3 mg, 14.9%). 1H NMR (400 MHz, CD3OD) δ 8.35 (IH, s), 8.09 (IH, s), 7.83-7.81 (IH, d, J = 6.8Hz ), 7.69-7.65 (2H, m), 6.90-6.87 (IH, d, J = 11.2 Hz), 6.75-6.72 (IH, d, J = 8.4 Hz), 6.53-6.50 (IH, d, J = 8.8 Hz), 3.85 (3H, s), 2.84-2.78 (2H, t, J = 11.4 Hz), 2.31 (3H, s), 1.30-1.14 (3H, t, J = 13.2 Hz); LC-MS m/z 514.1 (MH+), HPLC RT (min) 3.51 {method (A)}.
Using methods analogous to those described above in Examples 1-7, and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 1. In each case, the NMR spectrum was consistent with the assigned structure.
Table 1
2-[3-Cyclopropyl-4-
(2-methoxy-pyridin-3- yl)-l-(3-methyl- pyridin-2-yl)-lH- pyrazol-5-ylamino]-5- methyl-benzoic acid 3.29 456.2 (A)
2-[3-Cyclopropyl-l- (3 -methyl-pyridin-2- yl)-4-pyridin-3-yl-lH- pyrazol-5-ylamino]-5- ethyl-benzoic acid 2.51 440.2 (A)
2-[3-Cyclopropyl-4-
(6-methoxy-ρyridin-3- yl)-l-(3-methyl- pyridin-2-yl)-lH- pyrazol-5-ylamino]-5- ethyl-benzoic acid 3.50 470.2 (A)
2-[3-Cyclopropyl-4- (2-methoxy-pyridin-3 - yl)-l-(3-methyl- pyridin-2-yl)-lH- pyrazol-5-ylamino]-5- ethyl-benzoic acid 3.45 470.3 (A)
5-Chloro-2-(3-ethyl-l- pyridin-2-yl)-lH- pyrazol-5-ylamino)- benzoic acid 3.53 343.1 (A)
5-Ethyl-2-[3-ethyl-l- (3-methyl-pyridin-2- yl)-4-ρyridin-3-yl-lH- pyrazol-5-ylamino]- benzoic acid 2.45 428.2 (A) 2-[3-Ethyl-l-(3- methyl-pyridin-2-yl)- 4-pyridin-3-yl- 1 H- pyrazol-5-ylamino]-5- methyl-benzoic acid 2.39 414.2 (A)
2-[3-Ethyl-l-(3- methyl-pyridin-2-yl)- lH-pyrazol-5- ylamino]-5-methyl- benzoic acid 3.17 337.1 (A)
2-[3~Ethyl-4-(6- methoxy-pyridin-3 - yl)-l-(3-methyl- pyridin-2-yl)-lH- pyrazol-5-ylamino]-5- methyl-benzoic acid 3.21 444.1 (A)
2-[3-Ethyl-4-(3- fluoro-phenyl)- 1 -(3- methyl-pyridin-2-yl)- lH-pyrazol-5- ylamino]-5-methyl- benzoic acid 3.51 431.2 (A)
2- [4-Bromo-3-ethyl- 1 - (3-methyl-pyridin-2- yl)-lH-pyrazol-5- 415.0 ylamino]-5-methyl- & benzoic acid 3.50 417.0 (A)
2-[4-Bromo-3-ethyl-l-
(3-methyl-pyridin-2- yl)-lH-pyrazol-5- ylamino]-5- 484.9 trifluoromethoxy- & benzoic acid 3.73 486.9 (A) 5-Methyl-2-[3-methyl- l~(4-methyl-pyridin-3- yl)-lH-pyrazol-5- ylamino] -benzoic acid 2.94 323.2 (A)
5-Methoxy-2-[3- methyl- 1 - (4-methyl- pyridin-3~yl)-lH- pyrazol-5-ylamino]- benzoic acid 2.39 339.1 (A)
5-Fluoro-2-[3-methyl- 1 -(4-methyl-pyridin-3 - yl)-lH-pyrazol-5- ylamino] -benzoic acid 1.23 327.2 (A)
5-Chloro-2-[3-methyl- l-(4-methyl-pyridin-3- yl)-lH-pyrazol-5- ylamino] -benzoic acid 2.92 343.2 (A)
2-[3-Ethyl-l-(4- methyl-pyridin-3 -yl)- 4-pyridin-3-yl-lH- pyrazol-5-ylamino]-5- methyl-benzoic acid 2.14 414.2 (A)
2-[3-Ethyl-4-(6- methoxy-pyridin-3- yl)-l-(4~methyl- pyridin-3-yl)-lH- pyrazol-5-ylamino]-5- methyl-benzoic acid 2.82 444.1 (A) 2-[3-Ethyl-4-(2- fluoro-pyridin-3-yl)-l- (4~methyl~pyridin-3- yl)-lH-pyrazol-5- ylamino] -5-methyl- benzoic acid 2.74 432.1 (A)
2-[3-Ethyl-l-(4- methyl-pyridin-3 -yl)- 4-pyridin-4-yl-lH- pyrazol-5-ylamino] -5 - methyl-benzoic acid 2.07 414.2 (A)
2-[3-Ethyl-4-(6- fluoro-pyridin-3-yl)- 1 - (4-methyl-pyridin-3- yl)-lH-pyrazol-5- ylamino] -5-methyl- benzoic acid 2.88 432.2 (A)
2-[3-Ethyl-l-(2- methyl-pyridin-3-yl)- 4-pyridin-3-yl-lH- pyrazol-5 -ylamino] -5 - trifluoromethoxy- benzoic acid 2.37 484.2 (A)
2-[3-Ethyl-4-(6- methoxy-pyridin-3 - yl)-l-(2-methyl- pyridin-3-yl)-lH- pyrazol-5-ylamino]-5- trifluoromethoxy- benzoic acid 3.05 514.2 (A) 2-[3-Ethyl-4-(2- fluoro-pyridin-3-yl)-l-
(2-methyl-pyridin-3 - yl)-lH-pyrazol-5- ylamino]-5- trifluoromethoxy- benzoic acid 2.98 502.2 (A)
2-[3-Ethyl-4-(6- fluoro-pyridin-3 -yl) - 1 - (2-methyl-pyridin-3 - yl)-lH-pyrazol-5- ylamino]-5- trifluoromethoxy- benzoic acid 3.03 502.2 (A)
2-[3-Ethyl-l-(2- methyl-pyridin-3-yl)- 4-pyridin-4-yl- 1 H- pyrazol-5-ylamino] -5 - trifluoromethoxy- benzoic acid 2.29 484.1 (A)
2-[3-Ethyl-4-(2- methoxy-pyridin-3 - yl)-l-(2-methyl- pyridin-3-yl)-lH- pyrazol-5-ylamino]-5- trifluoromethoxy- benzoic acid 3.02 514.2 (A)
2-[3-Ethyl-4-(4- methoxy-pyridin-3- yl)-l-(2-methyl- pyridin-3-yl)-lH- pyrazol-5-ylamino]-5- trifluoromethoxy- benzoic acid 2.34 514.2 (A) 5-Chloro-2-(3-ethyl-l- pyridin-4-yl-4-pyridin- 3-yl-lH-pyrazol-5- ylamino)-benzoic acid 2.07 420.1 (A)
5-Chloro-2-[3-ethyl-4- (2-fluoro-pyridin-3 - yl)- 1 -pyridin-4-yl- 1 H- pyrazol-5-ylamino]- benzoic acid 2.6 438.2 (A)
5-Chloro-2-(3-ethyl- 1 ,4-di-pyridin-4-yl- lH-pyrazol-5- ylamino)-benzoic acid 2.03 420.1 (A)
5-Chloro-2-[3-ethyl-4- (6-fluoro-pyridin-3- yl)- 1 -pyridin-4-yl- 1 H- pyrazol-5-ylamino]- benzoic acid 2.82 438.1 (A)
2-(3-tert-Butyl-l- pyridin-4-yl-lH- pyrazol-5-ylamino)-5- methyl-benzoic acid 2.69 361.2 (A)
2-(3-tert-Butyl-l- pyridin-4-yl-lH- pyrazol-5-ylamino)-5- chloro-benzoic acid 2.79 371.3 (A)
2-[l-(3,6-Dimethyl- pyrazin-2-yl)-3-ethyl-
4-(6-fluoro-pyridin-3- yl)-lH-pyrazol-5- ylamino]-5-methyl-
69 benzoicacid 3.27 447.1 (A)
2-[3-Ethyl-4-(6- fluoro-pyridin-3-yl)- 1 -
(3-methyl-pyrazin-2- yl)~lH-pyrazol-5- ylamino]-5- trifluoromethoxy-
70 benzoic acid 3.37 503.1 (A)
2-[l-(3,6-Dimethyl- pyrazin-2-yl)-3-ethyl- 4-ρyridin-3-yl-lH- pyrazol-5 -ylamino] -5 -
71 ethyl-benzoic acid 2.94 443.2 (A)
2-[l-(3,6-Dimethyl- pyrazin-2-yl)-3-ethyl-
4-(6-methoxy-pyridin-
3-yl)-lH-pyrazol-5- ylamino]-5-ethyl-
72 benzoicacid 3.46 473.2 (A)
2-[l-(3,6-Dimethyl- pyrazin-2-yl)-3-ethyl- lH-pyrazol-5- ylamino]-5-methyl-
73 benzoic acid 3.29 352.1 (A) 2-[l-(3,6-Dimethyl- pyrazin-2-yl)-3 -ethyl- 4-(6-methoxy-pyridin- 3-yl)-lH-pyrazol-5- ylamino]-5-methyl-
74 benzoic acid 3.31 459.2 (A)
2-[3~Ethyl-4-(6- methoxy-pyridin-3- yl)-l-(3-methyl- pyrazin-2-yl)-lH- pyrazol-5 -ylamino] -5- trifluoromethoxy-
75 benzoic acid 2.42 515.2 (A)
2-[3-Ethyl-l-(3- methyl-pyrazin-2-yl)-
4-pyridin-3-yl-lH- pyrazol-5-ylamino]-5- trifluoromethoxy-
76 benzoicacid 2.53 485.2 (A)
2-[3-Ethyl-l-(3- methyl-pyrazin-2-yl)- lH-pyrazol-5- ylamino]-5- trifluoromethoxy-
77 benzoic acid 3.4 408.1 (A)
2-[l-(2,6-Dimethyl- pyrimidin-4-yl)-3- ethyl-4-pyridin-3-yl- lH-pyrazol-5- ylamino]-5-methyl-
78 benzoicacid 2.39 429.2 (A)
2-[l-(2,6-Dimethyl- pyrimidin-4-yl)-3- ethyl- 1 H-pyrazol-5- ylamino]-5-methyl-
79 benzoic acid 2.94 352.2 (A)
Example 82
Preparation of 5-CycIopropyl-2-r3-cyclopropyl-4-(6-methoxy-pyridin-3-yl)-l-(3- methvI-pyridin-2-yl)-lH-pyrazoI-5-ylamino1-benzoic acid
Step 1: Preparation of 3-cvclopropyl-3-oxo-propionitrile
A solution of ethyl cyclopropylcarboxylate (6.79 g, 58.891 mmol) and acetonitrile (2.90 g, 70 669 mmol) in THF (15 niL) was added dropwise to a suspension of sodium hydride (2.59 g, 64.78 mmol, 60%) in refluxing THF (60 mL). The mixture was heated to reflux under nitrogen for 15 h and cooled to rt. The mixture was diluted with ethyl acetate (150 mL) and washed with 2 N HCl (50 mL). The organic layer was isolated and washed with brine, then dried over MgSO4 and concentrated. The product was isolated as a golden yellow oil which was used in the next step without further purification. Step 2: Preparation of 3-Cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5-amine
To solution of S-cyclopropyl-S-oxo-propionitrile (6.4 g, 46.917 mmol) and N- benzhydrylidene-N'-(3~methyl-pyridin-2-yl)-hydrazine (7.49 g, 26.065 mmol) in ethanol
(133 mL) was added p-toluene sulfonic acid (4.958 g, 26.065 mmol) and cone HCl (10 mL).
The mixture was heated to reflux under nitrogen for 15 h and then concentrated. The residue was taken up in ethyl acetate (200 mL) and water (100 mL) and solid NaHCO3 added cautiously till there was no more bubbling (due to the formation of CO2 gas). The organic layer was isolated and washed with brine, then dried over Na2SO4 and concentrated. The product was isolated as a pink viscous oil (4.06 g, 40%) by column chromatography (20 %
EtOAc in hexanes, then 100 % EtOAc). ES-MS m/z 215.1 (MH+); HPLC RT (min) 1.16
{method (A)}.
Step 3: Preparation of 5-Bromo-2-r3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5- ylaminol-benzoic acid methyl ester
To a mixture of 3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5-amine (1.0 g, 4.667 mmol) and 2,5-dibromo-benzoic acid methyl ester (1.25 g, 4.243 mmol) in toluene (20 mL) was added BINAP (0.264 g, 0.424 mmol), followed by Pd2(dba)3 (0.233 g, 0.255 mmol). To the mixture was added cesium carbonate (1.94 g, 5.94 mmol) and the suspension was heated at 118 °C overnight and cooled to rt. The cooled reaction mixture was diluted with ethyl acetate and filtered through Celite and concentrated. The product (0.61 g, 31%) was isolated by column chromatography (25% ethyl acetate/ hexanes), then on the HPLC (20 to 90 % acetonitrile). MS m/z 427.1 (M+); HPLC RT (min) 4.06 {method (A)}. Step 4: Preparation of 5-Cvclopropyl-2-r3-cvclopropyl-l-(3-memyl-pyridin-2-yl)-lH- pyrazol-5-ylaminol-benzoic acid methyl ester
To a solution of 5-bromo-2-[3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5- ylamino] -benzoic acid methyl ester (0.6 g, 1.404 rnmol) in toluene (15 niL) was added cyclopropylboronic acid (0.181 mmol) and K2PO4 (1.042 g, 4.914 mmol) and tricyclohexylphosphine (0.039 g, 0.140 mmol). The mixture was degassed for 10 min and Pd(OAc)2 (0.019 g, 0.084 mmol) was added. The mixture was heated at 100 0C for 3 h and then cooled to it. The mixture was filtered through a plug of Celite. After the solution was acidified and concentrated, the residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the desired product (0.47 g, 86%). MS m/z 389.3 (MH+); HPLC RT (min) 4.00 {method (A)}.
Step 5: Preparation of 2-r4-Bromo-3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5- ylaminol-5-cvclopropyl-benzoic acid methyl ester
l,3-dibromo-5,5-dimethylhydantoin (0.158 g, 0.541 mmol) was added to a cooled solution of 5-cyclopropyl-2- [3-cyclopropyl- 1 -(3-methyl-pyridin-2-yl)- lH-pyrazol-5-yl amino] -benzoic acid methyl ester (0.42 g, 1.081 mmol) in DCM (12 mL). The mixture was stirred at 0 0C for 3 h and allowed to warm to it. The mixture was diluted with DCM and the organic phase was separated and washed with water, sat. NaHCO3 and 10% sodium thiosufate, and dried over MgSO4 and then concentrated. The product (0.41 g, 81%) was isolated by column chromatography (25% ethyl acetate/hexanes). MS m/z 467.2 (MH+); HPLC RT (min) 3.88 {method (A) } . Step 6: Preparation of 5-Cvclopropyl-2-r3-cyclopropyl-4-(6-methoxy-pyridin-3-yl)-l-(3- methyl-pyridin-2-yl)-lH-pyrazol-5-ylaminol-benzoic acid methyl ester
To a solution of 2-[4-bromo-3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5- ylamino]-5-cyclopropyl-benzoic acid methyl ester (0.11 g, 0.235 mmol) in DMF (2.5 mL) was added 4-methoxy 3-pyridine boronic acid (0.108 g, 0.706 mmol) and 2 N Na2CO3 (0.588 mL, 1.177 mmol). The solution was degassed for 10 min and Pd(PPh3)4 (0.016 g, 0.014 mmol) was added. The mixture was heated in the microwave at 150 0C for 15 min and cooled to rt. The mixture was filtered through a plug of Celite. After the solution was acidified and concentrated, the crude product was purified on the HPLC (20 to 90% acetonitrile) to give 0.060 g (51%) of the title compound. ES-MS m/z 496.2 (MH+); HPLC RT (min) 4.03 {method (A)}.
Step 7: Preparation of 5-Cyclopropyl-2-r3-cvclopropyl-4-(6-methoxy-pyridin-3-yl)-l-(3- methyl-pyridin-2-yl)-lH-pyrazol-5-ylaminol-benzoic acid
A mixture of 2-[4-bromo-3-cyclopropyl-l-(3-methyl-pyridin-2-yl)-lH-pyrazol-5-ylamino]- 5-cycloρroρyl-benzoic acid methyl ester (0.052 g, 0.105 mmol) and LiOH (0.025 g, 1.049 mmol) in THF (1.60 mL), methanol (0.8 mL) and water (0.8 mL) was stirred at rt for 18 h and concentrated. The residue was taken up in water and acidified, then filtered. The residue was dried in vacuo to give 0.020 g (45%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 0.42 (m, 2H), 0.81 (m, 2H), 1.04 (m, 4H), 1.72 (m, IH), 2.10 (m, IH), 2.30 (s, 3H), 4.20 (s, 3H), 6.40 (d, IH), 6.78 (d, IH), 7.32-7.30 (m, 2H), 7.50 (d, IH), 7.70 (d, IH), 7.92 (d, IH), 8.35 (dd, 2 H), 8.65 (s, IH). ES-MS m/z 482.2 (MH+); HPLC RT (min) 3.49 {method (A)}.
Using the methods analogous to those described above in Example 82 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 2. In each case, the NMR spectra were consistent with the assigned structures.
Table 2
Example 101 Preparation of 3-methyl-2-{r3-(4-methylphenyl)-l-pyridin-2-yl-lH-pyrazoI- 5-vHamino}benzoic acid
Step 1. Preparation of 3-(methylphenyl)-l-pyridin-2-yl-lH-pyrazol-5-amine
To a solution of 2-pyridinium hydrazine (3 g, 27 mmol), 4-tolueneacetonitrile (4.3 g, 27 mmol) in ethanol (60 mL), acetic acid (3.3 g, 55 mmol) was added. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to rt and the solvent was evaporated, ethyl acetate (150 mL) was added and the organic layer was washed with sat. NaHCO3 (100 mL), water (100 mL), and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. It was purified by flash chromatography (60-100% EtOAc/hexane) to give the desired product 3-(methylphenyl)-l-pyridin-2-yl-lH-pyrazol-5-amine as light brown solid (3.0 g, 44%). 1H NMR (300 MHz, CDCl3) δ 8.40 (d, 1 H), 7.95 (d, 2 H), 7.70 (d, 2 H), 7.20 (m, 3 H), 6.90 (br s, 2 H), 5.90 (s, 1 H), 2.30 (s, 2 H). LC-MS m/z 251.3 (MH+), HPLC RT (min) 3.56 { method (A) } .
Step 2. Preparation of 3-methyl-2-{ r3-(4-methylphenylH-pyridin-2-yl-lH~pyrazol- 5-vHamino|benzoic acid
To a solution of 3-(methylphenyl)-l-pyridin-2-yl-lH-pyrazol-5-amine (300 mg, 1.2 mmol) and 2-bromo-3-methyl-benzoic acid (257 mg, 1.2 mmol) in DMF (5 mL) was added potassium carbonate (198 mg, 1.44 mmol) and Cu(OAc)2 (8.68 mg, 0.05 mmol). It was heated at 155 0C overnight in a sealed tube. It was cooled to rt, filtered and diluted with methanol. The crude product was separated by prep HPLC. The desired fractions were concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and sat. Na2CO3 (4 mL) was added. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired product 3-methyl-2-{[3-(4-methylphenyl)-l-pyridin-2-yl-lH-pyrazol- 5-yl]amino}benzoic acid as white solid (206 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 10.6 (s, 1 H), 8.45 (d, 1 H), 8.0 (m, 2 H), 7.7 (m, 3 H), 7.45 (d, 2 H), 7.30 (d, 1 H), 7.2 (m, 3 H), 5.60 (s, 1 H), 2.30 (s, 3 H), 2.20 (s, 3 H). LC-MS m/z 385.2 (MH+), HPLC RT (min) 3.85 {method (A)}.
Example 102 Preparation of 2-r3-(3-EthvIphenyI)-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-yIamino1- benzoic acid
Step 1. Preparation of 2-Bromo-l-(3-ethyl-phenyl)-ethanone
To a solution of 3-ethylacetophenone (9.0 g, 60.7 mmol) in methanol (63 mL) and
1,4-dioxane (45 mL) cooled in an ice bath, bromine (9.7 g, 60.7 mmol) was added slowly dropwise over 10 min through an addition funnel. The resulting mixture was allowed to warm up to rt over 4 h. The solvent was removed and the residue was partitioned between ether (400 mL) and aq. sodium thiosulfate solution (300 mL). The organic layer was separated and dried over Na2SO4, and evaporated to give the product 2-bromo-l-(3-ethyl- phenyl)-ethanone as a clear oil (12 g, 87%). 1H NMR (300 MHz, CDCl3) δ 7.8 (m, 2 H), 7.5 (m, 2 H), 4.9 (s, 2 H), 2.65 (q, 2 H), 1.2 (t, 3 H).
Step 2. Preparation of 3-(3-Ethylphenyl)-3-oxo-propionitrile
To a solution of crude 2-bromo-l-(3-ethylphenyl)-ethanone (12 g, 52.8 mmol) in 95% ethanol (80 mL), a solution of potassium cyanide (6.8 g, 105.6 mmol) in water (53 niL) was added in one portion, and the mixture was stirred at rt for 2 h. The mixture was then poured onto a mixture of crushed ice and water and acidified with acetic acid (pH = 5-6). Ethyl acetate (500 mL) was added and the organic layer was separated, dried over sodium sulfate, and concentrated to give the product 3-(3-ethylphenyl)-3-oxopropionitrile as brown oil (9 g, 98%). 1U NMR (300 MHz, CDCl3) δ 7.8 (m, 2 H), 7.5 (m, 2 H), 4.75 (s, 2 H), 2.65 (q, 2 H), 1.2 (t, 3 H).
Step 3. Preparation of 3-(3-Ethylphenyl)-l-(4-methylpyridin-3-yl)-lH-pyrazol-5-amine
To a solution of N-benzhydrylidene-N'-(4-methyl-pyridin-3-yl)-hydrazine (1.6 g, 5.7 mmol), 3-(3-ethylphenyl)-3-oxo-propionitrile (1.8 g, 10.4 mmol) and p-toluenesulfonic acid monohydrate (2.2 g, 11.5 mmol) in ethanol (50 mL), 36% HCl solution (4.8 mL, 57.7 mmol) was added. It was heated at 80 0C overnight. The reaction mixture was cooled to rt and the solvent was removed under vacuum. Sat. aq. NaHCO3 solution (300 mL) was added slowly and the aqueous mixture was basified continuously with solid NaHCO3 to pH 9. The resulting mixture was extracted with dichloromethane (2 X 200 mL), dried over sodium sulfate, filtered and concentrated to dryness. It was purified by flash chromatography (20- 40% EtOAc/hexane) to give the desired product 3-(3-ethylphenyl)-l-(4-methyl-pyridin~3- yl)-lH-pyrazol-5-amine as brown solid (1.2 g, 75%). 1H NMR (300 MHz, CDCl3) δ 8.5 (d, 1 H), 8.4 (s, 1 H), 7.55 (s, 1 H), 7.45 (M, 1 H), 7.4 (d, 1 H), 7.25 (t, 1 H), 7.1 (d, 1 H), 5.8 (s, 1 H), 5.3 (br s, 2 H), 2.6 (q, 2 H), 2.2 (s, 3 H), 1.2 (t, 3 H). LC-MS rn/z 279.2 (MH+), HPLC RT (min) 2.38 {method (A) } .
Step 4. Preparation of 2-r3-(3-Ethyl-ρhenyl)-l-(4-methyl-pyridin-3-vD-lH-pyrazol-5- ylaminol-benzoic acid methyl ester
To a solution of 2-iodo-benzoic acid methyl ester (188 mg, 0.7 mmol), 3-(3-ethyl- phenyl)-l-(4-methyl-pyridin-3-yl)-lH-pyrazol-5-amine (200 mg, 0.7 mmol), BINAP (44.7 mg, 0.07 mmol), Pd2(dba)3 (32 mg, 0.04 mmol) in toluene (30 mL) was added Cs2CO3 (327 mg, 1 mmol). The resulting reaction mixture was degassed for 15 min by passing nitrogen through and then heated at 118 0C overnight. The mixture was cooled to rt, diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (20-30% EtOAc/hexane) separated the mixture to give the desired product 2-[3-(3-ethylphenyl)-l-(4- methylpyridin-3-yl)-lH-pyrazol-5-ylamino]-benzoic acid methyl ester as off white solid (26 mg, 8.7%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1 H), 8.65 (s, 1 H), 8.8 (d, 1 H), 7.8 (d, 1 H), 7.75 (s, 1 H), 7.65 (d, 1 H), 7.5 (m, 2 H), 7.3 (t, 1 H), 7.25 (d, 1 H), 7.2 (d, 1 H), 7.0 (s, 1 H), 6.8 (t, 1 H), 3.8 (t, 3 H), 2.2 (q, 2 H), 1.2 (t, 3 H). LC-MS m/z 413.2 (MH+), HPLC RT (min) 3.64 {method (A)}.
Step 5. Preparation of 2-f3-(3-Ethylphenyl)-l-(4-methylpyridin-3-yl)-lH-pyrazol-5- ylaminol -benzoic acid
To a solution of 2-[3-(3-ethylphenyl)-l-(4-methylpyridin-3-yl)~lH-pyrazol-5- ylamino] -benzoic acid methyl ester (100 mg, 0.23 mmol) in methanol (10 mL), sodium hydroxide solution (40 mg, 1 mmol) was added and it was heated to 55 0C for 3 h. The reaction mixture was filtered and the filtrate was separated by prep HPLC. The fractions were concentrated to dryness in vacuo, the solid was dissolved in ethyl acetate (5 mL) and sat. aq. Na2CO3 (3 mL) was added. The organic layer was separated, dried over sodium sulfate and concentrated to give the desired product 2-[3-(3-ethylphenyl)-l-(4-methyl- pyridin-3-yl)-lH-pyrazol-5-ylamino]-benzoic acid as white solid (42.6 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 10.0 (s, 1 H), 8.65 (s, 1 H), 8.8 (d, 1 H), 7.8 (d, 1 H), 7.75 (s, 1 H), 7.65 (d, 1 H), 7.5 (m, 2 H), 7.3 (t, 1 H), 7.25 (d, 1 H), 7.2 (d, 1 H), 7.0 (s, 1 H), 6.8 (t, 1 H), 2.2 (q, 2 H), 1.2 (t, 3 H). LC-MS m/z 399.2 (MH+), HPLC RT (min) 3.29 {method (A)}.
Example 103 Preparation of 2-r3-(3-EthvIphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-vIamino1-5- fluorobenzoic acid
Step 1: Synthesis of 2-r3-(3-Ethylphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-ylaminol- 5-fluorobenzoic acid methyl ester
To a mixture of 3-(3-ethylphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-amine (1.43 g, 5.137 mmol), and 2-bromo-5-fluorobenzoic acid methyl ester (1.09 g, 4.67 mmol) in toluene (28.6 mL) was added BINAP (0.291 g, 0.467 mmol) followed by Pd2(dba)3 (0.257 g, 0.280 mmol). To the mixture was added cesium carbonate (2.13 g, 6.538 mmol) and the suspension was heated at 118 0C overnight and cooled to rt. Then diluted with ethyl acetate and filtered through Celite and concentrated. The product was purified by column chromatography (25 % EtOAc in hexanes) to give a bright yellow solid (1.60 g, 72 %). ES- MS m/z 431.2 (MH+); HPLC RT (min) 4.67 {method (A)}.
Step 2: Preparation of 2-r3-(3-Ethylphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5- ylaminol-5-fluorobenzoic acid
A mixture of 2-[3-(3-ethylphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-ylamino]-5- fluorobenzoic acid methyl ester (1.55 g, 3.601 mmol) and LiOH (0.862 g, 36.01 mmol) in
THF (30 mL), methanol (15 mL) and water (15 mL) was stirred at rt for 18 h and concentrated. The residue was taken up in water and acidified with 2 N HCl and the resulting suspension was filtered. The yellow solid was rinsed with water and dried under suction over the weekend to give the title compound (1.43 g, 95 %). 1H NMR (400 MHz, CD3OD) 5 1.22 (t, 3H), 2.40 (s, 3H), 2.65 (q, 2H), 7.15-7.19 (m, 2H), 7.22-7.29 (m, 2H),
7.40-7.75 (m, 5H), 8.38 (d, IH). ES-MS m/z All 2 (MH+); HPLC RT (min) 4.05 {method
(A)}. Example 104
Preparation of 2-Fl-(3.,6-DimethvIpyrazin-2-yl)-3-(3-ethvIphenyl)-lH-pyrazol-5- ylaminol -benzoic acid
Step 1: Preparation of l-(3,6-Dimethylpyrazm-2-yl)-3-(3-ethylphenyl)-lH-ρyrazol-5-amine
To a solution of (3, 6-dimethyl-pyrazin-2-yl) -hydrazine (500 mg, 3.62 mmol) in ethanol (40 mL) was added 3-(3-ethyl-phenyl)-3-oxo-propionitrile (626 mg, 3.62 mmol) and a catalytic amount of HCl. The resulting mixture was then heated at 100 0C overnight. The reaction mixture was cooled to rt and concentrated to dryness. The residue was dissolved in EtOAc and washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 15% EtOAc in hexane to afford 456 mg (43%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.41 (s, 1 H), 7.61 (s, 1 H), 7.65 (d, 1 H), 7.29 (t, 1 H), 7.17 (d, 1 H), 5.96 (s, 1 H), 2.69 (q, 2 H), 2.66 (s, 3 H), 2.58 (s, 3 H), 1.15 (t, 3 H); ES-MS m/z 294.2 (MH+); HPLC RT (min) 3.05 {method (A)}.
Step 2: Preparation of 2-ri-C3,6-Dimethylpyrazin-2-yl)-3-('3-ethylphenyl)-lH-Pyrazol-5- ylaminol -benzoic acid methyl ester
To a dried flask was added l-(3,6-dimethylpyrazin-2-yl)-3-(3-ethylphenyl)-lH- pyrazol-5 amine (110 mg, 0.39 mmol), 2-iodobenzoic acid methyl ester (93.6 mg, 0.36 mmol), Pd2(dba)3 (19.6 mg, 0.021 mmol), BlNAP ( 22.3 mg, 0.036 mmol) and Cs2CO3 (174 mg, 0.54 mmol). The flask was degassed followed by addition of toluene (10 niL), and the mixture was then heated to 120 0C for 20 h. The mixture was cooled to rt, filtered through a Celite plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 30% to 100% acetonitrile in water to afford 72 mg (45%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.44 (s, 1 H), 7.95 (dd, 1 H), 7.72 (s, 1 H), 7.67 (d, 1 H), 7.55 (d, 1 H), 7.48 (t, 1 H), 7,34 (t, 1 H), 7.21 (d, 1 H), 6.86 (t, 1 H), 6.79 (s, 1 H), 3.87 (s, 3 H), 2.71 (m, 8 H), 1.28 (t, 3H); ES-MS m/z 428.2 (MH+); HPLC RT (min) 4.50 {method (A)}.
Step 3: Preparation of l-r2-(3,6-Dimethylpyrazin-2-yl)-3-(3-ethylphenyl)-lH-pyrazol-5- ylaminol -benzoic acid
To a solution of l-[2-(3,6-dimethylpyrazin-2-yl)-3-(3-ethylphenyl)-lH-pyrazol-5- ylamino] -benzoic acid methyl ester (60.0 mg, 0.14 mmol) in methanol (4 niL) was added IN NaOH (1 mL) and the mixture was then heated to 50 0C for 18 h. The reaction mixture was cooled to rt, concentrated and the pH of the solution was adjusted to 5 by addition of 10% phosphoric acid solution. The resulting solid was filtered, washed with water, and dried under vacuum to give 45 mg (78 %) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.44 (s, 1 H), 7.95 (dd, 1 H), 7.72 (s, 1 H), 7.67 (d, 1 H), 7.55 (d, 1 H), 7.48 (t, 1 H), 7,34 (t, 1 H), 7.21 (d, 1 H), 6.86 (t, 1 H), 6.79 (s, 1 H), 2.71 (q, 2 H), 2.69 (s, 6 H),1.28 (t, 3H); ES- MS tn/z 414.2 (MH+); HPLC RT (min) 3.89 {method (A)}.
Using the methods analogous to those described above in Examples 101-104 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 3. In each case, the NMR spectrum was consistent with the assigned structure.
Example 136
Preparation of 2-ri-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol-5- yllaminobenzoic acid hydrochloride
CIH
Step 1: Preparation of 4-hydrazino-3,5-dimethylpyridine
3,5-Dimethylpyridine N-oxide (10.0 g, 81.2 mmol) was consecutively treated with concentrated nitric acid (10.1 mL) and concentrated sulfuric acid (43.3 mL). The resulting mixture was stirred at 110 0C for 1.5 h. After cooling to room temperature, the mixture was poured into ice water and the pH was adjusted to 12 by addition of solid potassium hydroxide. The resulting precipitate was collected by filtration. The mother liquor was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvents were evaporated off. The residue was combined with the solid obtained by filtration yielding 3,5-dimethyl-4-nitropyridine N-oxide (7.5 g, 50%) which was used for the next step without further purification.
A solution of 3,5-dimethyl-4-nitropyridine N-oxide (5.7 g, 33.9 mmol) in dichloromethane (100 mL) was cooled to 0 °C and treated with phosphorous trichloride (22.0 mL, 44.1 mmol). The mixture was subsequently stirred at room temperature for 30 min. Under vigorous stirring, the mixture was then poured into a freshly prepared warm 2N sodium hydroxide solution (250 mL). Stirring was continued for 10 minutes and the resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and the solvents were evaporated off. The crude product was filtered over a short pad of silica using cyclohexane/ethyl acetate 2:1 yielding 3,5-dimethyl-4-nitropyridine (3.75 g, 69%). ES-MS m/z 152.9 (MH+); HPLC RT (min) 1.79 method (H).
3,5-Dimethyl-4~nitropyridine (3.78 g, 21.4 mmol) was dissolved in hydrazine monohydrate (75 mL) and the resulting solution was stirred at 100 0C for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl actetate (100 mL). The solution was washed with a mixture of brine and sodium hydroxide solution, dried over MgSO4 and concentrated under reduced pressure yielding 4-hydrazino-3,4-dimethyl pyridine (2.2 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 2 H), 5.31 (s, br, 1 H), 3.72 (s, br, 2 H), 2.28 (s, 6 H). MS (DClTNH3) m/z 138 (MH+).
Step 2: Preparation of l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol~5-amine
A solution of 4-hydrazino-3,4-dimethyl pyridine (500 mg, 3.65 mol) and 3-(3-ethyl- phenyl)-3-oxo-propionitrile (568 mg, 3.28 mmol; cf. example 102) in toluene (15 mL) was treated with molecular sieves (4A). The mixture was heated in a microwave oven at 160 0C for 12 h. The resulting suspension was decanted from the molecular sieves, the solid was collected by filtration and washed with diethylether yielding l-(3,5-dimethylpyridin-4-yl)-3-
(3-ethylphenyl)-lH-pyrazol-5-amine (485 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 8.46 (s,
2 H), 7.67 (s, 1 H), 7.59 (d, 1 H), 7.30 (dd, 1 H), 7.16 (d, 1 H), 6.00 (s, 1 H), 3.57 (s, br, 2
H), 2.68 (q, 2 H), 2.18 (s, 6H), 1.28 (t, 3H). ES-MS m/z 293.1 (MH+); HPLC RT (min) 2.00 {method (I)}.
Step 3: Preparation of methyl 2-{ri-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)- lH-pyrazol-5-yπamino Ibenzoate
A mixture of l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol-5-amine
(150 mg, 0.51 mmol), methyl 2-bromobenzoate (132 mg, 0.62 mmol), tris(dibenzylidenacetone)palladium (9.4 mg, 0.01 mmol), Xantphos (9.8 mg, 0.02 mmol), potassium carbonate (177 mg, 1.28 mmol) and phenyl boronic acid (3.1 mg, 0.03 mmol) in toluene (9 mL) was stirred over night at 120 °C. Additional Pd2(dba)3 (9.4 mg, 0.01 mmol) was added and the mixture was continued to stir for an additional 24 h. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was purified by preparative HPLC yielding methyl 2-{[l-(3,5-dimethylpyridin-4-yl)-3-(3- ethylphenyl)-lH-pyrazol-5-yl]amino}benzoate (75 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2 H), 7.94 (d, 1 H), 7.73 (s, 1 H), 7.67 (d, 1 H), 7.42 (m, 2 H), 7.35 (dd, 1 H), 7.20 (d, 1 H), 6.84 (dd, 1 H), 6.62 (s, 1 H), 3.78 (s, 3H), 2.71 (q, 2 H), 2.17 (s, 6 H), 1.29 (t, 3H); ES-MS m/z 421.1 (MH+); HPLC RT (min) 3.15 {method (H)}.
Step 4: Preparation of 2-ri-(3,5-dimethylpyridin-4-yl)-3-(3-ethvbhenyl)-lH-pyrazol-5- yliaminobenzoic acid hydrochloride
A solution of 2-{[l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)- lH-pyrazol-5-yl]amino}benzoate (300 mg, 0.70 mmol) in 1,4-dioxane (30 mL) was treated with lithium hydroxide (51 mg, 2.11 mmol) and water (15 mL). The resulting mixture was stirred at room temperature over night. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. Crystallization from diethylether/pentane afforded 2-[l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol- 5-yl]aminobenzoic acid hydrochloride (240 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 10.53 (s, IH), 8.50 (s, 2 H), 8.09 (d, 1 H), 7.75 (s, 1 H), 7.69 (d, 1 H), 7.51 (m, 2 H), 7.38 (dd, 1 H), 7.22 (d, 1 H), 6.92 (dd, 1 H), 6.67 (s, 1 H), 2.75 (q, 2 H), 2.24 (s, 6 H), 1.30 (t, 3H); ES- MS m/z 413.1 (MH+); HPLC RT (min) 2.73 {method (H)}.
Example 137
Preparation of 2-ri-(3,5-dimethyIpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazoI-5- yπamino-5-fluorobenzoic acid hydrochloride
Step 1: Preparation of methyl 2-{[l-('3,5-dimethylpyridm-4-yl)-3-(3-ethylphenyl)- lH-pyrazol-5-yl1arnino)-5-fluorobenzoate
A mixture of l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol-5-amine (100 mg, 0.34 mmol; cf. example 136), methyl 5-fluoro-2- {[(trifluoromethyl)sulfonyl]oxy}benzoate (124 mg, 0.41 mmol), tris(dibenzylidenacetone)- palladium (6.3 mg, 0.007 mmol), Xantphos (6.5 mg, 0.014 mmol), potassium carbonate (118 mg, 0.86 mmol) and phenyl boronic acid (2.1 mg, 0.017 mmol) in toluene (6 mL) was stirred over night at 120 0C. Additional Pd2(dba)3 (9.4 mg, 0.01 mmol) was added and the mixture was continued to stir for an additional 24 h. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was purified by preparative HPLC yielding methyl 2-{ [l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol-5- yl]amino}-5-fluoro-benzoate (75 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 2 H), 7.71 (s, 1 H), 7.68 (d, 1 H), 7.64 (dd, IH), 7.40 (m, 1 H), 7.34 (dd, 1 H), 7.21 (m, 2 H), 6.58 (s, 1 H), 3.80 (s, 3H), 2.70 (q, 2 H), 2.15 (s, 6 H), 1.26 (t, 3H); ES-MS m/z 445.2 (MH+); HPLC RT (min) 3.02 {method (H) }.
Step 2: Preparation of 2-ri-(3.5-dimethylpyridin-4-yl)-3-(3-ethylphenylVlH-pyrazol-5- vnamino-5-fluorobenzoic acid hydrochloride
A solution of 2-{[l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)- lH-pyrazol-5-yl] amino }-5-fluorobenzoate (42 mg, 0.09 mmol) in 1,4-dioxane (4 mL) was treated with lithium hydroxide (7 mg, 0.28 mmol) and water (2 mL). The resulting mixture was stirred at room temperature over night. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. Crystallization from diethylether/pentane afforded 2-[l-(3,5-dimethylpyridin-4-yl)-3-(3-ethylphenyl)-lH-pyrazol- 5-yl]aminobenzoic acid hydrochloride (30 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 10.42 (s, IH), 8.51 (s, 2 H), 7.81 (dd, 1 H), 7.75 (s, IH), 7.68 (d, 1 H), 7.49 (dd, IH), 7.37 (dd, 1 H), 7.25 (dd, 1 H), 7.21 (d, 1 H), 6.63 (s, 1 H), 2.71 (q, 2 H), 2.25 (s, 6 H), 1.30 (t, 3H); ES- MS m/z 431.2 (MH+); HPLC RT (min) 2.61 {method (F) }.
Using the methods analogous to those described above in Examples 136/137 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 4. In each case, the NMR spectrum was consistent with the assigned structure.
Table 4
Example 154
Preparation of S-cyclopropyl-l-rS-O-ethylphenyD-l-O-trifluoromethylpyridin^-yl)- lH-pyrazoI-5-yIaminol -benzoic acid
Step 1: Preparation of 3-(3-ethylphenyl)-l-(3-trifluoromemylpyridin-2-yl)-lH-pyrazol-5- amine
To a solution of 3-(3-ethyl-phenyl)-3-oxo-propionitrile (3.34 g, 19.31 mmol) and (3- trifluoromethylpyridin-2-yl)-hydrazine (1.90 g, 10.73 mmol) in EtOH (30 mL), was added
AcOH. The mixture was refluxed overnight, and then cooled to rt. The solvent was removed under vacuum, EtOAc was added, and the mixture was washed with sat. Na2CO3. The organic layer was dried over MgSO4 and the solvent was evaporated. Column chromatography purification (hexane, then 10% EtOAc/hexane) afforded the title compound (1.3 g, 20.1%). 1H NMR (400 MHz, CD3OD) δ ppm 8.75-8.74 (IH, d, J = 6.4 Hz), 8.39-8.36
(IH, d, J = 9.6 Hz), 7.63-7.55 (3H, m), 7.30-7.26 (IH, t, J = 8.0 Hz), 7.18-7.15 (IH, d, J =
10.0 Hz), 5.96 (IH, s), 2.72 -2.66 (2H, q, J = 7.6 Hz), 1.30-1.23 (3H, t, J = 6.8 Hz); LC-MS m/z 332>2 (MH+), HPLC RT (min) 3.35 {method (A)}.
Step 2: Preparation of 5-bromo-2-r3-f3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)-lH- PVrazol-5-ylaminol-benzoic acid methyl ester
To a solution of 3-(3-ethylphenyl)-l-(3-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-5- amine (600 mg, 1.44 mmol) and 2,5-dibromo-benzoic acid methyl ester (552 mg, 1.88 mmol) in toluene (8 mL) was added BESfAP (89.93 mg, 0.14 mmol), Pd2(dba)3 (79.36 mg, 0.087 mmol) and cesium carbonate (659 mg, 2.02 mmol). The suspension was heated at 110 0C overnight and then cooled to rt. Column chromatography purification (hexane then 10% EtOAc/hexane) afforded pure product (342 mg, 43.4%). 1H NMR (400 MHz, CD3OD) 6 ppm 10.70 (IH, s), 8.87-8.86 (IH, d, J = 6.4 Hz), 8.41-8.39 (IH, d, J = 9.6 Hz), 8.02 (IH, s), 7.72-7.79 (7H, m), 6.80 (IH, s), 3.90 (3H, s), 2.73-2.68 (2H, q, J = 7.6 Hz), 1.31-1.23 (3H, t, J = 14.4 Hz).
Step 3: Preparation of 5-cvclopropyl-2-r3-(3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)- lH-pyrazol-5-ylaminoi-benzoic acid methyl ester
5-Bromo-2-[3-(3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)-lH-pyrazol-5-ylamino] benzoic acid methyl ester (240 mg, 0.44 mmol), cyclopropylboronic acid (113 mg, 1.32 mmol), Pd(OAc)2 (5.92 mg, 0.026 mmol), tricyclohexylphosphine (12.32 mg, 0.044 mmol), K3PO4 (326 mg, 1.54 mmol) were added to toluene (2 mL) and water ( 0.5 mL). The mixture was degassed for 10 min, heated at 100 0C for 3 h then cooled to rt. Column chromatography purification (hexane then 10% EtOAc/hexane) afforded pure product (150 mg, 67.3%). 1H NMR (400 MHz, CD3OD) δ ppm 10.54 (IH, s), 8.89-8.88 (IH, d, J = 4.8 Hz), 8.41-8.39 (IH, d, J = 9.2 Hz), 7.71 - 7.19 (8H, m), 6.72 (IH, s), 3.89 (3H, s), 2.74-2.68 (2H, q, J = 7.6 Hz), 1.87-1.85 (IH, t, J = 4.0 Hz), 1.31-1.23 (3H, m), 1.00-0.91 (2H, m), 0.63-0.62 (2H,m); LC-MS m/z 507.2 (MH+), HPLC RT (min) 4.75 {method (A)}.
Step 4: Preparation of 5-cyclopropyl-2-r3-(3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)- lH-pyrazol-5-ylaminol-benzoic acid
To a solution of 5-cyclopropyl-2-[3-(3-ethylphenyl)-l-(3-trifluoromethylpyridin-2-yl)-lH- pyrazol-5-ylamino] -benzoic acid methyl ester (150 mg, 0.296 mmol) in methanol (2 mL) was added 0.5 mL saturated LiOH. The mixture was heated at 40 0C overnight then cooled to rt and acidified with 2N HCl. The solid was removed by filtration and washed with methanol. HPLC purification of the filtrate afforded pure product (130.9 mg, 89.8%). 1H NMR (400 MHz, CD3OD) δ ppm 8.92-8.90 (IH, d, J = 6.0 Hz), 8.39-8.36 (IH, d, J = 10.0 Hz), 7.70-7.62 (4H, m), 7.37-7.29 (2H, m), 7.20-7.18 (IH, d, J = 8.0 Hz), 7.10-7.08 (IH, d, J = 10.8 Hz), 6.58 (IH, s), 2.74-2.68 (2H, q, J = 7.6 Hz), 1.86 (IH, m), 1.31-1.27 (3H, t, J = 7.6 Hz), 0.92-0.87 (2H, m), 0.67-0.63 (2H, m); LC-MS m/z 493.2 (MH+), HPLC RT (min) 3.84 {method (A)}.
Example 155
Preparation of 2-r3-ethyl-4-(2-methoxy-phenyI)-l-(3-methyl-pyridin-2-yl)-lH-pyrazoI- S-ylammoi-S-trifluoromethoxy-benzoic acid
Step 1: Preparation of 2-r3-ethyl-4-(2-methoxyphenyl)-l-(3-methylpyridin-2-yl)-lH- pyrazol-5-ylaminol-5-trifluoromethoxy-benzoic acid methyl ester
To a solution of 2-[4-bromo-3-ethyl-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-ylamino]-5- trifluoromethoxy-benzoic acid methyl ester (0.1 g, 0.200 mmol) in DMF (2.13 mL) was added 2-methoxy benzene boronic acid (0.091 g, 0.601 mmol) and 2 N Na2CO3 (0.5 mL, 1.001 mmol) and the solution was degassed for 10 min and Pd(PPh3)4 (0.014 g, 0.012 mmol) was then added. The mixture was heated at 110 0C for 15 min and cooled to rt. The mixture was filtered through a plug of Celite and the solution was purified by HPLC (40 to 90 % acetonitrile) to give the desired product (0.04 g, 40%). 1H NMR (400 MHz, CD3OD) δ 1.17 (t, 3H), 2.34 (s, 3H), 2.67 (q, 2H), 3.78 (s, 3H), 3.85 (s, 3H), 6.60 (d, IH), 6.84-6.91 (m, 2H), 7.19-7.33 (m, 2H), 7.53 (d, IH), 7.74 (d, IH), 8.36 (d, IH) ES-MS m/z 527.2 (MH+); HPLC RT (min) 4.36 {method (B) }.
Step 2: Preparation of 243-ethyl-4-(2-memoxyphenylM-(3-methylρyridm-2-yl)-lH- pyrazol-5-ylaminol -5-trifluoromethoxy-benzoic acid
A mixture of 2-[3-ethyl-4-(2-methoxyphenyl)-l-(3-methylpyridin-2-yl)-lH-pyrazol-5-yl amino]-5-trifluoromethoxy-benzoic acid methyl ester (0.030 g, 0.057 mmol) and LiOH (0.004 g, 0.171 mmol) in THF (1.5 mL), methanol (0.75 mL) and water (0.75 mL) was stirred at 35 0C for 2 h and concentrated. The residue was taken up in water and acidified, then filtered. The filter cake was dissolved in methanol and purified on the HPLC (35 to 90 % acetonitrile) to the give the desired product (0.026 g, 88 %). 1H NMR (400 MHz, CD3OD) δ 1.17 (t, 3H), 2.35 (s, 3H), 2.65 (q, 2H), 3.78 (s, 3H), 6.51 (d, IH), 6.81-6.96 (m, 2H), 7.21-7.38 (m, 2H), 7.58 (d, IH), 7.76 (d, IH), 8.36 (d, IH). ES-MS m/z 513.3 (MH+); HPLC RT (min) 3.74 {method (B)}.
Using the methods analogous to those described above in Examples 155 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 5. In each case, the NMR spectrum was consistent with the assigned structure.
Table 5
Example 162
Preparation of 2-{r3-(3-Ethylphenyl)-l-(2-methylquinolin-4-vI)-lH-pyrazol-5-vn aminolbenzoic acid hydrochloride
Step 1: Preparation of l-(3-ethylphenyl)-3,3-dimercaptoprop-2-en-l-one
In analogy to F. C. V. Larsson, S.-O. Lawesson, (Tetrahedron, 1972, 28, 5341-5357.), a solution of 3-ethylacetophenone (5.00 g, 33.7 mmol) and carbon disulfide (2.57 g, 33.7 mmol) in diethylether (25 mL) was slowly added to an ice cooled suspension of potassium 2-methylpropan-2-olate (7.57 g, 67.4 mmol) in diethylether (100 mL). The reaction mixture was stirred for an additional 40 min at rt. The reaction mixture was partitioned between tert-butylmethylether and a water/ice mixture. The organic phase was discarded. The aqueous phase was acidified with IN sulfuric acid while cooled in an ice bath and it was extracted three times with tert-butylmethylether. The organic extracts were dried over NaCl and evaporated to dryness in vacuo. This material was used in the next step without further purification.
Step 2: Preparation of ethyl 2-{r3-(3-ethylphenyl)-3-oxopropanethiovHamino|benzoate
A mixture of l-(3-ethylphenyl)-3,3-dimercaptoprop-2-en-l-one (2.50 g, 11.1 mmol) and ethyl 2-aminobenzoate (2.93 g, 14.4 mmol) in acetonitrile (2.4 mL) was heated at reflux for
3 h. According to LC-MS, the reaction mixture consists of two major components. One was ethyl 2-aminobenzoate and the other component contained a mixture of tautomers of ethyl 2-
{[3-(3-ethylphenyl)-3-oxopropanethioyl]amino}benzoate. Ethyl 2-aminobenzoate was removed by preparative RP-HPLC eluting with an acetonitrile/water/0.05% trifluoroacetic acid gradient. All fractions containing correct molecular mass of the desired product or possible tautomers (2.3 g) were combined, concentrated, and used without further purification.
Step 3: Preparation of ethyl 2-{r3-(3-ethylphenyl)-l-(2-methylquinolin-4-yl)-lH-pyrazol-5- yliamino Ibenzoate
Ethyl 2-{[3-(3-ethylphenyl)-3-oxopropanethioyl]amino}benzoate (150 mg, 0.422 mmol) and 4-hydrazino-2-methylquinoline hydrochloride (115 mg, 0.549 mmol) were suspended in acetic acid (0.50 mL) and heated at reflux for 3 h. The crude product was purified by preparative RP-HPLC eluting with an acetonitrile/water/0.05% trifluoroacetic acid gradient to give the desired compound (106 mg, 53 %). 1H NMR (400 MHz, DMSO-d6) 5 9.65 (IH, s), 8.06 (IH, d), 7.87-7.73 (6H, m), 7.59 (IH, t), 7.48 (IH, t), 7.38 (2H, t), 7.24 (IH, d), 7.13 (IH, s), 6.87 (IH, t), 4.14 (2H, q), 2.75 (3H, s), 2.68 (2H, q), 1.21 (3H, t), 1.20 (3H, t); MS (ES+) m/z 477 (MH+), HPLC RT (min) 5.249 {method (D) }.
Step 4: Preparation of 2-{ r3-(3-ethylphenyl)-l-(2-methylquinolin-4-yl)-lH-pyrazol-5-yl1 amino I benzoic acid hydrochloride
To a suspension of ethyl 2-{[3-(3-ethylphenyl)-l-(2-methylquinolin-4-yl)-lH-pyrazol-5- yl] amino jbenzoate (80 mg, 0.169 mmol) in dioxane/water (2 mL/1 mL), 2 N LiOH in water (423 μl, 0.847 mmol) was added. The mixture was heated to reflux for 2 h. After it was cooled to rt, the reaction mixture was acidified with 2 N hydrochloric acid, and the resulting suspension was filtered, repeatedly washed with water, and dried in vacuo to yield the desired compound (19.6 mg, 26 %). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (IH, br s), 10.17 (IH, s), 8.05 (IH, d), 7.82-7.73 (4H, m), 7.71 (IH, s), 7.67 (IH, d), 7.60-7.43 (3H, m), 7.37 (IH, t), 7.22 (IH, d), 7.12 (IH, s), 6.85 (IH, t), 2.72 (3H, s), 2.68 (2H, q), 1.22 (3H, t); MS (ES+) m/z 449 (MH+), HPLC RT (min) 4.825 {method (D)] . Example 163
Preparation of 2-{ri-(3,5-dichIoropyridin-4-yI)-3-phenyl-lH-pyrazoI-5-vnamino} benzoic acid hydrochloride
Step 1: Preparation of 3,3-dimercapto-l-phenylprop-2-en-l-one
In analogy to F. C. V. Larsson, S.-O. Lawesson (Tetrahedron, 1972, 28, 5341-5357.), a solution of acetophenone (15.0 g, 125 mmol) and carbon disulfide (9.51 g, 125 mmol) in diethylether (50 mL) was slowly added to an ice cooled suspension of potassium 2- methylpropan-2-olate (28.1 g, 250 mmol) in diethylether (500 mL). The reaction mixture was stirred in the ice bath for additional 40 min. The reaction mixture was partitioned between tert-butylmethylether and a water/ice mixture. The organic phase was discarded. The aqueous phase was acidified with IN sulfuric acid in an ice bath and then extracted three times with tert-butylmethylether. The combined organic extracts were dried over NaCl and evaporated to dryness in vacuo. This material (21 g) was used in the following step without further purification.
Step 2: Preparation of ethyl 2-r(3~oxo~3-phenylpropanethioyl)aminolbenzoate
A mixture of 3,3-dimercapto-l-phenylprop-2-en-l-one (10.0 g, 50.9 mmol) and ethyl 2- aminobenzoate (10.9 g, 66.2 mmol) in acetonitrile (10 mL) was heated under reflux for 3 h. According to LC-MS analysis, the reaction mixture consisted of two major components. One was ethyl 2-aminobenzoate and the other component contained a mixture of tautomers of ethyl 2-[(3-oxo-3-phenylpropanethioyl)amino]benzoate. Ethyl 2-aminobenzoate was removed by preparative RP-HPLC eluting with an acetonitrile/water/0.05 % trifluoroacetic acid gradient. All fractions containing correct molecular mass of the desired product and possible tautomers (5.2 g) were combined, concentrated, and used in the next step without further purification.
Step 3: Preparation of ethyl 2-{ri-(3,5-dichloropyridin-4-yl)~3-phenyl-lH-pyrazol-5-yll amino jbenzoate
Ethyl 2-[(3-oxo-3-phenylpropanethioyl)amino]benzoate (150 mg, 0.458 mmol) and 3,5- dichloro-4-pyridylhydrazine (106 mg, 0.596 mmol) were suspended in acetic acid (0.50 mL) and heated to reflux for 4 h. The crude product was purified by preparative RP-HPLC with an acetonitrile/water/0.05 % trifluoroacetic acid gradient to give the desired product (73 mg, 35 %). 1H NMR (400 MHz, DMSO-d6) δ 9.55 (IH, s), 8.98 (2H, s), 7.95-7.86 (3H, m), 7.53 (IH, t), 7.44 (2H, t), 7.42-7.32 (2H, m), 7.10 (IH, s), 6.93 (IH, t), 4.22 (2H, q), 1.27 (3H, t); MS (ES+) m/z 453 (MH+, Main Isotope), HPLC RT (min) 5.843 {method (D) }.
Step 4: Preparation of 2-{ri-(3,5-dichloropyridin-4-yl)-3-phenyl-lH-pyrazol-5-yl1amino} benzoic acid hydrochloride
To a suspension of ethyl 2-{[l-(3,5-dichloropyridin-4-yl)-3-phenyl-lH-pyrazol-5-yl]amino} benzoate (40.1 mg, 0.0885 mmol) in methanol (2 mL), 2N LiOH in water (221 μl, 0.442 mmol) was added and the mixture was heated to reflux for 1 h. The reaction mixture was acidified with 2N hydrochloric acid and water, and the resulting suspension was filtered, repeatedly washed with water, and dried in vacuo to yield the desired product (32.3 mg, 85.8 0Zo). 1H NMR (400 MHz, DMSOd6) δ 13.48 (IH, br s), 10.20 (IH, s), 8.98 (2H, s), 7.93 (2H, d), 7.90 (IH, d), 7.55 (IH, t), 7.50-7.42 (3H, m), 7.39 (IH, t), 7.10 (IH, s), 6.92 (IH, t); MS (ES+) m/z 425 (MH+, Main Isotope), HPLC RT (min) 5.015 {method (C) }.
Using the methods analogous to those described above in Examples 162 and 163 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 6. In each case, the NMR spectrum was consistent with the assigned structure.
Table 6
Example 185
Preparation of 2-ri-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol-5- vnamino-5-methylbenzoic acid hydrochloride
Step 1: Preparation of 3-isopropoxybenzoic acid
A solution of 3-hydroxybenzoic acid (60.0 g, 434 mmol), 2-iodopropane (47.7 mL, 478 mmol) and 53.6 g (955 mmol) potassium hydroxide in water (250 mL) was stirred at reflux temperature for 2 h. After cooling to room temperature, the aqueous system was extracted with diethylether and the combined organic layers were discarded. By addition of concentrated hydrochloric acid and saturated with sodium chloride, the pH value of the aqueous layer was adjusted to 5. The aqueous layer was then extracted with cyclohexane. The combined organic extracts were washed with brine, dried over MgSO4 and the solvents were evaporated off. The resulting solid was dissolved in methanol (40 mL) and water (500 mL) was added under vigorous stirring. The precipitate thus formed was collected by filtration and dried under reduced pressure yielding 3-isopropoxybenzoic acid (24 g, 29%). ES-MS m/z 179.1 (M-H+); HPLC RT (min) 1.97 {method (H) }.
Step 2: Preparation of tert-butyl 2-cvano-3-(3-isopropoxyphenyl)-3-oxopropanoate
A solution of 3-isopropoxybenzoic acid (10.0 g, 55.5 mmol) in dichloromethane (200 mL) was consecutively treated with 2 drops of DMF and with oxalyl chloride (9.6 mL, 111 mmol). The solution was stirred at room temperature for 2 h and the volatiles were subsequently removed under reduced pressure yielding the corresponding acid chloride. Separately, a solution of tert-butylcyano acetate (13.3 g, 94.3 mmol) in THF (50 mL) was added dropwise to a solution of potassium tert-butylate (8.7 g, 77.7 mmol) in THF (300 mL). The resulting solution was stirred for 30 min. at room temperature and was subsequently cooled to 0 0C. To this solution, the acid chloride described above was added dropwise as solution in THF (60 mL). The resulting mixture was stirred for an additional 2 h at room temperature and the volatiles were subsequently removed under reduced pressure. Thereby, the maximum temperature must not exceed 40 0C. The residue was dissolved in diethylether (250 mL) and the organic solution was extracted with an aqueous potassium hydroxide solution (1%). The aqueous extracts were acidified with hydrochloric acid to pH 1, saturated with sodium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and the volatiles were removed under reduced pressure yielding tert-butyl 2-cyano-3-(3-isopropoxyphenyl)-3-oxopropanoate (10.3 g, 53%). 1H NMR (400 MHz, CDCl3) δ 14.40 (s, IH), 7.53 (d, IH), 7.45 (s, IH), 7.36 (dd, IH), 7.08 (dd, IH), 4.57 (hept., IH), 1.61 (s, 9H), 1.35 (d, 6H). MS (ES") m/z 302.1 (M-H+), HPLC RT (min) 3.11 {method (H) }.
Step 3: Preparation of 3-(3-isopropoxyphenyl)-3-oxopropanenitrile
A solution of tert-butyl 2-cyano-3-(3-isopropoxyphenyl)-3-oxopropanoate (20.0 g, 65.9 mmol) in toluene (400 mL) was treated with para-toluenesulfonic acid (343 mg, 1.65 mmol) and the resulting solution was stirred at reflux temperature over night. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was treated with acetonitrile (300 mL) and the resulting suspension is filtered. The solvent was removed from the filtrate and the residue was re-dissolved in ethylacetate. The organic solution was extracted with an aqueous 2% potassium hydroxide solution. The pH of the combined extracts was adjusted to 7.5 and the aqueous solution was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvents were removed under reduced pressure furnishing 3-(3-isopropoxyphenyl)-3- oxopropanenitrile (10.4 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 3H), 7.15 (dd, IH), 4.60 (hept., IH), 4.05 (s, 2H), 1.35 (d, 6H). MS (ES") m/z 202.2 (M-H+), HPLC RT (min) 2.02 {method (H) }.
Step 4: Preparation of l-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol- 5-amine
A solution of 4-hydrazino-3,4-dimethyl pyridine (120 mg, 0.88 mol) and 3-(3- isopropoxyphenyl)-3-oxopropanenitrile (187 mg, 0.92 mmol) in xylene (4 niL) was treated with molecular sieves (4A). The mixture was heated at 150 0C for 2 days. The resulting suspension was decanted from the molecular sieves, the volatiles were removed under reduced pressure and the residue was purified by preparative HPLC furnishing l-(3,5- dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol-5-amine (160 mg, 50%). 1H
NMR (400 MHz, CDCl3) δ 8.47 (s, 2 H), 7.33 (m, 2 H), 7.27 (dd, 1 H), 6.83 (dd, 1 H), 5.96
(s, 1 H), 4.60 (hept, IH), 3.58 (s, br, 2 H), 2.18 (s, 6H), 1.33 (d, 6H). ES-MS m/z 323.3 (MH+); HPLC RT (min) 1.83 {method (F) }.
Step 5: Preparation of methyl 2-{ri-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)- 1 H-p yrazol-5- yll amino } -5-methylbenzoate
A mixture of l-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol-5- amine (80 mg, 0.25 mmol), methyl 2-bromo5-methylbenzoate (68 mg, 0.30 mmol), tris(dibenzylidenacetone)palladium (4.5 mg, 0.005 mmol), Xantphos (4.7 mg, 0.01 mmol), potassium carbonate (86 mg, 0.62 mmol) and phenyl boronic acid (1.5 mg, 0.012mmol) in toluene (4.5 mL) was stirred over night at 120 0C. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was purified by preparative HPLC yielding methyl 2-{[l-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH- pyrazol-5-yl]amino}-5-methylbenzoate (80 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2 H), 7.73 (s, 1 H), 7.42 (m, 2 H), 7.33 (dd, 1 H), 7.27 (dd, 1 H), 6.86 (dd, 1 H), 6.57 (s, 1 H), 4.62 (hept, IH), 3.78 (s, 3H), 2.32 (s, 3 H), 2.14 (s, 6 H), 1.35 (d, 6H); ES-MS m/z 427.1 (MH+); ES-MS m/z 471.2 (MH+); HPLC RT (min) 3.08 {method (F)}.
Step 6: Preparation of 2-ri-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol- 5-yl1amino-5-methylbenzoic acid hydrochloride
A solution of 2-{[l-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol- 5-yl] amino }-5~methylbenzoate (70 mg, 0.15 mmol) in 1,4-dioxane (4 mL) was treated with lithium hydroxide (14 mg, 0.60 mmol) and water (2 mL). The resulting mixture was stirred at room temperature for 4 h. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Crystallization from diethylether/pentane afforded 2-[l-(3,5-dimethylpyridin-4-yl)-3-(3-isopropoxyphenyl)-lH-pyrazol-5-yl]amino-5-methyl- benzoic acid hydrochloride (60 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 10.38 (s, IH), 8.49 (s, 2 H), 7.92 (s, 1 H), 7.42 (m, 3 H), 7.33 (m, 2 H), 6.89 (dd, 1 H), 6.60 (s, 1 H), 4.65 (hept, IH), 2.33 (s, 3 H), 2.23 (s, 6 H), 1.35 (d, 6H); ES-MS m/z 457.1 (MH+); HPLC RT (min) 2.92 {method (I)}.
Using the methods analogous to those described above in Example 185 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 7. In each case, the NMR spectrum was consistent with the assigned structure. Table 7
Example 198
Preparation of 2-ri-(3,6-dimethylpyrazin-2-yl)-3-(3-isopropylphenyl)-lH-pyrazol-5- yllamino-4-fluorobenzoic acid
Step 1: Preparation of 3-isopropylbenzoic acid
3-isopropylbenzoic acid was prepared following a known literature procedure from 1-bromo 3-isoproylbenzene (Smith, J.G.; Turle, R.A.; /. Org. Chem. 1972, 37, 126-131).
The following steps of the synthesis were performed analogously to the procedure described for Example 185 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.). The final product 2-[l-(3,6-dimethylpyrazin-2-yl)-3-(3- isopropylphenyl)-lH-pyrazol-5-yl]amino-4-fluorobenzoic acid was isolated in a total yield of 62.6 mg (6.6% over 5 steps). 1H NMR (400 MHz, DMSO-d6) δ 13.32 (IH, br s), δ 11.05 (s, IH), 8.53 (s, 1 H), 7.96 (t, 1 H), 7.82 (s, 1 H), 7.76 (d, 1 H), 7.37 (t, 1 H), 7.26 (m, 2 H), 7.14 (s, 1 H), 6.71 (dd, 1 H), 2.95 (hept, IH), 2.66 (s, 3 H), 2.61 (s, 6 H), 1.25 (d, 6H); ES- MS m/z 455.0 (MH+); HPLC RT (min) 3.15 {method (H)}.
Using the methods analogous to those described above in Example 198 and by selecting the appropriate starting materials and reagents (e.g. solvents, catalysts, etc.), additional compounds of the invention were prepared. These compounds are illustrated in Table 8. In each case, the NMR spectrum was consistent with the assigned structure.
Table 8
Example 211
Preparation of 2-{ri-(3,6-dimethylpyrazin-2-yl)-3-(3-ethyIphenyl)-lH-pyrazol-5-yll amino|-N-r(4-fluorophenyl)sulfonyllbenzamide
A solution of 2-{ [l-(3,6-dimethylpyrazin-2-yl)-3-(3-ethylphenyl)-lH-pyrazol-5-yl]amino} benzoic acid (40 mg, 0.097 mmol), 4-fluorobenzenesulfonicacid amide (18.6 mg, 0.106 mmol), 1,3-dicyclohexyl carbodiimide (22.0 mg, 0.106 mmol), and 4-dimethyl- aminopyridine (13.0 mg, 0.106 mmol) in dichloromethane (5 mL) was stirred at it overnight. The reaction mixture was washed with IN hydrochloric acid and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by preparative RP-HPLC with a water/acetonitrile/0.05% trifluoroacetic acid gradient to yield the desired product (16 mg, 30 %). 1H NMR (400 MHz, DMSO-d6) δ 10.7 (IH, br s), 8.51 (IH, s), 8.06-8.00 (2H, m), 7.88 (IH, d), 7.73 (IH, s), 7.71 (IH, d), 7.58-7.41 (4H, m), 7.34 (IH, t), 7.21 (IH, d), 6.92 (IH, t), 6.89 (IH, s), 2.66 (2H, q), 2.64 (3H, s), 2.57 (3H, s), 1.22 (3H, t); MS (ES+) m/z 571 (MH+), HPLC RT (min) 5.641 {method (D)}.
Example 212 Preparation of 2-[3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)-lH-pyrazol-5-yl]amino-5- methylbenzoic acid
Step 1: Preparation of 3-(3-isopropoxyphenvD-lH-pyrazol-5-amine
To a solution of 3-(3-isopropoxyphenyl)-3-oxopropanenitril (1.00 g, 4.92 mmol) and hydrazine hydrate (0.369 g, 7.38 mmol) in toluene (30 mL), molecular sieves (4A, 30 g) and acetic acid (0.7 mL) were added. The reaction mixture was stirred at 100 0C for 2 h. After cooling down to it, 6N HCl (30 mL) was added and the resulting solution was extracted with ethyl acetate. The aqueous solution was brought to pH 8 by addition of solid NaOH. The basic solution was extracted with ethyl acetate. The combined organic layers were washed (brine), dried (MgSO4), filtered and concentrated in vacuo. The product (1.1 g, 90%) was used in the following step without further purification.
ES-MS m/z 2.18 (MH+); HPLC RT (min) 2.83 {method (K).
Step 2: Preparation of 3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)-lH-pyrazol-5-amine
A solution of 3-(3-isopropoxyphenyl)-lH-pyrazol-5-amine (100 mg, 0.46 mmol), 2-bromo- 3-methylthiophene (0.12 g, 0.69 mmol), trans-N,N'-dimethyl-l,2-cyclohexandiamine (13 mg, 0.092 mmol), copper iodide (18 mg, 0.092 mmol), copper (I) oxide (13 mg, 0.09 mmol) and cesium carbonate (0.3 g, 0.09 mmol) in N-methyl pyrolidone (5 mL) was heated in a microwave reactor for 45 min at 220 0C. The reaction mixture was cooled to it, filtered
(celite) and concentrated in vacuo. The crude product was purified by preparative RP-HPLC to yield the desired product (29 mg, 19 %).
MS (ES+) m/z 314.1 (MH+), HPLC RT (min) 2.48 {method (I)}. Step 3: Preparation of methyl 2-{r3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)- lH-pyrazol-5-vnamino}-5-methylbenzoate
A mixture of 3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)-lH-pyrazol-5-amine (40 mg, 0.13 mmol), methyl 2-bromo-5-methylbenzoate (35 mg, 0.15 mmol), tris(dibenzylidenacetone)palladium (2.3 mg, 0.003 mmol), Xantphos (2.4 mg, 0.005 mmol), potassium carbonate (44 mg, 0.32 mmol) and phenyl boronic acid (0.8 mg, 0.006 mmol) in toluene (3 mL) was stirred over night at 120 0C. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC yielding 2-{ [3-(3-isopropoxyphenyl)-l~(3-methyl-2-thienyl)-lH-pyrazol-5- yl] amino }-5-methylbenzoate (19 mg, 32%). ES-MS m/z 427.1 (MH+); ES-MS m/z 462.1 (MH+); HPLC RT (min) 3.26 {method (F).
Step 4: Preparation of 2-{r3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)-lH-pyrazol- 5-vnamino|-5-methylbenzoic acid
A solution of 2-{[3-(3-isopropoxyphenyl)-l-(3-methyl-2-thienyl)-lH-pyrazol-5-yl]amino}- 5-methylbenzoate (19 mg, 0.04 mmol) in 1,4-dioxane (2 mL) was treated with lithium hydroxide (3 mg, 0.12 mmol) and water (1 mL). The resulting mixture was stirred at room temperature over night. After acidification with hydrochloric acid (IN), the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding 2-{[3-(3-isopropoxyphenyl)~l-(3- methyl-2-thienyl)-lH-pyrazol-5-yl]amino}-5-methylbenzoic acid (18 mg, 97 %). 1H NMR (400 MHz, CDCl3) δ 9.54 (s, INH), 7.41-7.48 (m, 2 H), 7.24-7.34 (m, 6 H), 6.92 (d, 1 H), 6.88 (dd, 1 H), 6.53 (s, 1 H), 6.60 (m, 1 H), 4.65 (hept., IH), 2,33 (s, 3 H), 2.13 (s, 3 H), 1.35 (d, 6 H); ES-MS m/z 448.1 (MH+); HPLC RT (min) 2.91 {method (F).
Example 213 Preparation of 2-r3-(3-ethoxyphenyl)-l-(4-methyI-3-thienyl)-lH-pyrazol-5-vnamino-4- fluorobenzoic acid
Step 1: Preparation of di-tert-butyl l-(4-methyl-3-thienyl)hydrazine-l,2-dicarboxylate
To a solution of 3-bromo-4-methylthiophene (3 g, 16.9 mmol) in THF (30 rnL), nBuLi (17.9 mL, 1.6 M in hexane) was added at -78 °C. After stirring for 60 min, di-tert-butyl-(E)- diazene-l,2-dicarboxylate (3 g, 13 mmol) dissolved in THF (20 mL) was added. The resulting mixture was stirred for 1 h at -78 0C, then slowly warmed to 0 0C and water (50 mL ) was added. After acidification (IN HCl), the solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The product was purified by Biotage MPLC technique (2.4 g, 39%).
ES-MS m/z 429.1 (MH+); HPLC RT (min) 2.67 {method (J)}. Step 2: Preparation of (4-methyl-3-thienyl)hvdrazine hydrochloride
Di-tert-butyl l-(4-methyl-3-thienyl)hydrazine-l,2-dicarboxylate ( 182 mg, 0.05 mmol) was dissolved in 5 mL HCl in dioxane (2.5 M) and stirred for 30 min at rt. The resulting reaction mixture was concentrated in vacuo. The resulting solid was used without further purification (78 mg, 86 %).
ES-MS m/z 129.0 (MH+); HPLC RT (min) 0.85 {method (K)}.
Step 3: Preparation of 3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5-amine
(4-Methyl-3-thienyl)hydrazine hydrochloride (73 mg, 0.36 mmol) and 3-(3-ethoxyphenyl)-3- oxopropanenitrile (68 mg, 0.36 mmol) were suspended in toluene (3.5 mL). Molecular sieves (0.5 g, 3 A) were added and the suspension was stirred over night at 120 0C. After cooling to rt and filtering, the crude product was purified by preparative RP-HPLC with a water/acetonitrile/0.05% hydrochloric acid gradient to yield the desired product (47 mg, 36 %). ES-MS m/z 300.1 (MH+); HPLC RT (min) 2.24 {method (J)}.
Step 4: Preparation of methyl 2-{r3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5- yll amino } -4-fluorobenzoate
A mixture of 3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5-amine (45 mg, 0.13 mmol), methyl 4-fluoro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (61 mg, 0.20 mmol), tris(dibenzylidenacetone)palladium (4.6 mg, 0.005 mmol), Xantphos (4.8 mg, 0.01 mmol), potassium carbonate (44 mg, 0.32 mmol) and phenyl boronic acid (1.5 mg, 0.013 mmol) in toluene (2 mL) was stirred over night at 120 0C. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC yielding 2-{ [3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5-yl]amino}-4- fluorobenzoate (27 mg, 44 %). ES-MS m/z 452.1 (MH+); HPLC RT (min) 3.21 {method (J)}.
Step 5: Preparation of 2-i r3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol- 5-vnamino|-4-fluorobenzoic acid
A solution of 2-{ [3-(3-ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5-yl]amino}-4- fluorobenzoate (26 mg, 0.04 mmol) in 1,4-dioxane (1.9 mL) was treated with lithium hydroxide (6.4 mg, 0.27 mmol) and water (0.9 mL). The resulting mixture was stirred at room temperature over night. After acidification with hydrochloric acid (IN), the mixture was diluted with acetonitrile and directly purified by preparative HPLC yielding 2-{[3-(3- ethoxyphenyl)-l-(4-methyl-3-thienyl)-lH-pyrazol-5-yl]amino}-4-fluorobenzoic acid (16 mg, 68 %). IH NMR (400 MHz, CDC13) δ 13.39 (s, OH), 10.34 (s, INH), 7.96 (dd, IH), 7.86 (d, IH), 7.45-7.54 (m, 2 H), 7.38 (dd, 1 H), 7.32 (t, 1 H), 7.12 (dd, 1 H), 7.05 (s, IH), 6.90 (dd, IH), 6.70 (dt, 1 H), 4.09 (q, 2H), 2.00 (s, 3 H), 2.13 (s, 3 H), 1.35 (t, 3 H); ES-MS m/z 438.1.1 (MH+); HPLC RT (min) 2.93 {method (J)}.
Example 214
Preparation of 2-{r3-(2-ethyIpyridin-4-yl)-l-(2-methyIphenyl)-lH-pyrazol-
5-ynamino}-5-methylbenzoic acid
Step 1: Preparation of tert-butyl 2-cvano-3-(2-ethylpyridm-4-yl)~3-oxopropanoate
A solution of 2-ethylisonicotinic acid (3.0 g, 20 mmol) in dichloromethane (200 mL) was consecutively treated with 2 drops of DMF and with oxalyl chloride (5.1 g, 40 mmol). The solution was stirred at room temperature for 2 h and the volatiles were subsequently removed under reduced pressure yielding the corresponding acid chloride. Separately, a solution of tert-butylcyano acetate (10.0 g, 71 mmol) in THF (50 mL) was added dropwise to a solution of potassium tert-butylate (6.8 g, 61 mmol) in THF (50 mL). The resulting solution was stirred for 30 min. at room temperature and was subsequently cooled to 0 0C. To this solution, the acid chloride described above was added dropwise as solution in THF (30 mL). The resulting mixture was stirred for an additional 16 h at room temperature.50 mL ofwater and 30 ml of ethyl acetate was addded. The aquous layer was carfully acidified to pH 4-5 by dropwise addition of IN HCl. The product was extracted with ethyl acetate. The organic phase was washed with brine, dired over Na2SO4 and partially evaoparated to yield the product as a crystalline solid. (3000mg, 54%). MS (ES') m/z 275.2 (M-H+), HPLC RT (min) 1.37 {method (H) }.
Step 2: Preparation of 3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH-pyraζol-5-amine
A solution of (2-methylphenyl)hydrazine hydrochloride (1040 mg, 6.6 mol), tert- butyl 2-cyano-3-(2-ethylpyridin-4-yl)-3-oxopropanoate (1500 mg, 5.5 mmol) and para- toluenesulfonic acid (5200mg, 27 mmol) in 2-ethoxyethanol (50 mL) was stirred at 140°c for 18h. The Reacion mixture was neutralized with a saturated solution of sodium bicarbonate and extracte wit ethyl acetate. The combined organic extracts were washed with brine dired over Na2SO4 and evaporated. The product was puriefied by column chromatography utilizing a gradient of ethyl acetate in hexanes. (233 mg, 15%). 1H NMR (400 MHz, CDCl3) 8.45 (d, 1 H), 7.58 (s, 1 H), 7.48 (d, 1 H), 7.38 (m, 2 H), 7.32 (m, 2 H), 5.96 (s, 1 H), 5.25 (s, 2 H), 2.75 (q., 2H), 2.10 (s, 3 H), 1.25 (t, 3H);MS (ES") m/z 279.3 (M-H+), HPLC RT (min) 0.94 {method (F) }.
Step 3: Preparation of methyl 2-i r3-f2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH- pyrazol-5-vH amino } -5-methylbenzoate
A mixture of 3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH-pyrazol-5-amine (80 mg, 0.29 mmol), methyl 2-bromo5-methylbenzoate (79 mg, 0.35 mmol), tris(dibenzylidenacetone)palladium (5.2 mg, 0.006 mmol), Xphos (5.5 mg, 0.012 mmol), potassium carbonate (99 mg, 0.71 mmol) and phenyl boronic acid (1.7 mg, 0.014mmol) in tert-butanol (4.5 mL) was stirred over night at 110 0C. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was purified by preparative HPLC yielding methyl 2-{[3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH- pyrazol-5-yl]amino}-5-methylbenzoate (50 mg, 41%). 1H NMR (400 MHz, CDCl3) 8.48 (d, 1 H), 7.74 (s, 1 H), 7.66 (m, 2 H), 7.42 (m, 3 H), 7.36 (m, 3 H), 7.03 (s, IH), 3.70 (s, 3 H), 2.75 (q., 2H), 2.25 (s, 3 H), 2.05 (s, 3 H), 1.25 (t, 3H);ES-MS mJz 427.2 (MH+); HPLC RT (min) 2.28 {method (G)).
Step 4: Preparation of 2-{r3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH-pyrazol- 5-vHarnino|-5-methylbenzoic acid
A solution of 2-{[3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH- pyrazol-5-yl] amino }-5-methylbenzoate (43 mg, 0.10 mmol) in 1,4-dioxane (4 mL) was treated with lithium hydroxide monohydrate (12 mg, 0.30 mmol) and water (2 mL). The resulting mixture was stirred at room temperature for 16 h. The solution was partially concentrated under reduced pressure to remove most of the organic solvent and slightly acidified with IN HCl to precipitate the product. The product was dried in high vacuum to afford 2-{ [3-(2-ethylpyridin-4-yl)-l-(2-methylphenyl)-lH-pyrazol-5-yl]amino}- 5- methylbenzoic acid (41 mg, 98%). 1H NMR (400 MHz, CDCl3) 8.75 (b, 1 H), 8.30 (m, 2 H), 7.70 (m, 1 H), 7.36-7,52 (m, 7 H), 3.10 (b, 2 H), 2.25 (b, 3 H), 2.05 (b, 3 H), 1.40 (b, 3H);ES-MS m/z 413.1 (MH+); HPLC RT (min) 1.96 {method (G)).
Medical Treatment
The compounds of the present invention may be employed in the treatment of diabetes, including both type 1 and type 2 diabetes (non-insulin dependent diabetes mellitus). Such treatment may also delay the onset of diabetes and diabetic complications. The compounds may be used to prevent subjects with impaired glucose tolerance from proceeding to develop type 2 diabetes. Other diseases and conditions that may be treated or prevented using compounds of the invention in methods of the invention include: Maturity- Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40, 1994); Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11:299, 1994); impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999); impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796, 1991); gestational diabetes (Metzger, Diabetes, 40:197, 1991); and metabolic syndrome X.
The compounds of the present invention may also be effective in such disorders as obesity, and in the treatment of atherosclerotic disease, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease, and hypertension), cerebrovascular disease and peripheral vessel disease.
The compounds of the present invention may also be useful for treating physiological disorders related to, for example, cell differentiation to produce lipid accumulating cells, regulation of insulin sensitivity and blood glucose levels, (which are involved in, for example, abnormal pancreatic beta-cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that are stimulatory to beta-cells), macrophage differentiation which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, reduction in the pancreatic beta-cell mass, insulin secretion, tissue sensitivity to insulin, liposarcoma cell growth, polycystic ovarian disease, chronic anovulation, hyperandrogenism, progesterone production, steroidogenesis, redox potential and oxidative stress in cells, nitric oxide synthase (NOS) production, increased gamma glutamyl transpeptidase, catalase, plasma triglycerides, HDL, and LDL cholesterol levels, and the like. Compounds of the invention may also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, β-adrenergic agents, α-interferon and drugs used to treat HIV infection. The compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diabetes and related disorders. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy. The compounds of the invention may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs. Such therapies may be administered prior to, concurrently with or following administration of the compounds of the invention. Insulin includes both long and short acting forms and formulations of insulin. PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof. For example, PPAR agonist may include agonists of PPAR-α, PPAR- γ, PPAR-δ or any combination of two or three of the subunits of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide, α-glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of the invention include acarbose, miglitol and voglibose. Insulin sensitizers that may be useful in treating diabetes include thiazolidinediones and non-thiazolidinediones. Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of the invention include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in treating diabetes when administered with a compound of the invention include sulfonylurea and non-sulfonylurea drugs: GLP-I, GIP, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-I includes derivatives of GLP-I with longer half-lives than native GLP-I, such as, for example, fatty-acid derivatized GLP-I and exendin. In one embodiment of the invention, compounds of the invention are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta-cells to the insulin secretagogue.
Compounds of the invention may also be used in methods of the invention in combination with anti-obesity drugs. Anti-obesity drugs include β-3 agonists, CB-I antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical). Compounds of the invention may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors.
Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with an insulin sensitizer and an anti- obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
As used herein, various terms are defined below.
When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.
The term "subject" as used herein includes mammals (e.g., humans and animals).
The term "treatment" includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a diabetic condition and/or disorder. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.
The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment. The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product. Based on well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds described herein may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both. Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, 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 such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or ^-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2- dimethyl-l,l-dioxolane~4-methanol, ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2- alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art {see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference. The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized,
Commonly used pharmaceutical ingredients which may be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.
Other pharmaceutical ingredients include, for example, but are not limited to, adsorbents (e.g., powdered cellulose and activated charcoal); aerosol propellants (e.g., carbon dioxide, CCl2F2, F2ClC-CClF2 and CClF3); air displacement agents (e.g., nitrogen and argon); antifungal preservatives (e.g., benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (e.g., block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (e.g., potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (e.g., edetate disodium and edetic acid); colorants (e.g., FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (e.g., bentonite); emulsifying agents (but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (e.g., gelatin and cellulose acetate phthalate); flavorants (e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (e.g., glycerin, propylene glycol and sorbitol); levigating agents (e.g., mineral oil and glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (e.g., diethyl phthalate and glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (e.g., cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (e.g., cocoa butter and polyethylene glycols (mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening e.g., aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (e.g., magnesium stearate and talc); tablet binders (e.g., acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (e.g., liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (e.g., dibasic calcium phosphate); tablet disintegrants (e.g., alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (e.g., colloidal silica, corn starch and talc); tablet lubricants (e.g., calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing agents (e.g., carnuba wax and white wax); thickening agents (e.g., beeswax, cetyl alcohol and paraffin); tonicity agents (e.g., dextrose and sodium chloride); viscosity increasing agents (e.g., alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (e.g., heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
The compounds described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-obesity, or with known antidiabetic or other indication agents, and the like, as well as with admixtures and combinations thereof.
The compounds described herein may also be utilized, in free base form or in compositions, in research and diagnostics, or as analytical reference standards, and the like. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.
Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art {see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000). The following examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.
Capsule Formulation
A capsule formula is prepared from: Compound of this invention 10 mg
Starch 109 mg Magnesium stearate 1 mg
The components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.
Tablet Formulation
A tablet is prepared from:
Compound of this invention 25 mg Cellulose, microcrystalline 200 mg
Colloidal silicon dioxide 10 mg
Stearic acid 5.0 mg
The ingredients are mixed and compressed to form tablets. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Sterile IV Solution
A mg/mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration with sterile 5% dextrose and is administered as an IV infusion.
Intramuscular suspension The following intramuscular suspension is prepared:
Compound of this invention 50 μg/mL
Sodium carboxymethylcellulose 5 mg/mL
TWEEN 80 4 mg/mL Sodium chloride 9 mg/mL
Benzyl alcohol 9 mg/mL
The suspension is administered intramuscularly.
Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Immediate Release Tablets/Capsules
These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.
Biological Evaluation
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.
Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia, the following assays may be used.
In vitro Assay
Insulin Secretion from Dispersed Rat Islet Cells
Insulin secretion of dispersed rat islets mediated by a number of compounds of the present invention was measured as follows. Islets of Langerhans, isolated from male Sprague-Dawley rats (200-250 g), were digested using collagenase. The dispersed islet cells were treated with trypsin, seeded into 96 V-bottom plates, and pelleted. The cells were then cultured overnight in media with or without compounds of this invention. The media was aspirated, and the cells were pre-incubated with Krebs-Ringer-HEPES buffer containing 3 niM glucose for 30 minutes at 37°C. The pre-incubation buffer was removed, and the cells were incubated at 37°C with Krebs-Ringer-HEPES buffer containing the appropriate glucose concentration (e.g., 8 mM) with or without compounds for an appropriate time. In some studies, an appropriate concentration of GLP-I or forskolin was also included. A portion of the supernatant was removed and its insulin content was measured by SPA. The results were expressed as "fold over control" (FOC), in accordance with standard practice in the field. The compounds of examples 6, 9, 19, 22, 23, 28, 29, 41, 43, 54, 63, 65, 67, 68, 71, 74, 75, 82, 92, 93, 94, 98, 103, 104, 111, 112, 113, 114, 115, 130, 131,133, 134, 136 - 140, 144, 145, 147 - 149, 151 - 153, 164, 166 - 171, 175 - 178, 180 - 182, 184 - 188, 198 - 201 and 203 - 205 were tested in this assay and showed results in the range of 0.8 - 6.8 FOC.
In vivo Assay
Effect of Compounds on Intraperitoneal Glucose Tolerance in Rats The in vivo activities of four compounds of this invention when administered via oral gavage were examined in rats. Rats fasted overnight were given an oral dose of vehicle control or compound. Three hours later, basal blood glucose was measured, and the rats were given 2 g/kg of glucose intraperitoneally. Blood glucose was measured again after 15, 30, and 60 min. Activity in this test is indicated by a finding of reduced blood glucose levels relative to the vehicle following the PGTT (Intraperitoneal Glucose Tolerance Test). The tested compounds were found to be active. Target Identification
Use of Formula (I) Compounds to Identify Biological Targets
Compounds of Formula (T) of the current invention are also useful for identifying their associated biological target(s) (e.g., nucleic acids, peptides, polypeptides, proteins, carbohydrates, lipids, or other molecules) effecting the functional response of insulin secretion. Such targets, or protein molecules that are modulated by the compounds of present invention can be identified by several means.
For example, one such method of target identification can be accomplished, by photoaffinity labeling techniques well-known in the art. In such a procedure, compounds of Formula (I) that contain a photoactive group, such as a benzoylphenyl group, are prepared and additionally labeled with a radioactive isotope such as tritium.
This probe molecule is then allowed to come in contact with pancreatic beta-cell lysate homogenate (or any biological sample, such as a sample obtained from an organism (e.g., mammal) or from components (e.g., cells, biological tissue or fluid) of an organism, cell line or tissue culture sample; or the sample may be a sample derived from a patient including, but are not limited to, tissue or cells therefrom) containing the suspected target(s), incubated for a period of time sufficient to effect association of the probe molecule with the target protein, then the mixture is irradiated with light at the wavelength of the photoactive group of the probe molecule. The protein and probe molecule that become covalently bound as a result of the irradiation is then purified using standard methods, facilitated by the radioactivity of probe/target complex as a means to differentiate it from the rest of the lysate mixture. Identification of the purified protein (the probe/target complex) is then conducted using methods well described in the art {see, e.g., Dorman, et al., Tibtech. 18:64-77, 2000). Another method using the compounds of Formula (I) to identify the biological target effecting the functional response of insulin secretion is the so called drug "pull-down" experiments (see, e.g., Graves, et al., Rec. Prog. Horm. Res. 58:1-24, 2003). Formula (I) compounds containing functional groups that are suitable for chemical coupling (e.g., carboxylic acid groups, amino groups, alcohol groups) may be coupled to a commercially available polymer (resins) containing a suitably reactive linker group. For example, polymeric beads containing an amino linker may be allowed to react with a Formula (T) compound where X = COOH to form an amide, said amide being bound to the polymeric beads and thus, immobilized. The polymeric beads containing immobilized Formula (I) compound may then be used as bait for appropriate pancreatic beta-cell tissue lysates, by allowing the polymer beads to come in contact with the lysate, incubating for a period of time sufficient for the target proteins to form a complex with the polymer, removing the unbound protein material from the polymer, and cleaving of the bound protein from the polymer. Thus, purified protein target(s) of interest may then be identified by mass spectrometric analysis using techniques well know in the art {see, e.g., Kim, et al., Biochem. MoI. Biol. 36:299-304, 2003.
AU publications and patents mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the described compositions and methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the field of molecular biology or related fields are intended to be within the scope of the following claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:
1. An anilinopyrazole derivative of formula (I)
(I) wherein R1 is H,
(Q-C^alkyl optionally substituted with one (C1-C4)EIkOXy, (C3-C6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C1-C3)alkyl, CF3, and halo,
(CrC3)haloalkyl, or phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo, (Ci-C6)alkyl optionally substituted with one (C1-C4)alkoxy,
(C3-C6)cycloalkyl (Ci-C6)alkoxy, (C3-C6)cycloalkoxy (CrC3)haloalkyl, (Ci-C3)haloalkoxy, cyano, nitro, and (Q-C^acyl,
R2 is H, halo,
(Ci-C6)alkyl, (C3-C6)cycloalkyl, (Ci-C3)haloalkyl, or phenyl, 1,3-benzodioxolane, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of
(Ci-C4)alkyl optionally substituted with halogen and/or with one (C1-C4)alkoxy, (C3-C6)cycloalkyl,
(C1-C4)alkoxy (C3-C6)cycloalkoxy, halo,
(C1-C3)haloalkoxy, cyano,
(C1-C4)acyl, and benzoyl,
R3 represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from
(Ci-C4)alkoxy,
(C3-C6)cycloalkoxy
(Ci-C3)haloalkoxy, (Ci-C6)alkyl optionally substituted with one (Q-C-øalkoxy,
(C3-C6)cycloalkyl,
(C1-C3)haloalkyl, halo, and cyano, with the provisos that a) when R3 is unsubstituted pyridyl and R and R2 are H and X is CO2H, then R1 is other than H or methyl, b) when R3 is unsubstituted 2-pyridyl and R and R2 are H and X is CO2H and n is 2 and both R4 groups are F, then R1 is other than ethyl, and c) when R3 is 6-methyl-2-pyridyl or 4,6~dimethyl-2-pyridyl and R and R2 are H and
X is CO2H, then R1 is other than methyl,
R4 is (Q-GOalkyl, (C3-C6)cycloalkyl, (C1-C3)RIkOXy, (C1-C3)haloalkyl, (C1-C3)IIaIOaIkOXy, or halo,
n = 0, 1, 2, or 3;
X is CO2R8, CONR5R6, or SO2NHR7;
R5 is H,
(d-C4)alkyl, or
SO2-phenyl, said phenyl being optionally substituted with up to two substituents selected from the group consisting of halo
(Ci-C4)alkyl optionally substituted with one (C1-C^aIkOXy,
(C1-C^aIkOXy,
(C1-C3)haloalkyl, and
(Q-C^haloalkoxy,
R6 is H or (C1-C6)alkyl;
R7 is H or methyl; and
R8 is H, or
(d-C4)alkyl, or a pharmaceutically acceptable salt thereof.
2. The anilinopyrazole derivative or salt thereof of claim 1 wherein
R1 is H,
(C1-C6)alkyl optionally substituted with one (C1-C4)alkoxy, (C3-C6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (Ci-C3)alkyl, CF3, and halo, (Q-QOhaloalkyl, or phenyl optionally substituted with up to two substituents selected from the group consisting of halo,
(C1-C4)alkyl optionally substituted with one (Ct-Gøalkoxy, (C3-C6)cycloalkyl
(Ci-C4)alkoxy, (C3-C6)cycloalkoxy (C1-C3)haloalkyl, (Ci-C3)haloalkoxy, cyano, nitro, and (Ci-C4)acyl,
R2 is H, halo,
(Ci-QOalkyl, (C3-C6)cycloalkyl, (C1-C3)haloalkyl, pyridyl optionally substituted with up to two substituents selected from the group consisting of
(d-C3)alkoxy, (C3-C6)cycloalkoxy, (Ci-C3)haloalkoxy, (Ci-QOhaloalkyl, halo, and
(d-C^alkyl; pyrimidyl, optionally substituted with (Q-C4)alkyl or (Ci-C4)alkoxy, or phenyl optionally substituted with up to two substituents selected from the group consisting of (Ci-C4)alkyl,
(C3-C6)cycloalkyl,
(Ci-C4)alkoxy,
(C3-C6)cycloalkoxy, halo,
(C1-C3)IIaIOaIkOXy, (C1-C^aCyI, and benzoyl,
R3 represents optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R3 are selected from the group consisting of
(Ci-C4)alkoxy, (C3-C6)cycloalkoxy
(C1-C3)haloalkoxy, (d-C6)alkyl, (C3-C6)cycloalkyl, and (Ci-C3)haloalkyl, and the number of said optional substituents on R3 is 0, 1, or 2.
3. The anilinopyrazole derivative or salt thereof of claim 1 wherein R1 is H, (Ci-C6)alkyl optionally substituted with one (Q-GOalkoxy,
(C3-C6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (Ci-C3)alkyl, CF3, and halo, or (C1-C3)haloalkyl,
R2 is H, phenyl, 1,3-benzodioxolane, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of
(Ci-C4)alkyl optionally substituted with halogen and/or one
(Ci-C4)alkoxy (C3-C6)cycloalkyl,
(Q-C4)alkoxy (C3-C6)cycloalkoxy, halo, (C1-C3)IIaIOaIkOXy, cyano,
(C1-COaCyI, and benzoyl, and
X is CO2R8 .
4. The anilinopyrazole derivative or salt thereof of claim 1 wherein R1 is phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
(Ci-C6)alkyl optionally substituted with one (Q-GOalkoxy, (C3-C6)cycloalkyl (Ci-C6)alkoxy,
(C3-C6)cycloalkoxy (Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, cyano, nitro, and
(Q-Gύacyl,
R2 is H,
(C1-C^aIkVl, or (C3-C6)cycloalkyl,
R3 represents an aromatic 5- or 6-membered heteroaryl ring which is optionally fused to phenyl, said heterocycle or fused heterocycle is optionally substituted with up to three substituents selected from (Q-GOalkoxy,
(C3-C6)cycloalkoxy
(C i -C3)haloalkoxy ,
(Ci-C6)alkyl optionally substituted with one (C1-C^aIkOXy, (C3-C6)cycloalkyl, (Ci-C3)haloalkyl, halo, and cyano,
provisos a), b), and c) no longer apply,
R4 is (Ci-C4)alkyl,
(C3-C6)cycloalkyl, (Ci-C3)alkoxy,
(C1-C3)haloalkyl, (C1-C3)IIaIOaIkOXy, or halo,
n = 0, 1, 2, or 3; and
X is CO2R8 .
5. The anilinopyrazole derivative or salt thereof of claim 4 wherein
R1 is phenyl or pyridyl optionally substituted with up to two substituents selected from the group consisting of halo,
(C1-C6)alkyl optionally substituted with one (C1-C4^aIkOXy, (C3-C6)cycloalkyl
(Ci-C6)alkoxy, (C3-C6)cycloalkoxy (Ci-C3)haloalkyl, (d-C3)haloalkoxy, cyano, nitro, and (C1-C^aCyI, R2 is H, or
(Ci-QOalkyl,
R3 represents optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine, wherein said optional substituents on R3 are selected from the group consisting of (Ci-C4)alkoxy, (C3-C6)cycloalkoxy (CrC3)haloalkoxy, (C1-C6)alkyl optionally substituted with one (Q-GOalkoxy,
(C3-C6)cycloalkyl, (CrC3)haloalkyl, halo, and cyano;
R4 is (Ci-COalkyl,
(C3-C6)cycloalkyl, (CrC3)alkoxy, (C1-C3)haloalkyl, (d-C3)haloalkoxy, or halo, and
n = 0, 1, or 2.
The anilinopyrazole derivative or salt thereof of claim 5 wherein
R1 is phenyl substituted in meta-position with one substituent selected from the group consisting of halo, (Ci-C6)alkyl optionally substituted with one (d-C4)alkoxy,
(C1-C6)alkoxy, and (C3-C6)cycloalkoxy, R2 is H; and
R4 is (d-C4)alkyl,
(Ci-C3)alkoxy, (d-C3)haloalkyl,
(C1-C3)IIaIOaIkOXy, or halo.
7. The anilinopyrazole derivative or salt thereof of claim 1 wherein
R is H; R1 is methyl, ethyl, tert-butyl, cyclopropyl, or phenyl optionally substituted with one substituent selected from the group consisting of (Ci-C6)alkyl optionally substituted with one (Q-GOalkoxy,
(C1-C6)alkoxy, (C3-C6)cycloalkoxy (Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, and cyano,
R2 is H, phenyl, pyridyl or pyrimidyl optionally substituted with up to two substituents selected from the group consisting of (Ci-C4)alkyl,
(C3-C6)cycloalkyl, (Ci-C4)alkoxy halo,
(C i -C3)haloalkoxy , cyano, and R3 represents pyridine, pyrimidine, or pyrazine, optionally substituted with up to two substituents selected from
(Ci-GOalkoxy,
(CrC6)alkyl optionally substituted with one (C1-C^aIkOXy, (C3-C6)cycloalkyl,
(Ci-C3)haloalkyl, halo, and cyano, with the provisos that a) when R3 is unsubstituted pyridyl and R and R2 are H and X is CO2H, then R1 is other than methyl, b) when R3 is unsubstituted 2-pyridyl and R and R2 are H and X is CO2H and n is 2 and both R4 groups are F, then R1 is other than ethyl, and c) when R3 is 6-methyl-2-pyridyl or 4,6-dimethyl-2-pyridyl and R and R2 are H and X is CO2H, then R1 is other than methyl,
R4 is (Ci-C4)alkyl, (d-C3)alkoxy, (Ci-C3)haloalkyl, (C1-C3)haloalkoxy, or halo,
n = O, 1, or 2; and
X is CO2R8 .
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
9. A method of treating diabetes or a diabetes-related disorder comprising administering to a patient in need thereof an effective amount of a compound of claim 1.
10. The method of claim 9 wherein the diabetes is type 1 diabetes, type 2 diabetes, maturity onset diabetes of the young, latent autoimmune diabetes adult, or gestational diabetes.
11. The method of claim 9 wherein said diabetes-related disorder is syndrome X, impaired glucose tolerance, impaired fasting glucose, obesity, hyperlipidemia, hypercholesteremia, low LDL levels, cardiovascular disease, cerebrovascular disease, peripheral vessel disease, and secondary causes of diabetes.
12. The method of claim 11 wherein the cardiovascular disease is atherosclerosis, coronary heart disease, coronary artery disease, or hypertension.
13. The method of claim 11 wherein the secondary cause of diabetes is glucocorticoid excess, growty hormone excess, pheochromocytoma, or drug-induced diabetes.
14. A method of treating diabetes or a diabetes-related disorder comprising administering to a patient in need thereof an effective amount of a compound of claim 1 and at least one pharmaceutical agent other than a compound of claim 1.
15. The method of claim 14 wherein the diabetes is type 1 diabetes, type 2 diabetes, maturity onset diabetes of the young, latent autoimmune diabetes adult, or gestational diabetes.
16. The method of claim 14 wherein said diabetes-related disorder is syndrome X, impaired glucose tolerance, impaired fasting glucose, obesity, hyperlipidemia, hypercholesteremia, low LDL levels, cardiovascular disease, cerebrovascular disease, peripheral vessel disease, or a secondary cause of diabetes.
17. The method of claim 16 wherein the cardiovascular disease is atherosclerosis, coronary heart disease, coronary artery disease, or hypertension.
18. The method of claim 16 wherein the secondary cause of diabetes is glucocorticoid excess, growth hormone excess, pheochromocytoma, or drug-induced diabetes.
19. The method of claim 14, wherein the pharmaceutical agent other than a compound of claim 1 is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, and insulin and anti- obesity drugs.
20. The method of claim 14 wherein the compound of claim 1 and the pharmaceutical agent other than a compound of claim 1 are administered concurrently.
21. The method of claim 14 wherein the compound of claim 1 and the pharmaceutical agent other than a compound of claim 1 are administered as a single pharmaceutical dosage formulation.
22. The method of claim 14 wherein the compound of claim 1 and the pharmaceutical agent other than a compound of claim 1 are administered non-concurrently.
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