WO2005091857A2 - 1,6-naphthyridine and 1,8-naphthyridine derivatives and their use to treat diabetes and related disorders - Google Patents

1,6-naphthyridine and 1,8-naphthyridine derivatives and their use to treat diabetes and related disorders Download PDF

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WO2005091857A2
WO2005091857A2 PCT/US2005/005367 US2005005367W WO2005091857A2 WO 2005091857 A2 WO2005091857 A2 WO 2005091857A2 US 2005005367 W US2005005367 W US 2005005367W WO 2005091857 A2 WO2005091857 A2 WO 2005091857A2
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carbon atoms
heteroatoms selected
heterocycloalkyl
heterocycloalkenyl
membered
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PCT/US2005/005367
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French (fr)
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WO2005091857A3 (en
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Rainer Heurich
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Bayer Pharmaceuticals Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

  • the present invention relates to 1,6-naphthyridine and 1,8-naphthyridine derivatives, pharmaceutical compositions containing them, and their use for treating diabetes and related disorders in a subject.
  • 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.
  • IDDM insulin dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • the current treatment for type 1 diabetic patients is the 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.
  • cAMP is a major regulator of glucose-stimulated insulin secretion. However, it has little if any effects on insulin secretion in the absence of or at low glucose concentrations (Weinhaus, et al., Diabetes 47:1426-1435, 1998). The effects of cAMP on insulin secretion are thought to be mediated by a protein kinase A pathway.
  • Endogenous secretagogues like pituitary adenylate cyclase activating peptide (PACAP), VIP, and GLP-1 use the cAMP system to regulate insulin secretion in a glucose-dependent fashion ( Komatsu, et al., Diabetes 46: 1928-1938, 1997). Also, phosphodiesterases (PDEs) are known to be involved in the regulation of the cAMP system.
  • PDEs phosphodiesterases
  • PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells.
  • Three different PACAP receptor types Rl, R2, and R3 have been described (Harmar, et al., Pharmacol. Reviews 50: 265-270, 1998).
  • the insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca++]i, and promoting the exocytosis of insulin- containing secretory granules.
  • Vasoactive intestinal peptide is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218, 1970; U.S. Patent No. 3,879,371).
  • This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon.
  • the biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. These receptors were originally known as VIP-R1 and VIP- R2, however, they were later found to be the same receptors as PACAP-R2 and PACAP-R3.
  • GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i.e., it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in ⁇ -cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, et al., New Eng. J. Med.
  • the invention provides compounds, pharmaceutical compositions, and methods of using the same for treating diabetes and related disorders.
  • Compounds of the invention include compounds of formula (I)
  • R 1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R 9 , or
  • R 13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
  • R 11 and R 12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
  • A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
  • R 9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A- R 14 , NR"R l2 ; or
  • R 2 is selected from NR 15 R 16 , S(O) 0 _ 2 R 17 , and OR 17 ;
  • R 18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
  • R 18 is A-R 9 ;
  • R 16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R 9 , or
  • R 3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR 19 R 20 , A-OR 19 , A-NR I9 R 20 , and A-R 20 ;
  • R 19 and R 20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R 9 , or
  • R 21 is hydrogen, or
  • R 5 and R 6 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R 10 , or
  • R 22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;
  • R 23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or
  • R 24 and R 25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1 -6 carbon atoms, and A-R 23 , or
  • R 26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR 22 )-R 23 , and A-R 23 , or
  • R 27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R 23 , or
  • R 30 is selected from alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon
  • R 7 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms, all of which may be substituted with 1-3 of R 10 , or
  • the compound is not: 1,5- dimethy l-2-(methylamino)-7-(4-morpholiny 1)- 1 ,8-naphthyridin-4( 1 H)-one, 1 ,5-di methyl-2- (methylamino)-7-(4-methyl-l-piperazinyl)-l,8-naphthyridin-4(lH)-one, l,5-dimethyl-2- (methylamino)-7-( 1 -pyrrolidinyl)- 1 ,8-naphthyridin-4( 1 H)-one, 1 ,5-dimethyl-2-(methylamino)-7- (l-piperidinyl)-l,8-naphthyridin-4(lH)-one, l,5-dimethyl-2-(methylamino)-7-(4-methyl-l- piperazinyl)-3-nitro-l
  • R 1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A- R 9 , or
  • R 13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
  • R" and R 12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
  • A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
  • R 9 is selected from hydroxy, alkoxy of 1 -6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R 14 , NR"R 12 ; or
  • R 2 is NR 15 R 16 ;
  • R 18 is selected from alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
  • R 18 is A-R 9 ;
  • R 3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O) 0 - 2 and O, both of which may be substituted with 1-3 of R 10 , or
  • R 3 is selected from alkyl of 1 -6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR I9 R 20 , A-OR 19 , A-NR 19 R 20 and A-R 20 ;
  • R 1 and R 20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R 9 , or
  • R 19 and R 20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O) 0 _ 2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O) 0 .
  • heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(0)o- 2 and O
  • R 21 is hydrogen, or
  • R 5 and R 6 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1 -3 of R'°, or
  • R 22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms;
  • R 24 and R 25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R 23 , or
  • R 27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R 23 , or
  • R 7 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R 10 , or
  • the invention relates generally to naphthyridine derivatives of the formula
  • R 1 ' , R 2' , R 3' , R 4' , R 5' , R 7' and R 8' correspond to R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 , respectively, of formula (I).
  • Such compounds may be used in the treatment of diabetes and related disorders.
  • the invention relates to compounds of formula (I), as described above.
  • the invention relates to compounds of formula (I), wherein R 1 is phenyl, which may be substituted with 1-3 of R 10 , R 2 is NR 15 R 16 , R 3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O) 0 .
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general synthetic schemes are presented to aid the reader in synthesizing compounds of this invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
  • the close analogy between Flow Diagram I and V demonstrates that the routes used to synthesize Formula (I) may be applied to synthesize Formula (II).
  • the routes shown in Flow Diagram II to IV maybe used to synthesize Formula (II) from appropriately substituted nicotinic acid.
  • nicotinic acids used in the above flow diagrams could be purchased from commercial sources, prepared according to Flow Diagram VI, or prepared according to literature in this field (Biorg. Med. Chem. Lett. 2001, 475-477; J. Prakt. Chem. 2002, 33; Eur. J. Org. Chem. 2001, 1371 ; J. Org. Chem. 2000, 65, 4618; /. Med. Chem. 1997, 40, 2674; Bioorg. Med. Chem. Lett. 2000, 10, 1151; US patent 3838156, etc.).
  • Flow Diagram X illustrates manipulations of R 4 in formula (I), which could also be used on R 4 in formula (II). [032] Flow Diagram X alkylation or reduction Mitsunobu
  • Flow Diagram XI illustrates manipulations of R 6 in formula (I). These manipulations could also be applied to R and R in formula (I), R , R , and R in formula (II).
  • Flow Diagram XII illustrates manipulations on R 7 of formula (I). These manipulations could also be applied to R 5 in formula (I), R 5 and R 7 in formula (II).
  • E + is alkyl halide, aldehydes, halogen, C0 2 , 0 2 , activated ester, etc.
  • Flow Diagram XIV illustrates the transformations of some functional groups which are present in Formula (I) or (II).
  • 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 can 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, salicyclic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.
  • Tautomers of the compounds of the invention are encompassed by the present invention.
  • a carbonyl includes its hydroxy tautomer.
  • the protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
  • the Prodrugs f0461 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, abso ⁇ tion, biostability and release time (see “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 N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see 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 inco ⁇ orated by reference).
  • A-Q-R refers to a group which is formed by linking group A, group Q and group R in the designated order and the attachment of this group "A-Q-R” is any position on group A to form a stable structure.
  • Group Q may be linked to any position on group A to form a stable structure and group R may be linked to any position on group Q to form a stable structure.
  • halogen refers to a halogen radical selected from fluoro, chloro, bromo or iodo.
  • alkyl refers to a saturated aliphatic hydrocarbon radical.
  • Alkyl refers to both branched and unbranched alkyl groups. Examples of “alkyl” include alkyl groups that are straight chain alkyl groups containing from one to ten carbon atoms and branched alkyl groups containing from three to ten carbon atoms. Other examples include alkyl groups that are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms.
  • alk alkoxy, ethylthio, “alkylamino” refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term in examplified by groups such as trifluomethyl. The more preferred haloalkyl groups are alkyl groups substituted with one or more fluro or chloro.
  • haloalkoxy refers to haloalkyl groups linked to a second group via an oxygen atom.
  • alkenyl refers to a mono or polyunsatuarted aliphatic hydrocarbon radical.
  • the mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon double bond.
  • Alkenyl refers to both branched and unbranched alkenyl groups, each optionally partially or fully halogenated. Examples of “alkenyl” include alkenyl groups that are straight chain alkenyl groups containing from two to ten carbon atoms and branched alkenyl groups containing from three to ten carbon atoms.
  • alkenyl groups that are straight chain alkenyl groups containing from two to six carbon atoms and branched alkenyl groups containing from three to six carbon atoms. This term is exemplified by groups such as ethenyl, propenyl, n- butenyl, isobutenyl, 3-methylbut-2-enyl, w-pentenyl, heptenyl, octenyl, decenyl, and the like.
  • alkynyl refers to a mono or polyunsatuarted aliphatic hydrocarbon radical.
  • the mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon triple bond.
  • Alkynyl refers to both branched and unbranched alkynyl groups, each optionally partially or fully halogenated. Examples of “alkynyl” include alkynyl groups that are straight chain alkynyl groups containing from two to ten carbon atoms and branched alkynyl groups containing from four to ten carbon atoms.
  • alkynyl groups that are straight chain alkynyl groups containing from two to six carbon atoms and branched alkynyl groups containing from four to six carbon atoms. This term is exemplified by groups such as ethynyl, propynyl, octynyl, and the like.
  • cycloalkyl refers to the mono- or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl, and the like.
  • cycloalkenyl refers to the mono- or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom that results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms. Other examples include cycloalkenyl groups containing four to six carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornene, and the like.
  • heterocycloalkyl refers to the mono- or polycyclic structures of "cycloalkyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure.
  • heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms.
  • heterocycloalkyl groups include mo ⁇ holino, pyrazino, tetrahydrofurano, and the like.
  • heterocycloalkenyl refers to the mono- or polycyclic structures of "cycloalkenyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure.
  • heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms.
  • heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.
  • cycloalkyloxy refers to a monovalent radical of the formula -O-cycloalkyl, i.e., a cycloalkyl group linked to a second group via an oxygen atom.
  • aryl refers to 6-10 membered mono- or polycyclic aromatic carbocycles, for example, phenyl and naphthyl. Unless otherwise specified, the aryl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure.
  • aryl refers to non-substituted aryls and aryls optionally substituted with one or more of the following groups: halogen, C1 -C6 alkyl, C3- C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, -NHMe and -N(Me) 2 ), Cl- C6 acyl, thiol, alkylthio, carboxylic acid.
  • heteroaryl refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical.
  • Each heteroaryl contains 1- 10 carbon atoms and from 1 to 5 heteroatoms independently chosen from nitrogen, oxygen and sulfur, wherein any sulfur heteroatom may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or quaternized.
  • the heteroaryl ring may be attached at any suitable heteroatom or carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom that results in a stable structure.
  • heteroaryl includes heteroaryl groups that are non-substituted or those optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, -NHMe and -N(Me) 2 ), Cl- C6 acyl, thiol, alkylthio, carboxylic acid.
  • heteroaryl examples include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl
  • heteroaryloxy refers to heteroaryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • HPLC-MS spectra were obtained using a Hewlett-Packard 1 100 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% CH 3 CN in water with 0.02% TFA and B: 2% water in CH 3 CN with 0.018% TFA. Gradient elution from 10% B to 95% 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.
  • HN0 3 ( 13.3 mL) was added to cooled (0 °C) cone.
  • H 2 S0 4 (60 mL) maintaining the internal temperature below 10 °C.
  • the acid mixture was heated to 70 °C and commercially available (Maybridge) 2,6-dichloro-4-(trifluoromethyl)nicotinonitrile (20.0 g, 83 mmol) was added.
  • the temperature was raised until the internal temperature of the reaction reached 100 °C. After heating for 1 h TLC analysis revealed that the reaction was complete.
  • the reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation and extracted with Et 2 0 (3X). The organic layers were combined and washed with brine.
  • a solution of NaOBr was prepared by adding Br 2 (11.4 g, 3.66 mL, 71.3 mmol) to a cooled (0 °C) and stirred solution of NaOH (7.8 g, 196 mmol) in water (90 mL). This solution was warmed to room temperature and was then added to a solution of commercially available (Aldrich) 2-hydroxy-6-methylpyridine-3-carboxylic acid (10.0 g, 65.1 mmol) and NaOH (7.8 g, 196 mmol) in water (30 mL). After stirring for 5 min, the mixture was cooled to 0 °C and carefully acidified with cone. HCl.
  • the reaction mixture was cooled to -60 °C using an acetone/dry ice bath and 2-anilino-7-ethoxy-5-methyl-l-phenyl-l ,8-naphthyridin-4(lH)-one (100 mg, 0.269 mmol) was added via syringe as a solution in THF (5 mL). The mixture was stirred for 1 h. Mel was added via syringe and the reaction was allowed to warm to room temperature and stirred for 18 h. A saturated aqueous solution of NH 4 C1 (20 mL) and EtOAc (20 L) was added, and the organic layer was separated, dried over MgS0 and concentrated in vacuo.
  • Example 27 (35 mg, 32 %)
  • Example 28 (1 1 mg, 10 %)
  • Example 29 (16 mg, 14 %).
  • Example 30
  • LDA was made by adding n-BuLi (0.31 mL, 0.5 mmol, 1.6 M) to diisopropylamine (50 mg, 0.5 mmol) in THF (15 mL) at -15 °C.
  • Examples 40 and 41 can be prepared in the same manner as that for Example 39 above. [258] Example 40:
  • Example 48 2-anilino-7-methyl-l-phenyl-5-(2,2,2-trifluoroethoxy)-l,6-naphthyridin-4(lH)-one
  • Trifluoroethanol (0.08 L, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1.1 mmol) in DMSO (4 mL) at 0 °C, and the mixture was heated at 60 °C for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5-chloro-7-methyl-l- phenyl-l ,6-naphthyridin-4(lH)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH 2 C1 2 .
  • 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 (LAD A) (Zimmet, et al., Diabetes Med. 1 1 :299, 1994); impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp.
  • 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 blood glucose levels, blood insulin levels, insulin sensitivity, and insulin secretion, 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 pancreatic 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 (NO
  • compounds of the invention may also be used in methods of the invention to activate or repair beta-cells in the pancreas. That is, the compounds of the present invention may be utilized to increase the number of pancreatic beta islet cells or to preserve or reduce the rate of loss of pancreatic beta islet cells by preventing or reducing apoptosis.
  • 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. l):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 HIN 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 ligands (e.g., agonists, antagonists), insulin secretagogues, for example, sulfonylurea drugs and non-sulfonylurea secretagogues, - glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, insulin and insulin derivatives, and anti-obesity drugs.
  • Such therapies may be administered prior to, concurrently with, or following administration of the compounds of the invention.
  • Insulin and insulin derivatives include both long and short acting forms and formulations of insulin.
  • PPAR ligands may include agonists and/or antagonists of any of the PPAR receptors or combinations thereof.
  • PPAR ligands may include ligands of PPAR- ⁇ , PPAR- ⁇ , PPAR- ⁇ or any combination of two or three of the receptors of PPAR.
  • PPAR ligands include, for example, rosiglitazone, troglitazone, and pioglitazone.
  • Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, tolbutamide, 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 PPAR- ⁇ agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other thiazolidinedione and non-thiazolidinedione compounds; biguanides such as metformin and phenformin; protein tyrosine phosphatase- 1 B (PTP-1B) inhibitors; dipeptidyl peptidase IN (DPP-1N) inhibitors; and l lbeta-HSD inhibitors.
  • PGP-1B protein tyrosine phosphatase- 1 B
  • DPP-1N dipeptidyl peptidase IN
  • Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of the invention include, for example, glucagon anatgonists and 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-1, GJP, PACAP, secretin, and derivatives thereof; nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
  • GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty -acid derivatized GLP-1 and exendin.
  • Anti-obesity drugs include ⁇ -3 agonists; CB-1 antagonists; neuropeptide Y5 inhibitors; Ciliary ⁇ eurotrophic Factor and derivatives (e.g., Axokine); 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.
  • drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, fatty acid lowering compounds (e.g., acipi ox); lipid lowering drugs (e.g., stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid derivatives.
  • HMG-CoA reductase inhibitors e.g., nicotinic acid, fatty acid lowering compounds (e.g., acipi ox); lipid lowering drugs (e.g., stanol esters, sterol glycoside
  • HMG-CoA reductase inhibitors include, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522.
  • Fibric acid derivatives include, for example, clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil.
  • Sequestrants include, for example, cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran.
  • Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, ⁇ -blockers and ACE inhibitors.
  • additional anti- hypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone),
  • ET receptor antagonists e.g., sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
  • 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.
  • 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.
  • prodrug includes a compound that is a drug precursor that, following administration to a subject and subsequent abso ⁇ tion, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.
  • 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.
  • 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 pu ⁇ ose 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.
  • 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.
  • 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 n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • 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 inte ⁇ eritoneally, 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
  • 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.
  • suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl
  • 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
  • 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. For this pu ⁇ ose, 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.
  • 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.
  • 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, inco ⁇ orated herein by reference). Such patches may be constructed for continuous
  • 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.
  • 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, CC1 F 2 , F 2 C1C-CC1F 2 and CC1F 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 hydroxy
  • 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).
  • 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.
  • Islets of Langerhans isolated from male Sprague-Dawley rats (200-250 g), are digested using collagenase.
  • the dispersed islet cells are treated with trypsin, seeded into 96 V-bottom plates, and pelleted.
  • the cells are then cultured overnight in media with or without compounds of this invention.
  • the media is aspirated, and the cells are pre-incubated with Krebs-Ringer-HEPES buffer containing 3 mM glucose for 30 minutes at 37°C.
  • the pre-incubation buffer is removed, and the cells are 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.
  • a portion of the supernatant is removed and its insulin content was measured by SPA.
  • hApoAl mice obtained from Jackson Laboratories, Bar Harbor, ME are bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound once daily for 8 days. The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined. In each case, triglyceride levels are measured using a Technicon Axon Autoanalyzer (Bayer Co ⁇ oration, Tarrytown, NY).
  • mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test compound for 7 days, and then bled again on day 8. Plasma is analyzed for HDL- cholesterol using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA).
  • CX4 Synchron Clinical System
  • obese monkeys are bled, then orally dosed once daily with vehicle or test compound for 4 weeks, and then bled again. Serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides, and glucose using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA). Lipoprotein subclass analysis is performed by NMR spectroscopy as described by Oliver et al., (Proc. Natl. Acad. Sci. USA 98:5306-5311 , 2001).
  • CX4 Synchron Clinical System
  • Cardiovascular parameters e.g., heart rate and blood pressure
  • SHR rats are orally dosed once daily with vehicle or test compound for 2 weeks.
  • Blood pressure and heart rate are determined using a tail-cuff method as described by Grinsell et al., (Am. J. Hypertens. 13:370-375, 2000).
  • blood pressure and heart rate are monitored as described by Shen et al., (J. Pharmacol. Exp. Therap. 278:1435-1443, 1996).

Abstract

The invention relates generally to naphthyridine derivatives of the formula (A) wherein one of U, X, Y and Z is nitrogen and the others are C-R, where R is hydrogen or a substituent. More specifically, the invention relates to 1,6-naphthyridine and 1,8-naphthyridine derivatives and pharmaceutical compositions containing such derivatives. Methods of the invention comprise administration of a naphthyridine derivative of the invention for the treatment of diabetes and related disorders.

Description

1,6-NAPHTHYRIDINE AND 1,8-NAPHTHYRIDINE DERIVATIVES AND THEIR USE TO TREAT DIABETES AND RELATED DISORDERS
[001] This application claims benefit of U.S. Provisional Application Serial No. 60/552,971 ; filed on March 12, 2004, the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[002] The present invention relates to 1,6-naphthyridine and 1,8-naphthyridine derivatives, pharmaceutical compositions containing them, and their use for treating diabetes and related disorders in a subject.
DESCRIPTION OF THE RELATED ART
[003] 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.
[004] The current treatment for type 1 diabetic patients is the 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.
[005] 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.
[006] 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 strategy to develop the new therapy disclosed herein is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion. [007] Metabolism of glucose promotes the closure of ATP-dependent K+ channels, which leads to cell depolarization and subsequent opening of Ca++ channels. This in turn results in the exocytosis of insulin granules. cAMP is a major regulator of glucose-stimulated insulin secretion. However, it has little if any effects on insulin secretion in the absence of or at low glucose concentrations (Weinhaus, et al., Diabetes 47:1426-1435, 1998). The effects of cAMP on insulin secretion are thought to be mediated by a protein kinase A pathway.
[008] Endogenous secretagogues like pituitary adenylate cyclase activating peptide (PACAP), VIP, and GLP-1 use the cAMP system to regulate insulin secretion in a glucose-dependent fashion (Komatsu, et al., Diabetes 46: 1928-1938, 1997). Also, phosphodiesterases (PDEs) are known to be involved in the regulation of the cAMP system.
[009] PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells. Three different PACAP receptor types (Rl, R2, and R3) have been described (Harmar, et al., Pharmacol. Reviews 50: 265-270, 1998). The insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca++]i, and promoting the exocytosis of insulin- containing secretory granules.
[010] Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218, 1970; U.S. Patent No. 3,879,371). This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon. The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. These receptors were originally known as VIP-R1 and VIP- R2, however, they were later found to be the same receptors as PACAP-R2 and PACAP-R3.
[011] GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i.e., it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in β-cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, et al., New Eng. J. Med. 326:1316-1322, 1992) and with longer infusions improved the beta cell function to those of normal subjects (Rachman, et al., Diabetes 45: 1524-1530, 1996). A recent report has shown that GLP-1 improves the ability of β- cells to respond to glucose in subjects with impaired glucose tolerance (Byrne, et al., Diabetes 47: 1259-1265, 1998). All of these effects, however, are short-lived because of the short half-life of the peptide. SUMMARY OF THE INVENTION
[012] The invention provides compounds, pharmaceutical compositions, and methods of using the same for treating diabetes and related disorders. Compounds of the invention include compounds of formula (I)
Figure imgf000004_0001
(I)
wherein
R1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R1 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0_2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=0)o-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0_2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=0) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1 -6 carbon atoms, haloalkoxy of 1 -6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, NR"R12, C(=0)ORn, C(=0)NHR", NHC(=0)R13, NHS(=0)2R13, S(=O)0.2R'3, S(=0)2NHR", cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5- 7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0. 2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A- R14, NR"Rl2; or
R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0_2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or
R is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0_2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1- 2 heteroatoms selected from N, S(=O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, all of which may be substituted with 1-3 of R10; R2 is selected from NR15R16, S(O)0_2R17, and OR17;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o.2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o.2 and O, A-R9, C(=0)R18, C(=0)NHR18, S(=0)2NHR18;
R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
R18 is A-R9;
R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, all of which may be substituted with 1-3 of R10, or
R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0_2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0_2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10; R17 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, A-R9, or
R17 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0- and O, all of which may be substituted with 1-3 of R10;
R3 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0_2, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(0)o-2 and O, all of which may be substituted with 1-3 of R10, or
R3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NRI9R20, and A-R20;
R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(0)o-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(O)0_2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0_2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R4 is selected from =0, =S, and OR21;
R21 is hydrogen, or
R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5- 7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0. 2 and O, all of which may be substituted with 1-3 of R10;
R5 and R6 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or
R5 and R6 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A- R23, A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, or A-C(=0)NR24R25, or
R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1 -8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR2 R25, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25;
Q is selected from O and S(=O)0-2;
R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or
R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(=0)o-2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)-R23 that when R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1 -6 carbon atoms, and A-R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0_2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0_2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o_2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)-R23, and A-R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=0)o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or
R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(=O)0_2, and O, all of which may be substituted with 1-3 of R10, or
R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0_2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(=0)R24, C(=0)OR26, C(=0)NR25R30, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25, or
R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)-R23, and A-R23, or
R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10;
R29 is selected from alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(=0)R24, A-C(=0)OR24, A-C(=0)NR24R25, A-
NR27R28, or
R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2, and O, all of which may be substituted with 1-3 of R10, or
R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R7 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms, all of which may be substituted with 1-3 of R10, or
R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1 - 2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R , A(OR )-R , A-R23, A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25 , S(=0)2R26, A-C(=0)R24, A- C(=0)OR24, or A-C(=0)NR24R25, or
R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R , A(OR )-R , NR27R28, A-NR 7R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, A- C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25;
and pharmaceutically acceptable salts thereof, with the provisio that the compound is not: 1,5- dimethy l-2-(methylamino)-7-(4-morpholiny 1)- 1 ,8-naphthyridin-4( 1 H)-one, 1 ,5-di methyl-2- (methylamino)-7-(4-methyl-l-piperazinyl)-l,8-naphthyridin-4(lH)-one, l,5-dimethyl-2- (methylamino)-7-( 1 -pyrrolidinyl)- 1 ,8-naphthyridin-4( 1 H)-one, 1 ,5-dimethyl-2-(methylamino)-7- (l-piperidinyl)-l,8-naphthyridin-4(lH)-one, l,5-dimethyl-2-(methylamino)-7-(4-methyl-l- piperazinyl)-3-nitro-l,8-naphthyridin-4(l H)-one, l,5-dimethyl-2-(methylamino)-3-nitro-7-(l - pyrrolidinyl)-l,8-naphthyridin-4(lH)-one, or l-(3-chlorophenyl)-2-(4-morpholinyl)-l ,8- naphthyridin-4(lH)-one.
[013] Another aspect of the invention includes compounds of formula (I) wherein R1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A- R9, or
R1 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0_2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0),all of which may be substituted with 1-3 of
R'°;
R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, NRπR12, C(=0)ORπ, C(=0)NHRu, NHC(=0)R13, NHS(=0)2R13, S(=O)0.2R13, S(=0)2NHRH, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0_2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=O)0_2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R" and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1 -6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NR"R12; or
R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0_2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2- 5 carbon atoms and 1 -3 heteroatoms selected from N, S(=0)o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0_2 and O, all of which may be substituted with 1-3 of R10;
R2 is NR15R16;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, A-R9, C(=0)R18, C(=0)NHR18, S(=0)2NHR18;
R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o_2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, all of which may be substituted with 1-3 of R10, or
R18 is selected from alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
R18 is A-R9;
R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, all of which may be substituted with 1-3 of R10, or
R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, or a 5- 7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or
R3 is selected from alkyl of 1 -6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NRI9R20, A-OR19, A-NR19R20 and A-R20;
R1 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0_2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0.2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(0)o-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10; R4 is selected from =0, =S, and OR21;
R21 is hydrogen, or
R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, all of which may be substituted with 1-3 of R10;
R5 and R6 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1 -3 of R'°, or
R5 and R6 are independently selected from is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, or A-C(=0)NR24R25, or
R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1 -6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A- NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, A-C(=0)R24, A-C(=0)OR24, and A- C(=0)NR24R25;
Q is selected from O and S(=O)0.2;
R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o-2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O,
Figure imgf000017_0001
wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)-R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0_2, and O, all of which may be substituted with 1-3 of R'°, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=0)o_2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(0R22)-R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O,
Figure imgf000018_0001
wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or
R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(=0)R24, C(=0)0R26, C(=0)NR25R30, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25, or
R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(0R22)-R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=0)o_2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; and
R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(=0)R24, A-C(=0)OR24, A-
C(=0)NR24R25, A-NR27R28, or
R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o_2, and O, all of which may be substituted with 1 -3 of R10, or
R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, O, S(=O)0_2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R7 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or
R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=0)o-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=O)0_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 -3 of R10, A-R23, A-NR24R25, C(=0)R24, C(=0)0R24, C(=0)NR24R25, S(=0)2R26, A-C(=0)R24, A- C(=0)OR24, or A-C(=0)NR24R25, or
R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2- 6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25; and pharmaceutically acceptable salts thereof with the provisio that the compound is not: l,5-dimethyl-2-(methylamino)-7-(4-morpholinyl)-l,8-naphthyridin-4(lH)-one, 1,5- dimethyl-2-(methylamino)-7-(4-methyl- 1 -piperazinyl)- 1 ,8-naphthyridin-4( 1 H)-one, 1 ,5- dimethy l-2-(methylamino)-7-( 1 -pyrrolidinyl)- 1 ,8-naphthyridin-4( lH)-one, 1 ,5-dimethyl-2- (methylamino)-7-(l -piperidinyl)- 1 ,8-naphthyridin-4(lH)-one, 1 ,5-dimethyl-2- (methylamino)-7-(4-methyl-l-piperazinyl)-3-nitro-l ,8-naphthyridin-4(lH)-one, 1 ,5- dimethyl-2-(methylamino)-3-nitro-7-(l-pyrrolidinyl)-l ,8-naphthyridin-4( 1 H)-one, or 1 -(3- chlorophenyl)-2-(4-morpholinyl)-l,8-naphthyridin-4(lH)-one.
DETAILED DESCRIPTION OF THE INVENTION
[014] The invention relates generally to naphthyridine derivatives of the formula
Figure imgf000020_0001
wherein one of U, X, Y and Z is nitrogen and the others are C-R, where R is hydrogen or a substituent such as R5, R6 or R7, as described above for formula (I). R1, R2, R3 and R4 are as defined above for formula (I). The invention also relates to compounds of formula (I), described above, and to compounds of formula (II)
Figure imgf000021_0001
wherein R1 ', R2', R3', R4', R5', R7' and R8' correspond to R1, R2, R3, R4, R5, R6 and R7, respectively, of formula (I). Such compounds may be used in the treatment of diabetes and related disorders.
[015] In one embodiment, the invention relates to compounds of formula (I), as described above. In another embodiment, the invention relates to compounds of formula (I), wherein R1 is phenyl, which may be substituted with 1-3 of R10, R2 is NR15R16, R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0.2 and O, both of which may be substituted with 1-3 of R10, or R3 is selected from alkyl of 1 -6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20, and R4 is =0.
General Preparative Methods
[016] The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general synthetic schemes are presented to aid the reader in synthesizing compounds of this invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
[017] In general, compounds of Formula (I) (R4 is =0) may be prepared from the appropriately substituted nicotinic acid through several routes summarized in Flow Diagram I to IV. Compounds of Formula (II) (R4 is =0) may be prepared from the appropriately substituted nicotinic acid through the route summarized in Flow diagram V. The close analogy between Flow Diagram I and V demonstrates that the routes used to synthesize Formula (I) may be applied to synthesize Formula (II). The routes shown in Flow Diagram II to IV maybe used to synthesize Formula (II) from appropriately substituted nicotinic acid. 81 Flow Diagram I
Figure imgf000022_0001
base
Figure imgf000022_0002
(I) when R2 = NR15R16 R4 = =0
1 Flow Diagram II
Base, CW2
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
hydrolysis and decarboxylation such as HCI/HOAc
Figure imgf000023_0004
X = halogen hydrolysis and decarboxylation such as HCI/HOAc W = S or O Ra = alkyl, aryl Rb = alkyl
Figure imgf000023_0005
(I) when R2 = SR17 or OR 7 R4 = =0 [020] Flow Diagram III
Figure imgf000024_0001
acid, base, or heat
Figure imgf000024_0002
Figure imgf000024_0003
.17 (I) when R3 _ R H202/HOAc| R " SR ' R4 = =0 1 — »- R2 = SS((==00^)1.2R1
[Q211 Flow Diagram IV
Figure imgf000024_0004
(I) when R2 = NR15R16 R3 = H -C(=0)Rc = activated ester such as -C(=0)OPh-N02 or -C(=0)CI R4 = =0 Rd = alkyl, aryl X = halogen
r0221 Flow Diagram V
Figure imgf000025_0001
(II) when R2' = NR15R16 R3' = H R4' = =0
[023] The nicotinic acids used in the above flow diagrams could be purchased from commercial sources, prepared according to Flow Diagram VI, or prepared according to literature in this field (Biorg. Med. Chem. Lett. 2001, 475-477; J. Prakt. Chem. 2002, 33; Eur. J. Org. Chem. 2001, 1371 ; J. Org. Chem. 2000, 65, 4618; /. Med. Chem. 1997, 40, 2674; Bioorg. Med. Chem. Lett. 2000, 10, 1151; US patent 3838156, etc.).
Flow Diagram VI
Figure imgf000025_0002
[025] Further manipulations of Formula (I) (when R4 is =0) and (II) (when R4 is =0) could lead to more diversely substituted compounds. These manipulations include aromatic nucleophilic substitutions, metal-mediated couplings, reductions, oxidations, amide formations, etc.
[026] Flow Diagram VII illustrates alkylation, and amide, urea, and sulfonamide formations in Formula (I) when R2 = NHR16. Similar transformations could be carried out in Formula (II) when R2' = NHR16.
[0271 Flow Diagram VII
Figure imgf000026_0001
[028] Flow Diagram VIII and IX illustrate transformations at R3 in Formula (I). These transformations could also be applied to R3 in Formula (II). r0291 Flow Diagram VIII
alkylation or Mitsunobu
Figure imgf000027_0001
Figure imgf000027_0002
ro3oι Flow Diagram IX
Figure imgf000027_0003
metal-mediated coupling or alkylation or reductive amination
Figure imgf000027_0004
[031] Flow Diagram X illustrates manipulations of R4 in formula (I), which could also be used on R4 in formula (II). [032] Flow Diagram X alkylation or reduction Mitsunobu
Figure imgf000028_0003
Figure imgf000028_0001
Figure imgf000028_0002
[033] Flow Diagram XI illustrates manipulations of R6 in formula (I). These manipulations could also be applied to R and R in formula (I), R , R , and R in formula (II).
[034] Flow Diagram XI
C(=0)OR -.24
Figure imgf000029_0001
[035] Flow Diagram XII illustrates manipulations on R7 of formula (I). These manipulations could also be applied to R5 in formula (I), R5 and R7 in formula (II).
Flow Diagram XII
X =
Figure imgf000030_0001
[037] Flow Diagram XIII illustrates manipulations on R5 of formula (I). These manipulations could also be applied to R7 in formula (I), R5 and R7 in formula (II).
0381 Flow Diagram XIII
Figure imgf000031_0001
E+ is alkyl halide, aldehydes, halogen, C02, 02, activated ester, etc.
[039] Flow Diagram XIV illustrates the transformations of some functional groups which are present in Formula (I) or (II).
1 Flow Diagram XIV
k, R1 = H, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl =. ha*logen-*****---* u" = nucleophiles such as carbanion, amine, alcohol, thiol
Figure imgf000032_0001
Figure imgf000032_0002
O X, ,OMe RmMgBr A
Figure imgf000032_0003
reduction
Figure imgf000032_0004
Figure imgf000032_0005
Alternative Forms Of Novel Compounds
[041] 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.
(a) The Stereoisomers
[042] The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can 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.
(b) The Pharmaceutically-Acceptable Salts
[043] 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, salicyclic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.
(c) The Tautomers
[044] Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer. (d) The Protected Acids and the Conjugate Acids
[045] The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
(e) The Prodrugs f0461 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, absoφtion, biostability and release time (see "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 N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see 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 incoφorated by reference).
[047] The following definitions pertain to the structure of the compounds: In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified, for example, alkyl of 1-8 carbon atoms or C1-C8 alkyl. The use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms controls and conventional stable atom valences are presumed and achieved in all formulas and groups.
[048] When symbols such as "A-Q-R" is used, it refers to a group which is formed by linking group A, group Q and group R in the designated order and the attachment of this group "A-Q-R" is any position on group A to form a stable structure. Group Q may be linked to any position on group A to form a stable structure and group R may be linked to any position on group Q to form a stable structure.
[049] When symbols such as "A(OR')-R" is used, it refers to a group which is formed by susbstituting group A with both group OR' and group R and the attachment of this group "A(OR')- R" is any position on group A to form a stable structure. Group OR' and group R maybe linked to any position on group A to form a stable structure.
[050] The term "halogen" refers to a halogen radical selected from fluoro, chloro, bromo or iodo.
[051] The term "alkyl" refers to a saturated aliphatic hydrocarbon radical. "Alkyl" refers to both branched and unbranched alkyl groups. Examples of "alkyl" include alkyl groups that are straight chain alkyl groups containing from one to ten carbon atoms and branched alkyl groups containing from three to ten carbon atoms. Other examples include alkyl groups that are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. This term is examplified by groups such as methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), 1 ,1-dimethylethyl (tert-butyl), and the like. It may be abbreviated "Alk". It should be understood that any combination term using an "alk" or "alkyl" prefix refers to analogs according to the above definition of "alkyl". For example, terms such as "alkoxy", "alkylthio", "alkylamino" refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
[052] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term in examplified by groups such as trifluomethyl. The more preferred haloalkyl groups are alkyl groups substituted with one or more fluro or chloro. The term "haloalkoxy" refers to haloalkyl groups linked to a second group via an oxygen atom.
[053] The term "alkenyl" refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon double bond. "Alkenyl" refers to both branched and unbranched alkenyl groups, each optionally partially or fully halogenated. Examples of "alkenyl" include alkenyl groups that are straight chain alkenyl groups containing from two to ten carbon atoms and branched alkenyl groups containing from three to ten carbon atoms. Other examples include alkenyl groups that are straight chain alkenyl groups containing from two to six carbon atoms and branched alkenyl groups containing from three to six carbon atoms. This term is exemplified by groups such as ethenyl, propenyl, n- butenyl, isobutenyl, 3-methylbut-2-enyl, w-pentenyl, heptenyl, octenyl, decenyl, and the like.
[054] The term "alkynyl" refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon triple bond. "Alkynyl" refers to both branched and unbranched alkynyl groups, each optionally partially or fully halogenated. Examples of "alkynyl" include alkynyl groups that are straight chain alkynyl groups containing from two to ten carbon atoms and branched alkynyl groups containing from four to ten carbon atoms. Other examples include alkynyl groups that are straight chain alkynyl groups containing from two to six carbon atoms and branched alkynyl groups containing from four to six carbon atoms. This term is exemplified by groups such as ethynyl, propynyl, octynyl, and the like.
[055] The term "cycloalkyl" refers to the mono- or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl, and the like.
[056] The term "cycloalkenyl" refers to the mono- or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom that results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms. Other examples include cycloalkenyl groups containing four to six carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornene, and the like.
[057] The term "heterocycloalkyl" refers to the mono- or polycyclic structures of "cycloalkyl" where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkyl groups include moφholino, pyrazino, tetrahydrofurano, and the like.
[058] The term "heterocycloalkenyl" refers to the mono- or polycyclic structures of "cycloalkenyl" where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.
[059] The term "cycloalkyloxy" refers to a monovalent radical of the formula -O-cycloalkyl, i.e., a cycloalkyl group linked to a second group via an oxygen atom.
[060] The term "acyl" refers to a monovalent radical of the formula -C(=0)-alkyl and -C(=0)- cycloalkyl, i.e., an alkyl or cycloakyl group linked to a second group via caronyl group C(=0), wherein said alkyl maybe further substituted with cycloalkyl, aryl, or heteroaryl. Examples of acyl groups include -C(=0)Me (acetyl), -C(=0)CH2-cyclopropyl (cyclopropylacetyl), - C(=0)CH2Ph (phenylacetyl), and the like.
[061] The term "aryl" refers to 6-10 membered mono- or polycyclic aromatic carbocycles, for example, phenyl and naphthyl. Unless otherwise specified, the aryl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. The term "aryl" refers to non-substituted aryls and aryls optionally substituted with one or more of the following groups: halogen, C1 -C6 alkyl, C3- C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, -NHMe and -N(Me)2), Cl- C6 acyl, thiol, alkylthio, carboxylic acid. All the above subtsitutions can further be substituted with optionally selected groups to form a stable structure. It may be abbreviated "Ar". It should be understood that any combination term using an "ar" or "aryl" prefix refers to analogs according to the above definition of "aryl". For example, terms such as "aryloxy", "arylthio", "arylamino" refer to aryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
[062] The term "heteroaryl" refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heteroaryl contains 1- 10 carbon atoms and from 1 to 5 heteroatoms independently chosen from nitrogen, oxygen and sulfur, wherein any sulfur heteroatom may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom that results in a stable structure. The term "heteroaryl" includes heteroaryl groups that are non-substituted or those optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, -NHMe and -N(Me)2), Cl- C6 acyl, thiol, alkylthio, carboxylic acid. Examples of "heteroaryl" include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. Terms such as "heteroaryloxy", "heteroarylthio", "heteroarylamino" refer to heteroaryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively. [063] The terms "optional" or "optionally" mean that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
[064] 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 incoφorated by reference.
[065] For puφoses 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, inside cover.
Abbreviations and Acronyms
[066] When the following abbreviations are used throughout the disclosure, they have the following meaning: CH2C12 methylene chloride THF tetrahydrofuran CH3CN acetonitrile Na2S04 anhydrous sodium sulfate MgS04 anhydrous magnesium sulfate DMSO dimethylsulfoxide EtOAc ethyl acetate Et20 diethyl ether Et3N triethylamine H2 hydrogen CO carbon monoxide HCl hydrochloric acid Hex hexanes 'H NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography K2C03 potassium carbonate Cs2C03 cesium carbonate NH4C1 ammonium chloride LC/MS liquid chromatography / mass spectroscopy MeOH methanol
MS ES mass spectroscopy with electrospray
NaHC03 sodium bicarbonate
NaOH sodium hydroxide
RT retention time h hour min minutes
Pd(OAc)2 palladium acetate
Ni(dppp)Cl2 [ 1 ,3-bis(diphenylphosphino)propane]dichloronickel(II)
DMF /V,/V-dimethylformamide
EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
LTMP Lithium tetramethylpiperidine
BuLi butyllithium
TLC thin layer chromatography
TFA trifluoacetic acid
TMEDA tetramethylethylenediamine
BΓNAP 2,2'-bis(diphenylphosphino)- 1 , l'binaphthyl
HOBt 1 -hydroxybenzotriazole hydrate
NaH sodium hydride
MeMgBr methylmagnesium bromide
DPPP (diphenylphosphino)propane
DME dimethoxyethane
AICI3 aluminum chloride
TEA triethyl amine
CS2 carbon disulfide
Mel methyl iodide t-BuOK potassium tert-butoxide
KHMDS potassium hexamethyldisilazide
LiHMDS lithium hexamethyldisilazide
NaOBr sodium hypobromite
Br2 bromine
Cone. Concentrated
Pd/C palladium on carbon
EtOH ethanol
NH3 ammonia
NaOMe sodium methoxide PPh3 triphenylphosine NaH sodium hydride LDA lithium diisopropylamide S0C12 thionyl chloride MsCl methanesulfonyl chloride DMAP 4-dimethylaminopyridine NMM 4-methylmoφholine AcOH acetic acid Na2S203 sodium thiosulfate H2S04 sulfuric acid CHCI3 chloroform Mn02 manganese(IN) oxide LAH lithium aluminum hydride ADDP l,l '-(azodicarbonyl)-dipiperidine EDTA ethylenediaminetetraacetic acid CC12FCC1F2 1,1,2-trichlorotrifluoroethane NaN02 sodium nitrite
Preparative Examples
[067] Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In tables 1 A and 2A, the synthesis of each compound is referenced back to these exemplary preparative steps. In tables IB and 2B, the proposed synthesis of each compound is referenced back to these exemplary preparative steps.
[068] All reactions were carried out under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. 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.
[069] Unless otherwise stated, 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 (°C). Unless otherwise indicated, all parts and percentages are by volume.
[070] Proton (Η) nuclear magnetic resonance (ΝMR) spectra were measured with a Varian Mercury (300 MHz) or a Bruker Avance (500 MHz) spectrometer with either Me4Si (6 0.00) or residual protonated solvent (CHC13 δ 7.26; MeOH 6 3.30; DMSO δ 2.49) as standard. The ΝMR data of the synthesized examples, which are not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.
[071] The HPLC-MS spectra were obtained using a Hewlett-Packard 1 100 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% CH3CN in water with 0.02% TFA and B: 2% water in CH3CN with 0.018% TFA. Gradient elution from 10% B to 95% 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.
[072] Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. The results of elemental analyses, if conducted but not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.
[073] The following specific examples are presented to illustrate the invention related to Formula (I) as described herein, but they should not be construed as limiting the scope of the invention in any way.
[074] Intermediate A:
2,6-dichloro-4-methyl-nicotinic acid
Figure imgf000041_0001
[075] Method 1
A solution of sodium nitrite (2.73 g, 39.6 mmol) in water (15 L) was added slowly to a solution of commercially available (Maybridge) 2,6-dichloro-4-methyl-nicotinamide (4.5 g, 22 mmol) in concentrated sulfuric acid resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60 °C for 7 h. The solution was cooled to 0 °C and then water (15 L) was added. The resulting white precipitate was collected by filtration and washed with hexane. The aqueous filtrate was extracted with EtOAc (3X) and the combined organic extracts were dried over MgS04 and concentrated in vacuo. The residue was combined with the white precipitate to afford 2,6-dichloro-4-methyl-nicotinic acid (4.39 g, 97%) as a white solid: LCMS RT: 1.20 min, MH+: 206.3. [076] Method 2
Concentrated nitric acid (14 mL) was added to cooled (0 °C) concentrated sulfuric acid (43 mL) maintaining the internal temperature below 10 °C. After addition, the acid mixture was heated to 70 °C and commercially available (Avocado) 2,6-dichloro-4-methyInicotinonitrile (20.0 g, 107 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 105 °C. At this point the heating was stopped and after 2 h, TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation. The solid was filtered and washed with cold water (10 mL). The solid was dissolved in EtOAc (100 mL) and the solution was dried over Na2S04 and concentrated to give 2,6-dichloro-4-methyl-nicotinic acid (21.0 g, 96%) as a white solid: R = 0.20 (1:1 EtOAc:Hex).
[077] Intermediate B:
2,6-dichloro-4-methyl-nicotinoyl chloride
Figure imgf000042_0001
[078] A solution of 2,6-dichloro-4-methyl-nicotinic acid (3.94 g, 19.1 mmol) in thionyl chloride (18 mL) was heated to 80 °C for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-methyl-nicotinoyl chloride as yellow oil. It was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
[079] Intermediate C:
3,3-dichloro-l-(2,6-dichloro-4-methyl-pyridin-3-yI)-propenone
Figure imgf000042_0002
[080] A solution of the 2,6-dichloro-4-methyl-nicotinoyl chloride from the previous reaction in CH2C12 (10 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of A1C13 (2.54 g, 19.1 mmol) in CH2C12 (54 mL). After 15 min, vinylidene chloride (1.5 mL, 1.85 g, 19.1 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and the ice slurry was acidified using 1 N HCl (50 mL). Stirring was continued for 20 min and then the product was extracted with CH2C12 (3X). The combined organic extracts were dried over Na2S04 and concentrated in vacuo to give 3,3-dichloro-l-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone (4.22 g, 77 %) as a yellow oil: LCMS RT: 3.25, MH+: 284.3, R/ = 0.47 (4: 1 Hex:EtOAc).
[081] Intermediate D: l-(2,6-Dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone
Figure imgf000043_0001
[082] A solution of aniline (4.04 mL, 44.4 mmol) in TEA (6.2 mL, 44.4 mmol) was added slowly to a cooled (0 °C) and stirred solution of 3,3-dichloro-l-(2,6-dichloro-4-methyl-pyridin-3- yl)-propenone (4.22 g, 14.8 mmol) in dioxane (50 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with EtOAc (3X). The combined organic extracts were washed with water, dried over Na2S04 and concentrated in vacuo. Silica gel flash chromatography of the residue using 7:1 EtOAc:Hex gave l-(2,6-dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone as yellow solid (2.22 g, 40 %): LCMS RT: 3.21 min; MH+: 398.2, R = 0.27 (2: 1 Hex:EtOAc).
[083] Intermediate E:
7-Chloro-5-methyl-l-phenyl-2-phenylamino-lH-[l,8]-naphthyridin-4-one
Figure imgf000043_0002
[084] A mixture of l-(2,6-dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone (2.17 g, 5.45 mmol) and t-BuOK (1.10 g, 9.81 mmol) in dioxane (55 mL) was heated to 80 °C overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1: 1 EtOAc:Hex provided 7-chloro-5-methyl-l-phenyl-2-phenylamino-lH-[l ,8]naphthyridin-4-one (1.297 g, 66%) as an orange solid: LCMS RT: 2.52 min, MH+: 362.3, R = 0.18 (1 : 1 EtOAc:Hex) This transformation can also be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.
[085] Intermediate F:
2,6-dichloro-4-(trifluoromethyl)nicotinic acid
Figure imgf000044_0001
[086] Method 1
A solution of NaN02 (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4-(trifluoromethyl)nicotinamide (20.0 g, 77 mmol) in cone. H2S04 resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60 °C for 18 h. The solution was cooled to 0 °C and then water (15 mL) was added. The resulting mixture was extracted with Et20 (3X) and the combined organic extracts were dried over MgS04 and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19 g, 95%) as an off-white solid: R/ = 0.30 (9: 1 CH2Cl2:MeOH), Η-NMR (d6-DMSO, 300 MHz) δ 8.18 (s, IH).
[087] Method 2
Cone. HN03 ( 13.3 mL) was added to cooled (0 °C) cone. H2S04 (60 mL) maintaining the internal temperature below 10 °C. After addition, the acid mixture was heated to 70 °C and commercially available (Maybridge) 2,6-dichloro-4-(trifluoromethyl)nicotinonitrile (20.0 g, 83 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 100 °C. After heating for 1 h TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation and extracted with Et20 (3X). The organic layers were combined and washed with brine. The solution was dried over Na2S04 and concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19.1 g, 89%) as an off-white solid: R/ = 0.30 (9: 1 CH2Cl2:MeOH), Η-NMR (d6-DMSO, 300 MHz) δ 8.18 (s, I H). [088] Intermediate G: 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride
Figure imgf000045_0001
[089] A solution of 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (3.22 g, 13.2 mmol) in thionyl chloride (9 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride as a yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
[090] Intermediate H:
3,3-dichloro-l-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-l-one
Figure imgf000045_0002
[091] A solution of the 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride from the previous reaction in CH2Cl2 (14 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of A1C13 (4.4 g, 33.0 mmol) in CH2C12 (14 mL). After 15 min, vinylidene chloride (2.6 mL, 33.0 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2C12. The organic layer was collected and cooled to 0 °C before TEA (4.6 mL, 33 mmol)was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with IN HCl, NaHC03, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-l-one: (4.3 g, 95%) as a brown oil: LCMS RT: 3.59, MH+: 488.1 , R/ = 0.44 (EtOAc). [092] Intermediate I:
3,3-dianilino-l-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-l-one
Figure imgf000046_0001
[093] A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0 °C) and stirred solution of 3,3-dichloro-l-[2,6-dichloro-4-(trifluoromethyl)-3- pyridinyl]-2-propen-l-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCl and extracted with Et20 (3X). The combined organic extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6: 1 Hex:EtOAc gave 3,3-dianilino-l -[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-l-one as an off-white solid (13.10 g, 43%): Η-NMR (d6-DMSO, 300 MHz) δl2.24 (br s, I H), 9.20 (br s, I H), 7.95 (s, IH), 7.12- 7.42 (m, 10H), 4.82 (s, IH); R/ = 0.60 (6: 1 Hex:EtOAc).
[094] Intermediate J:
2-anilino-7-chloro-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one
Figure imgf000046_0002
[095] A mixture of 3,3-dianilino-l-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-l- one (12.9 g, 28.5 mmol) and t-BuOK (28.5 mL, 28.5 mmol, IM in THF) in dioxane (200 mL) was heated at reflux overnight. The reaction was cooled, concentrated in vacuo, treated with saturated NH4C1 and extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried over MgS04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 6: 1 Hex:EtOAc provided 2-anilino-7-chloro-l-phenyl-5-(trifluoromethyl)-l ,8-naphthyridin- 4(lH)-one (11.2 g, 95%) as an off-white solid: LCMS RT: 3.00 min, MH+: 416.7, R/ = 0.25 (3:1 Hex:EtOAc). This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH. [096] intermediate K: 2,6-dichloro-5-fluoronicotinoyl chloride
Figure imgf000047_0001
[097] A solution of commercially available (Aldrich) 2,6-dichloro-5-fluoronicotinic acid (5.00 g, 23.8 mmol) in thionyl chloride (15 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-5-fluoronicotinoyl chloride as a brown oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
[098] Intermediate L:
3,3-dichloro-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l-one
Figure imgf000047_0002
[099] A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH2C12 (25 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of A1C13 (7.9 g, 59.5 mmol) in CH2C1 (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2C12. The organic layer was collected and cooled to 0 °C before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with IN HCl, NaHC03, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3- dichloro-l -(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l-one: (6.1 g, 90%) as a brown oil: Η- NMR (d6-DMSO, 300 MHz) δ 8.43 (d, IH, J = 8.4 Hz), 7.56 (s, IH), R/ = 0.76 (3: 1 Hex:EtOAc).
[100] Intermediate M:
3,3-dianilino-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l-one
Figure imgf000047_0003
[101] To a O °C solution of 3,3-dichloro-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l -one (6.70 g, 23.2 mmol) in dioxane (50 mL) was added TEA (9.7 mL, 69.6) followed by aniline (6.3 L, 69.6 mmol). After 1 h the reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with CH2C12 (2X). The combined organic extracts were washed with water, dried over Na2S04 and concentrated in vacuo. Purification of the residue by silica gel Biotage chromatography provided 3,3-dianilino-l-(2,6-dichloro-5-fluoro-3- pyridinyl)-2-propen-l -one as yellow solid (4.2 g, 49%): LCMS RT: 3.47 min; MH+: 402.6.
[102] Intermediate N:
2-anilino-7-chloro-6-fluoro-l-phenyI-l,8-naphthyridin-4(lH)-one
Figure imgf000048_0001
[103] A mixture of 3,3-dianilino-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l-one (2.3 g, 5.7 mmol) and -BuOK (1.28 g, 1 1.4 mmol) in dioxane (80 mL) was stirred at 80 °C overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue provided 2-anilino-7-chloro-6-fluoro-l- phenyl-1 ,8-naphthyridin-4(lH)-one (1.0 g, 50%) as a light yellow solid: LCMS RT: 2.60 min, MH+: 366.8. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.
[104] Intermediates N Nι2 were synthesized from 3,3-dichloro-l-(2,6-dichloro-5-fluoro-3- pyridinyl)-2-propen-l-one as above for Intermediate N using the appropriate amine: ri051 Intermediate Nύ
Figure imgf000048_0002
LCMS RT: 2.81 min, MH+: 402.3 π061 Intermediate N7:
Figure imgf000049_0001
LCMS RT: 2.73 min, MH+: 402.4
[107] Intermediate N3
Figure imgf000049_0002
LCMS RT: 2.30 min, MH+: 298.1 π081 Intermediate N4
Figure imgf000049_0003
LCMS RT: 2.88 min, MH+: 394.3
f109l Intermediate Ns:
Figure imgf000049_0004
LCMS RT: 2.78 min, MH+: 426.3 π 101 Intermediate N^:
Figure imgf000050_0001
LCMS RT: 3.09 min, MH+: 434.5
T1111 Intermediate N;:
Figure imgf000050_0002
LCMS RT: 3.07 min, MH+: 378.2
T1121 Intermediate Ng:
Figure imgf000050_0003
LCMS RT: 3.15 min, MH+: 422.4
π 131 Intermediate Ng:
Figure imgf000050_0004
LCMS RT: 2.90 min, MH+: 486.3 π 141 Intermediate :
Figure imgf000051_0001
LCMS RT: 2.22 min, MH+: 294.2
T1151 Intermediate Nπ :
Figure imgf000051_0002
LCMS RT: 3.05 min, MH+: 430.4
T1161 Intermediate Nr?:
Figure imgf000051_0003
LCMS RT: 2.51 min, MH+: 468.3
π 171 Intermediate NL
Figure imgf000051_0004
LCMS RT: 3.10 min, MH+: 430.4 [118] Intermediate O: 2,6-dichloronicotinoyl chloride
Figure imgf000052_0001
[119] A solution of commercially available (Aldrich) 2,6-dichloro-nicotinic acid (2.0 g, 10.4 mmol) in thionyl chloride (10 mL) was heated to 80 °C for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-nicotinoyl chloride as yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
[120] Intermediate P:
3,3-dichloro-l-(2,6-dichloro-3-pyridinyl)-2-propen-l-one
Figure imgf000052_0002
[121] A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2C12 (5 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of A1C1 (0.64 g, 4.76 mmol) in CH2C12 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2C12 (3X). The combined organic extracts were dried over Na2S04 and concentrated in vacuo to give 3,3-dichloro-l -(2,6-dichloro-3-pyridinyl)-2-propen-l-one (0.88 g, 68% ) as a light yellow oil: Η-NMR (CDC13, 300 MHz) δ 8.38, d, J = 8.4, IH). 7.40 (d, J = 8.4, IH), 7.10 (s, IH); Rf = 0.51 (4: 1 Hex:EtOAc).
[122] Intermediate Q: 3,3-dianilino-l-(2,6-dichloro-3-pyridinyl)-2-propen-l-one
Figure imgf000053_0001
[123] A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 1 1.1 mmol) was added slowly to a cooled (0 °C) and stirred solution of 3,3-dichloro-l-(2,6-dichloro-3-pyridinyl)-2- propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3X). The combined organic extracts were washed with water, dried over Na2S04 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6: 1 EtOAc:Hex gave 3,3-dianilino-l-(2,6- dichloro-3-pyridinyl)-2-propen-l-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH+: 384.2.
[124] Intermediate R:
2-anilino-7-chloro-l-phenyl-2,3-dihydro-l,8-naphthyridin-4(lH)-one
Figure imgf000053_0002
[125] A mixture of 3,3-dianilino-l-(2,6-dichloro-3-pyridinyl)-2-propen-l-one (0.08 g, 0.21 mmol) and NaH ( 0.009 g, 0.23 mmol) in THF (6 mL) was heated to 80 °C overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S0 , and concentrated in vacuo. Silica gel flash chromatography of the residue using 3: 1 Hex:EtOAc provided 2-anilino-7-chloro- l-phenyl-2,3-dihydro-l,8-naphthyridin-4(lH)-one (49 mg, 68%) as an off- white solid: LC-MS RT: 2.56 min, MH+: 348.2. This transformation can be accomplished by using the combination of other aprotic solvents such as dioxane and DMF with other bases such as t-BuOK. [126] Intermediate S: Ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate
[127] Ethyl 3-(2-chloro-6-methyl(3- xpyridXyl))-3X-oxopro°pa"noate was prepared by the general procedure described in the Journal of Medicinal Chemistry, 1986, 29, 2363. The product had: MH+: 242.1, LCMS RT: 2.33 and 3.06 min (keto-enol).
[128] Intermediate T:
Ethyl (2Z)-2-[(2-chloro-6-methyI(3-pyridyI))carbonyl]-3,3-dimethyIthio-prop-2-enoate
Figure imgf000054_0001
[129] Cs2C03 (24.0 g, 72.5 mmol) was added to a solution of ethyl 3-(2-chloro-6-methyl(3- pyridyl))-3-oxopropanoate (7.0 g, 29 mmol) in THF (290 mL). The reaction mixture was cooled to -10 °C and after 15 min, CS2 (8.7 mL, 145 mmol) was added. Stirring was continued for 2 h and Mel (4.5 mL, 72.5 mmol) was added. The reaction was slowly warmed to room temperature over 18 h and filtered. The filtrate was concentrated in vacuo to provide ethyl (2Z)-2-[(2-chloro- 6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate as a yellow oil that was used without purification. LCMS RT: 2.79 min, MH+: 345.8. A variety of alkyl halides can be used to quench the generated sulfur anion.
[130] Intermediate U:
Ethyl (2i5)-3,3-bis(phenylamino)-2-[(2-chloro-6-methyl(3-pyridyI))-carbonyl]prop-2-enoate
Figure imgf000054_0002
[131] A solution of ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop- 2-enoate (100. mg, 0.28 mmol) and aniline (0.076 mL, 0.83 mmol) in THF (1.4 mL) was heated at reflux for 18 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 1 :1 EtOAc:Hex provided ethyl (2E)-3,3- bis(phenylamino)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]prop-2-enoate (55.6 mg, 44%): LCMS RT: 3.56 min, MH+: 436.3.
[132] Intermediate V:
Ethyl 7-methyl-2-methylthio-4-oxo-l-phenylhydropyridino[2,3-b]-pyridine-3-carboxylate
Figure imgf000055_0001
[133] Aniline (3.96 mL, 43.5 mmol) was added to a solution of ethyl (2Z)-2-[(2-chloro-6- methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate (5.13 g, 14.5 mmol) in DMSO (72.5 mL). The reaction solution was heated to 70 °C for 18 h and then cooled to room temperature. The solution was diluted with EtOAc, washed with water and brine, dried over Na2S04, and concentrated in vacuo. Trituration of the resulting orange oil with Et20 afforded some desired product as a yellow solid. Additional product was obtained by silica gel flash chromatography of the mother liquor using 1: 1 EtOAc:Hex. The two purifications provided ethyl 7-methyl-2- methylthio-4-oxo-l-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (2.87 g, 56%) as a yellow solid: LCMS RT: 2.85 min, MH+: 355.0.
[134] Intermediate W:
Ethyl 7-methyl-4-oxo-l-phenyl-2-(phenylamino)hydro-pyridino[2,3-b]-pyridine-3- carboxylate
Figure imgf000055_0002
[135] A solution of ethyl (2£)-3,3-bis(pheny lamino)-2-((2-chloro-6-methy 1(3- pyridyl))carbonyl)prop-2-enoate (85.0 mg, 0.195 mmol) and t-BuOK (67 mg, 0.60 mmol) in dioxane (2 mL) was heated at reflux for 48 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc to 100% EtOAc gave ethyl 7-methyl-4-oxo-l-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridine- 3-carboxylate (39 mg, 49%) as a white solid: LCMS RT: 2.80 min, MH+ 400.0. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.
[136] Intermediate X:
Ethyl 2-[(4-chlorophenyl)amino]-7-methyl-4-oxo-l-phenyl-hydropyridino-[2,3-b]pyridine-3- carboxylate
Figure imgf000056_0001
[137] KHMDS (0.5 M in toluene, 0.84 mL, 0.42 mmol) was added to a cooled (-78 °C) solution of 4-chloroaniline (71.4 mg, 0.560 mmol) in THF (0.70 mL). After 2 h, a solution of ethyl 7- methyl-2-methylthio-4-oxo-l -phenylhydropyridino[2,3-b]pyridine-3-carboxylate (100 mg, 0.28 mmol) in THF (0.70 mL) was added resulting in immediate formation of an orange solution. The reaction was slowly warmed to room temperature, stirred for 21 h, and quenched with saturated aqueous NH C1. The aqueous solution was extracted with Et20 (3X) and the combined organic extracts were washed with water and brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave ethyl 2-[(4- chlorophenyl)amino]-7-methyl-4-oxo- 1 -phenylhydropyridino[2,3-b]pyridine-3-carboxylate (30.0 mg, 25%) as a white solid: LCMS RT: 2.98 min, MH+ 434.0.
[138] Intermediate Y: 5-Bromo-2-hydroxy-6-methylnicotinc acid
Figure imgf000056_0002
[139] A solution of NaOBr was prepared by adding Br2 (11.4 g, 3.66 mL, 71.3 mmol) to a cooled (0 °C) and stirred solution of NaOH (7.8 g, 196 mmol) in water (90 mL). This solution was warmed to room temperature and was then added to a solution of commercially available (Aldrich) 2-hydroxy-6-methylpyridine-3-carboxylic acid (10.0 g, 65.1 mmol) and NaOH (7.8 g, 196 mmol) in water (30 mL). After stirring for 5 min, the mixture was cooled to 0 °C and carefully acidified with cone. HCl. The precipitate was filtered and dried over MgS0 to afford 5-bromo-2-hydroxy- 6-methylnicotinc acid (15.0 g, 99%): Η NMR (DMSO-d6) 8.25 (s, IH), 2.41 (s, 3H); MH+: 232.0. Elemental analysis calculated for C7H6BrN03: C, 36.23; H, 2.61; N, 6.04; Br, 34.44; Found: C, 36.07; H, 2.44; N, 5.91 ; Br, 34.43.
[140] Intermediate Z (Same as Intermediate BA):
2,4-dichloro-6-methylnicotinic acid
Figure imgf000057_0001
[141] A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3- carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80 °C for 4 h. The mixture was acidified using 50% H2S04 and filtered. The solid was washed with cold water and dried to give of 2,4-dichloro-6- methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.
[142] Intermediate AA (Same as Intermediate BB):
3,3-dichloro-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one
Figure imgf000057_0002
[143] The compound was prepared according to the procedure described for Intermediate BB below. LCMS RT: 3.13 min, MH+: 284.6.
[144] Intermediate AB (Same as intermediate BC):
3,3-dianilino-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one
Figure imgf000057_0003
[145] The compound was prepared according to the procedure described for Intermediate BC below: LCMS RT: 3.06 min, MH+: 398.7. [146] Intermediate AC:
(2Z)-3-anilino-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen -1-one
Figure imgf000058_0001
[147] 3,3-dichloro-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l-one (374.0 mg, 1.29 mmol) was dissolved in CH2C12 (5 mL) and cooled to 10 °C. Aniline (120.0 mg, 1.29 mmol) and isopropylamine (76.5 mg, 1.29 mmol) were added dropwise as a mixture in 3 mL of 1,4-dioxane. TEA (0.897 mL, 6.45 mmol) was added and the reaction mixture was warmed to room temperature and left to stir for 2 h. The dioxane was removed in vacuo and the brown residue was partitioned between EtOAc and saturated aqueous NaHC03. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 6: 1 to 7:3 Hex:EtOAc provided (2Z)-3-anilino-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2- propen-1-one (45 mg, 10%) as an off-white solid: LCMS RT: 3.63 min, MH+: 368.2.
[148] Intermediate AD:
4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate
Figure imgf000058_0002
[149] To a warmed (40 °C ) suspension of niflumic acid ( 10.0 g, 35.4 mmol) and 4-nitrophenol (4.9 g, 35.4 mmol) in CH2Cl2 (80 mL) was added a suspension of EDCI (6.8 g, 35.4 mmol) in CH2Cl2 (20 mL). The reaction was stirred for 16 h, and then cooled to room temperature. The solution was quenched with water (50 mL), and the aqueous layer was extracted with CH2C12. The combined organic extracts were washed with water and dried over Na2S04. The solvent was removed in vacuo, and the residue was purified by trituration with Hex:CH2Cl to afford 4- Nitrophenyl 2-{ [3-(trifluoromethyl)phenyl]amino}nicotinate (4.5 g, 31%): LCMS RT: 4.03 min, MH+: 404.1.
[150] Intermediate AE:
Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate
Figure imgf000059_0001
[151] To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4- nitrophenyl 2-{ [3-(trifluoromethyl)phenyl]amino}nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH2C12 (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2X) and dried over Na2S04. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5:1 to 2:1 Hex:EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3-(2-{ [3- (trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate.(6 g, 87%): LCMS RT: 2.83 min, MH+: 378.0.
[152] Intermediate AF:
2-Amino-l-[3-(trifluoromethyl)phenyl]-l,8-naphthyridin-4(lH)-one
Figure imgf000059_0002
[153] Ethyl 2-cyano-3-oxo-3-(2-{ [3-(trifluoromethyl)phenyl]amino}-3-pyridinyl) propanoate (2.0 g, 5.3 mmol) was heated to 120 °C in a mixture of cone. HCl (4 mL) and glacial acetic acid (2 mL) for 3 h. The reaction mixture was cooled to room temperature, and neutralized by slow addition of NaOH pellets. The mixture was extracted with CH2C12 (3X). The combined organic extracts were washed with saturated aqueous NaHC03 (10 mL) and brine (10 mL), dried over MgS04, and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150 x 20 mm I.D.; 30-70% CH3CN in water, 20 min.) to afford 2-Amino-l-[3- (trifluoromethyl)phenyl]-l,8-naphthyridin-4(lH)-one (880 mg, 55%): LCMS RT: 2.03 min, MH+: 306.3.
[154] Intermediate AG :
7-chloro-6-fluoro-2-(isopropylamino)-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000060_0001
[155] (2Z)-3-Anilino-l-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-l-one (40.0 mg, 0.109 mmol) was dissolved in 4 L of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85 °C under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-(isopropylamino)- l-phenyl-l,8-naphthyridin-4(lH)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH+: 332.2.
[156] Intermediate AH:
2-anilino-7-chloro-6-fluoro-5-methyl-l-phenyl-l,8-naphthyridin-4(l f)-one
Figure imgf000060_0002
[157] A solution of LTMP [freshly prepared at 0 °C from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol)] in THF (5 mL) was added to a cooled (-40 °C) and stirred solution of 2-anilino-7-chloro-6-fluoro-l-phenyl-l ,8- naphthyridin-4(l )-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0 °C, for 1 h and then re-cooled to -40 °C. Mel (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1 : 1 EtOAc:Hex afforded 2-anilino-7-chloro- 6-fluoro-5-methyl-l-phenyl-1 ,8-naphthyridin-4(l/ )-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH+: 380.3. This transformation can also be accomplished by using other amide bases such as LDA.
[158] Intermediate Al:
2-anilino-7-chloro-6-fluoro-l-phenyl-5-(trifluoroacetyl)-l,8-naphthyridin-4(l )-one
Figure imgf000061_0001
[159] A solution of LTMP [freshly prepared at 0 °C from tetramethylpiperidine (154 mg, 1.10 mmol), TMEDA (127.8 mg, 1.10 mmol) and n-BuLi (0.688 mL, 1.10 mmol)] in THF (5 mL) was added to a cooled (-40 °C) stirred solution of 2-anilino-7-chloro-6-fluoro-l-phenyl-l,8- naphthyridin-4(l /)-one (100 mg, 0.273 mmol) in THF(10 mL). The reaction was stirred for 1 h and then cooled to -78 °C. Methyl trifluoroacetate (350 mg, 2.74 mmol) was added and stirring was continued for 2 h. The reaction was quenched carefully with water (50 mL), warmed to room temperature and extracted with EtOAc . The combined organic extracts were washed with brine, dried over Na2S0 , and concentrated in vacuo. Silica gel flash chromatography of the residue using 3: 1 Hex:EtOAc gave 2-anilino-7-chloro-6-fluoro-l-phenyl-5-(trifluoroacetyl)-l,8- naphthyridin-4(l//)-one (71 mg, 56%) as a light yellow solid: LCMS RT: 3.43 min, MH+: 462.3. The anion generated from LTMP deprotonation can be quenched with other electrophiles including carbon dioxide and 4-nitrophenyl acetate.
[160] Intermediate AJ:
7-chloro-5-methyl-2-[methyl(phenyl)amino]-l-phenyl-l,8-naphthyridin-4(lil/)-one
Figure imgf000061_0002
[161] Mel (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2C03 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-l-phenyl-l,8-naphthyridin-4( l/-r)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40 °C and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na S04 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]- 1 -phenyl- 1 ,8-naphthyridin-4( 1 /)- one (18 mg, 35%): LCMS RT: 2.24 min, MH+: 376.6, Rf = 0.76 (4: 1 Hex:EtOAc).
[162] Intermediate AK:
N-(7-chloro-5-methyl-4-oxo-l-phenyl-l,4-dihydro-l,8-naphthyridin-2-yl)-N'-(4- fluorophenyl)-N-phenylurea
Figure imgf000062_0001
[163] 4-Fluorophenyl isocyanate (45.0 mg, 0.33 mmol) was added to a stirred solution of 2- anilino-7-chloro-5-methyl-l-phenyl-l ,8-naphthyridin-4(lH)-one (100 mg, 0.276 mmol) in CH2C12 (3 mL). After 16 h, an additional equivalent of 4-fluorophenyl isocyanate (45.0 mg) was added, and the reaction stirred for an additional 16 h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with 1 N HCl, dried over MgS0 , and concentrated in vacuo. Purification of the residue using reverse phase prep-HPLC afforded N-(7- chloro-5-methyl-4-oxo-l-phenyl-1 ,4-dihydro-l,8-naphthyridin-2-yl)-N'-(4-fluorophenyl)-N- phenylurea (2.2 mg, 1.6%): LCMS RT: 3.47 min, MH+: 499.1 , R/ = 0.52 (1: 1 EtOAc:Hex).
[164] Intermediate AL:
2-anilino-7-chloro-3-iodo-5-methyl-l-phenyl-l,8-naphthyridin-4(l /)-one
Figure imgf000062_0002
[165] K2C03 (210 mg, 1.52 mmol) and I2 (390 mg, 1.52 mmol,) were added to a solution 2- anilino-7-chloro-5-methyl-l-phenyl-l ,8-naphthyridin-4(lH)-one (500 mg, 1.38 mmol) in DMF ( 10 mL). The mixture was stirred for 30 min and then poured into an aqueous solution of saturated Na2S203 (10 mL). The aqueous solution was extracted with EtOAc. The combined organic extracts were dried over MgS04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 4: 1 to 1 : 1 Hex:EtOAc afforded 2-anilino-7-chloro-3-iodo-5-methyl-l-phenyl- l,8-naphthyridin-4(l )-one (380 mg, 56%): LCMS RT: 3.45 min, MH+: 488.2, R = 0.5 (2: 1 Hex:EtOAc).
[166] Intermediate AM:
2-anilino-7-chloro-6-fluoro-5-(l-hydroxypropyl)-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000063_0001
[167] A -40 °C solution of 2-anilino-7-chloro-6-fluoro-l-phenyl-l,8-naphthyridin-4(lH)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramefhyl piperidine and n-BuLi at 0 °C for 30 min.). The mixture was then allowed to warm to 0 °C for 2 h. The reaction mixture was cooled to -30 °C and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stirred at -30 °C for 2 h before it was slowly quenched with saturated aqueous NH4C1. The mixture was extracted with EtOAc and the organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(l -hydroxypropyl)-l-phenyl-l,8- naphthyridin-4( lH)-one ( 120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.
[168] Example 1 :
2-anilino-5-methyl-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000063_0002
[169] A solution of 2-anilino-7-chloro-5-methyl-l-phenyl-l,8-naphthyridin-4(lH)-one (95.0 mg, 0.263 mmol), TEA (0.65 mmol), and 10% Pd/C in EtOAc (2.5 mL) and EtOH (2.5 mL) was stirred under H2 (1 atm) for 3.5 h. The reaction mixture was filtered through a pad of Celite using EtOH and EtOAc to rinse. The combined filtrates were concentrated in vacuo, and purified with Biotage silica gel chromatography using 1 : 1 EtOAc:Hex to afford 2-anilino-5-methyl-l-phenyl-l,8- naphthyridin-4(lH)-one (84 mg, 98%) as a pale yellow solid. LCMS RT: 2.26 min, MH+: 328.4, R/= 0.1 (l: l EtOAc:Hex),
[170] Example 2:
5-MethyI-7-morpholin-4-yl-l-phenyl-2-phenyIamino-lH-[l,8]-naphthyridin-4one
Figure imgf000064_0001
[171] A mixture of 7-chloro-5-methyl-l -phenyl-2-phenylamino-lH-[ l ,8]naphthyridin-4-one (68.3 mg, 0.189 mmol) and moφholine (0.05 mL, 0.48 mmol) in dioxane (3 mL) was heated to 80°C for 2 d. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried over Na2S0 , and concentrated in vacuo to give 5-methyl-7-moφholin-4-yl-1-phenyl-2-phenylamino-lH- [l,8]naphthyridin-4-one (67 mg, 92%) as yellow solid: LCMS RT: 2.33 min, MH+: 413.4, R/ = 0.49 (EtOAc).
[172] Example 3:
5-Methyl-l-phenyl-2,7-bis-phenyIamino-lH-[l,8]naphthyridin-4-one
Figure imgf000064_0002
[173] A mixture of 7-chloro-5-methyl-l-phenyl-2-phenylamino-lH-[l,8]naphthyridin-4-one ( 15.1 mg, 0.042 mmol), aniline (2 drops), Pd(OAc)2 (0.27 mg, 0.001 mmol), Cs2C03 (19.5 mg, 0.06 mmol), and BINAP (1.68 mg, 0.003 mmol) in THF (0.5 mL) was heated at reflux for 16 h. The reaction was quenched with water and extracted with EtOAc (3X). The combined organic extracts were washed brine, dried over Na2S04, and concentrated in vacuo to give 5-methyl-l- phenyl-2,7-bis-phenylamino-lH-[l ,8]naphthyridin-4-one (6.0 mg, 38%): LCMS RT: 2.57 min, MH+: 419.5, R/= 0.18 (EtOAc).
[174] Example 4:
2-anilino-l,7-diphenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one
Figure imgf000065_0001
[175] A solution of 2-anilino-7-chloro-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)- one (10.0 mg, 0.241 mmol), Ph3P (6.00 mg, 0.024 mmol) and phenylboronic acid (36.0 mg, 0.290 mmol) in DME was treated with 2M K2C03 (0.482 mL, 0.964 mmol) and Pd(OAc)2 (1.35 mg, 0.006 mmol). The mixture was heated at reflux for 24 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino- l,7-diphenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one (45.0 mg, 41%): LCMS RT: 3.76 min, MH+: 458.4.
[176] Example 5:
2-anilino-7-benzyl-5-methyl-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000065_0002
[177] To a solution of 2-anilino-7-chloro-5-methyl-l-phenyl-l ,8-naphthyridin-4( lH)-one ( 100 mg, 0.277 mmol) in THF was added Ni(dppp)Cl2 (37.0 mg, 0.069 mmol). After stirring for 5 min, benzylmagnesium chloride (2M , 1.45 L, 2.90 mmol) was added dropwise via syringe and the mixture was allowed to stir for 24 h. The mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% MeNC in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-benzyl-5-methyI-l-phenyl-l,8-naphthyridin-4(lH)-one (47.3 mg, 41 %): LCMS RT: 2.85 min, MH+: 418.3.
[178] Example 6:
Ethyl{[7-aniIino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-l,8-naphthyridin-2- yljsulfanyl Jacetate
Figure imgf000066_0001
[179] NaH (60% dispersion in oil, 18.0 mg, 0.434 mmol) was added to a cooled (0 °C) and stirred solution of ethyl mercaptoacetate (0.05 mL, 0.434 mmol) in DMF. After 0.5 h, 2-anilino-7- chloro-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one (150.0 mg, 0.361 mmol) was added as a solid in a single portion. The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS0 , and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided ethyl { [7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-l ,8- naphthyridin-2-yl]sulfanyl}acetate (50 mg, 53%): LCMS RT: 3.91 min, MH+: 500.2, Rf = 0.24 (l:l EtOAc:Hex).
[180] Example 7:
{[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-l,8-naphthyridin-2- yl]sulfanyl}acetic acid
Figure imgf000066_0002
[181] NaOH (160 mg, 4.0 mmol) was added to a stirred solution of ethyl { [7-anilino-5-oxo-8- phenyl-4-(trifluoromethyl)-5,8-dihydro-l,8-naphthyridin-2-yl] sulfanyl } acetate (30.0 mg, 0.060 mmol) in aqueous EtOH (lOmL EtOH in 4mL H20). The mixture was allowed to stir for 4 h and was then concentrated in vacuo. The reaction was acidified with 1 N HCl and extracted with CH2C12. The organic layer was dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided { [7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-l ,8-naphthyridin-2- yl]sulfanyl }acetic acid (19.0 mg, 66%): LCMS RT: 2.50 min, MH+: 472.1
[182] Example 8
2-anilino-l-phenyI-7-(l-piperidinyl)-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one
Figure imgf000067_0001
[183] To a solution of 2-anilino-7-chloro-l-phenyl-5-(trifluoromethyl)-1 ,8-naphthyridin-4(lH)- one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40.9 mg, 0.481 mmol). The mixture was left to stir at 80 °C overnight. The mixture was cooled to room temperature, poured into IN HCl (1 mL) and extracted with CH2C12. The organic extracts were combined, washed with saturated aqueous NaHC03, dried over Na2S0 , and concentrated in vacuo. The residue was purified by Biotage silica gel chrmoatography (1 :1 EtOAc:Hex) to provide 2-anilino- l-phenyl-7-(l-piperidinyl)-5-(trifluoromethyl)-l ,8-naphthyridin-4(lH)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH+: 465.5.
[184] Example 9:
2-anilino-7-[2-(2-oxo-l-pyrrolidinyl)ethoxy]-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin- 4(lH)-one
Figure imgf000067_0002
[185] NaH (60% dispersion, 20.0 mg, 0.514 mmol) was added to a cooled (0 °C) and stirred solution of l-(2-hydroxyethyl)-2-pyrrolidinone (0.06 mL, 0.514 mmol) in DMF. After 0.5 h, 2- anilino-7-chloro-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one (178 mg, 0.428 mmol) was added as a solid in a single portion and the mixture was heated to 130 °C for 48 h. After cooling to room temperature the mixture was quenched with saturated aqueous NFLCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-[2-(2-oxo-l- pyrrolidinyl)ethoxy]-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one (0.047 g, 64%): LCMS RT: 2.40 min, MH+: 509.2. This transformation can be accomplished by using other aprotic solvents such as DMSO, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.
[186] Example 10:
2-anilino-5-(hydroxymethyl)-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000068_0001
[187] A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (-78 °C) and stirred suspension of 2-anilino-5-methyl- 1 - phenyl- l,8-naphthyridin-4(lH)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a fritted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature. The reaction was quenched with water and IM HCl (5 mL), and then extracted with CH2C12. The organic phase was dried over Na2S0 and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5- (hydroxymethyl)-l -phenyl- l,8-naphthyridin-4(lH)-one (1.38 g, 53%): LCMS RT: 2.01 min, MH+: 344.3, R/ = 0.22 (95:5 CH2Cl2:MeOH). [188] Example 1 1: 2-anilino-l-phenyl-5-(l-piperazinylmethyl)-l,8-naphthyridin-4(lH)-one
Figure imgf000069_0001
[189] A solution of 2-anilino-5-(hydroxymethyl)-l-phenyl-l,8-naphthyridin-4(lH)-one (180 mg, 0.52 mmol), N,N-diisopropylethylamine (0.10 mL, 0.52 mmol) and SOCl2 (0.12 L, 1.57 mmol) in CH2C12 (7 mL) was stirred at room temperature for 2 h. Excess SOCl2 and solvent were removed in vacuo to afford a brownish solid. Crude 2-anilino-5-(chloromethyl)-l -phenyl- 1 ,8- naphthyridin-4(lH)-one was used without further purification: LCMS RT: 2.50 min, MH+: 362.3.
DMF (1 mL) was added to a stirred suspension of crude 2-anilino-5-(chloromethyl)-l-phenyl-l,8- naphthyridin-4(lH)-one (15.0 mg, 0.041 mmol), N,N-diisopropylethylamine (0.036 mL, 0.21 mmol), and piperazine (36 mg, 0.21 mmol) in 1,4-dioxane (2 mL). The solution was heated to 50 °C overnight, cooled to room temperature and concentrated in vacuo. Reverse phase preparative HPLC (0.1 % TFA in CH3CN and water) of the residue gave 2-anilino-l-phenyl-5-(l- piperazinylmethyl)-l ,8-naphthyridin-4(lH)-one (8.0 mg, 37%) as the TFA salt: LCMS RT: 0.71 min, MH+: 412.2.
[190] Example 12:
5-Methyl-l-phenyl-2-phenylamino-7-piperazin-l-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000069_0002
[191] A mixture of 5-methyl-l-phenyl-2-phenylamino-7-piperazin-l-yl-lH-[l ,8]naphthyridin-4- one (22.6 mg, 0.055 mmol) and MsCl (0.083 mmol, 0.006 mL) in CH2Cl2 (0.8 mL) was stirred at room temperature overnight at which time the solvent was removed in vacuo. The resulting residue was purified by prep-TLC to give 7-(4-methanesulfonyl-piperazin-1 -yl)-5-methyl-l- phenyl-2-phenylamino-lH-[l,8]naphthyridin-4-one (3.4 mg, 6%): LCMS RT: 2.36 min, MH+: 490.3.
[192] Example 13:
5-methyl-l-phenyl-2-phenylamino-7-(4-propionyl-piperazin-l-yl)-lH-[l,8]naphthyridin-4- one
Figure imgf000070_0001
[193] A mixture of 5-methyl-l-phenyl-2-phenylamino-7-piperazin-l-yl-lH-[l ,8]naphthyridin-4- one (21.0 mg, 0.052 mmol), propionic acid (0.004 mL, 0.055 mmol), EDCI (11.9 mg, 0.062 mmol), DMAP (7.6 mg, 0.062 mmol), and NMM (0.006 mL, 0.062) in CH2C12 (0.8 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with CH2C12. The combined organic extracts were washed with 0.5 N HCl and brine and concentrated in vacuo. The residue was purified by prep-TLC eluting with 100% EtOAc to give 5-methyl-l- phenyl-2-phenylamino-7-(4-propionyl-piperazin-l-yl)-lH-[l ,8]naphthyridin-4-one (9.0 mg, 37%): LCMS RT: 2.29 min, MH+: 468.3.
[194] Example 14:
2-anilino-5-bromo-6-fluoro-7-methoxy-l-phenyl-l,8-naphthyridin-4(li )-one
Figure imgf000070_0002
[195] A solution of LTMP [freshly prepared at 0 °C from tetramethylpiperidine (785.4 mg, 5.6 mmol), TMEDA (651 mg, 5.6 mmol) and n-BuLi (3.5 mL, 5.6 mmol)] in THF ( 10 mL) was added to a cooled (-40 °C) stirred solution of 2-anilino-6-fluoro-7-methoxy-l-phenyl-l ,8-naphthyridin- 4(lH)-one (507 mg, 104 mmol) in THF (20 mL). The reaction mixture was warmed to room temperature. After 1 h, the mixture was cooled to -30 °C and 1,2-dibromotetrachloroethane (457 mg, 1.4 mmol) was added. After 30 min, water (50 mL) was added slowly, and then the reaction was warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using EtOAc afforded 2-anilino-5-bromo-6-fluoro-7-methoxy- 1 -phenyl- 1 ,8- naphthyridin-4( l r/)-one (101 mg, 16%) as a light yellow solid: LCMS RT: 2.75 min, MH+: 440.3.
[196] Example 15:
7-Methyl-l-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridin-4-one
Figure imgf000071_0001
[197] Ethyl 7-methyl-4-oxo-l-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridine-3- carboxylate (67 mg, 0.17 mmol) was dissolved in a 2:1 HC AcOH solution (8.5 mL). The reaction was heated to 120 °C for 5 h then cooled to room temperature. The aqueous solution was washed with Et20 and then neutralized with 2 N NaOH and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHC03 and brine, dried over anhydrous Na2S0 , and concentrated in vacuo to provide 7-methyl-l-phenyl-2- (phenylamino)hydropyridino[2,3-b]pyridin-4-one (40 mg, 72%): LCMS RT: 2.28 min, MH+:328.4.
[198] Example 16:
2-anilino-5-chloro-7-methyI-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000071_0002
[199] A mixture of 3,3-dianilino-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one(100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80 °C for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgS0 , and concentrated in vacuo. Silica gel flash chromatography of the residue using 1 : 1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl- l-phenyl- l ,8-naphthyridin-4(l H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH+: 362.6. 2-anilino-5-chloro- 7-methyl-l -phenyl- l,6-naphthyridin-4(lH)-one was also isolated (68 mg, 75%): LCMS RT: 2.24 min, MH+: 362.6. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH. [200] Example 17: Ethyl 7-anilino-3-fluoro-5-oxo-8-phenyI-5,8-dihydro-l,8-naphthyridine carboxylate
Figure imgf000072_0001
[201] 2-anilino-7-chloro-6-fluoro-l-phenyl-l ,8-naphthyridin-4(lH)-one (200 mg, 0.55 mmol), DPPP (12 mg, 0.030 mmol), Pd(OAc)2 (6.0 mg, 0.028 mmol), and Cs2C03 (1 14 mg, 0.42 mmol) was dissolved in a 1: 1 mixture of EtOH (3 mL) / DMF (3 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The solution was saturated with CO by evacuating the flask followed by back filling the flask with CO. This was repeated 3 times before heating the solution to 70 °C. After 4 h of stirring all of the starting material had been consumed and the reaction was cooled to room temperature. The solution was diluted with EtOAc and was washed with water. The organic layer was collected, dried over Na2S04, and concentrated in vacuo. The crude solid was triturated with Et20, filtered and dried to give ethyl 7-anilino-3- fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2-carboxylate as a light brown solid (900 mg, 81%): LCMS RT: 2.63 min, MH+: 404.4
[202] Example 18:
7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2-carboxamide
Figure imgf000072_0002
[203] A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2- carboxylate (50 mg, 0.12 mmol), and NH4C1 (10 mg, 0.19 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et20, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8- dihydro-1 , 8-naphthyridine-2-carboxam.de as a yellow solid (32 mg, 71 %): LCMS RT: 1.93 min, MH+: 375.3. This trasformation can also be accomplished using EDCI/HOBT coupling with NH3. [204] Example 19:
7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2- carboxamide
Figure imgf000073_0001
[205] 7-anilino-4-methyl-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2-carboxylic acid (50 mg, 0.14 mmol), N,0-dimethylhydroxylamine hydrochloride (39 mg, 0.40 mmol), HOBT (28 mg, 0.21 mmol), EDCI (40 mg, 0.21 mmol) were dissolved in CH2C12 (3 mL). To this solution was added TEA (78 uL, 0.56 mmol). The reaction was stirred for 1 h and was diluted with CH2C1 , washed with 0.5N HCl, saturated NaHC03, and brine. The organic layer was collected, dried over Na2S04, and concentrated in vacuo. The solid obtained was triturated with Et20 and dried to give 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-l ,8-naphthyridine-2-carboxamide as a light yellow solid (34 mg, 59%): LCMS RT: 2.28 min, MH+: 415.2. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.
[206] Example 20:
7-acetyl-2-anilino-5-methyl-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000073_0002
[207] To a suspension of 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-l,8- naphthyridine-2-carboxamide ( 100 mg, 0.24 mmol) in THF (5 mL) at 0 °C was added MeMgBr (3M in Et20, 322 uL, 0.97 mmol). The suspension became a red solution. As the reaction proceeded the solution lost its red color. After 1 h the reaction was quenched with saturated NH4C1, diluted with EtOAc, and washed with brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude residue was purified by a Biotage silica gel chromatography using EtOAc to afford 7-acetyl-2-anilino-5-methy 1-1 -phenyl- l ,8-naphthyridin-4(lH)-one as a light yellow solid (65 mg, 74%): LCMS RT: 2.63 min, MH+: 370.4. [208] Example 21: 2-anilino-7-(butyIsulfonyl)-l-phenyl-S-(trifluoromethyI)-l,8-naphthyridin-4(lH)-one
Figure imgf000074_0001
[209] To a solution of montmorillonite K10 (107.5 mg) in CHC13 was added 13 uL of water. 2- anilino-7-(butylsulfanyl)-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(lH)-one (25 mg, 0.06 mmol) was then added followed by oxone (85.2 mg, 0.14 mmol). The reaction was allowed to stir for 24 h at room temperature. After 24 h the solution was bright bluish-green in color and was filtered and washed with copious amounts of CHC13. The filtrate was then concentrated in vacuo. Silica gel flash chromatography using 3: 1 Hex:EtOAc provided 2-anilino-7-(butylsulfonyl)-l- phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4(1 H)-one as a yellow oil (13.8 mg, 46%): LCMS RT: 3.14, MH+ 502.2.
[210] Example 22:
N-[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-l,8-naphthyridin-2- yl]methanesulfonamide
Figure imgf000074_0002
[211] To a solution of 2-anilino-7-chloro-l-phenyl-5-(trifluoromethyl)-l,8-naphthyridin-4( lH)- one (100 mg, 0.241 mmol) in DMSO (5 mL) was added methyl sulfonamide and K2C03 (76.5 mg, 0.554 mmol). The reaction was stirred at 120 °C for 24 h. The reaction was then cooled to room temperature, quenched with water and extracted with Et20. The organic layers were dried over MgS04, and concentrated in vacuo. The crude residue was then passed through a plug of silica gel eluting with 1 : 1 Hex:EtOAc to 9: 1 CH2CI2:MeOH to afford N-[7-anilino-5-oxo-8-phenyl-4- (trifluoromethyl)-5,8-dihydro- l ,8-naphthyridin-2-yl]methanesulfonamide as a white solid (4.4 mg, 4%): LCMS RT: 2.45, MH+: 475.2. [212] Example 23: 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2-carbaldehyde
Figure imgf000075_0001
[213] 2-anilino-6-fluoro-7-(hydroxymethyl)- 1 -phenyl- 1 ,8-naphthyridin-4( 1 H)-one (100 mg, 0.277 mmol) was dissolved in 4.5 mL CHC13. Mn02 (311 mg, 3.05 mmol) was added and the reaction was heated to 70 °C under argon for 3 d. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 3: 1 to 100:0 EtOAc:Hex provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l ,8-naphthyridine-2- carbaldehyde (15 mg, 15%) as a white solid: LCMS RT: 2.18 min, MH+: 360.2.
[214] Example 24:
7-amino-2-anilino-5-methyl-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000075_0002
[215] Pd/C (30 mg, 1.75 mmol, 10%) was added to a 25 mL round bottom flask and was blanketed with argon. 7-(allylamino)-2-anilino-5-methyl-l -phenyl- l,8-naphthyridin-4(lH)-one (150 mg, 0.392 mmol) was dissolved in EtOH (2 mL) and was added to the Pd/C followed by methane sulfonic acid (0.041 mL, 0.63 mmol). The reaction was heated to 80 °C for 3 d at which time it was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by Biotage silica gel chromatrography eluting with 100% EtOAc to provide 7-amino-2-anilino-5-methyl-l-phenyl-l ,8- naphthyridin-4(lH)-one (182 mg, 41%) as a yellow solid: LCMS RT: 2.01 min, MH+: 343.3. [216] Example 25: 2-anilino-7-(hydroxymethyl)-5-methyl-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000076_0001
[217] To a 0 °C suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8- naphthyridine-2-carboxylate (100.0 mg, 0.25 mmol) in THF (2.5 mL) was added LAH (0.750 mmol, IM in THF) dropwise over 10 min. After 5 min. the reaction was slowly quenched with EtOAc (10 mL), was left to stir for 15 min and was concentrated in vacuo. The resiude was taken up in CH2C12 (10 mL) and IN HCl (5 mL) and was left to stir for 30 min. The layers were separated and the aqueous layer was extracted with CH2C1 . The combined organic extracts were washed with brine, dried over MgS0 , and concentrated in vacuo. Trituation with Et20 provided 2-anilino-6-fluoro-7-(hydroxymethyl)-l -phenyl-l,8-naphthyridin-4(l//)-one (55.2 mg, 61 %) as a tan solid: LCMS RT: 2.01 min, MH+: 362.3.
[218] Example 26:
2-anilino-7-[(4-methoxyphenoxy)methyl]-5-methyI-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000076_0002
[219] 2-anilino-6-fluoro-7-(hydroxymethyl)-l-phenyl-l,8-naphthyridin-4(l//)-one (62 mg, 0.175 mmol) was dissolved in CH2C12 (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph3P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 7:3 to 9: 1 EtOAc:Hex provided 2-anilino-6-fluoro-7-[(4- methoxyphenoxy)methyl]-l-phenyl-l,8-naphthyridin-4(l/ )-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH+: 464.2. [220] Example 27: 7-ethoxy-5-ethyl-2-[methyl(phenyl)amino]-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000077_0001
[221] and Example 28: 2-anilino-7-ethoxy-5-ethyl-3-methyl-l-phenyI-l,8-naphthyridin-4(lH)-one
Figure imgf000077_0002
[222] and Example 29: 7-ethoxy-5-ethyl-3-methyl-2-[methyl(pherιyl)amino]-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000077_0003
[223] To a suspension of 2,2,6,6-tetramethylpiperidine (153 mg, 0.18 mL, 1.08 mmol) in THF (10 mL) at 0 °C, was added n-BuLi via syringe (1.6 M, 0.68 mL, 1.08 mmol) and TMEDA. The reaction mixture was stirred for 1 h under argon. The reaction mixture was cooled to -60 °C using an acetone/dry ice bath and 2-anilino-7-ethoxy-5-methyl-l-phenyl-l ,8-naphthyridin-4(lH)-one (100 mg, 0.269 mmol) was added via syringe as a solution in THF (5 mL). The mixture was stirred for 1 h. Mel was added via syringe and the reaction was allowed to warm to room temperature and stirred for 18 h. A saturated aqueous solution of NH4C1 (20 mL) and EtOAc (20 L) was added, and the organic layer was separated, dried over MgS0 and concentrated in vacuo. The residue was purified by silica gel flash chromatography using 7:3 to 100:0 EtOAc:Hex to give 3 products as follows: Example 27: (35 mg, 32 %), Example 28: (1 1 mg, 10 %), Example 29: (16 mg, 14 %). [224] Example 30:
2-anilino-6-fluoro-7-methyl-l-phenyI-l,8-naphthyridin-4(lH)-one
Figure imgf000078_0001
[225] To 2-anilino-7-chloro-6-fluoro-l-phenyl-l,8-naphthyridin-4(lH)-one (100 mg, 0.273 mmol) in THF (5 mL) was added Pd(PPh3)4 (13 mg, 0.001 mmol) and methyl zinc chloride (2M, 0.819 mL, 1.64 mmol) and the reaction was heated to 75 °C for 18 h. The reaction was then cooled to room temperature and poured into a solution of EDTA in water (2.5 g/20 mL) and extracted with Et20. The organic layer was washed with brine and concentrated in vacuo. The residue was then taken up in MeOH and filtered. The filtrate was concentrated in vacuo to give 2- anilino-6-fluoro-7-methyl-l -phenyl- l ,8-naphthyridin-4(lH)-one (83.0 mg, 89%): LCMS RT: 2.43 min, MH+: 346.4.
[226] Example 31:
Methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridin-3-yl)-2- propenoate
Figure imgf000078_0002
[227] To a suspension of 2-anilino-6-bromo-7-methyl- 1 -phenyl- 1 ,8-naphthyridin-4( 1 / )-one (41 mg, 0.1 mmol) in DMF (2.0 mL) were successively added Pd(OAc)2 (0.70 mg, 0.003 mmol), Ph3P (5.2 mg, 0.02 mmol), TEA (0.03 mL) and methyl acrylate (17.2 mg, 0.2 mmol). The suspension was heated at 120 °C in a sealed tube for 64 h. The residue obtained after concentration in vacuo was washed with water and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. Purification by prep-HPLC provided methyl (2E)-3-(7-anilino-2-methyl-5- oxo-8-phenyl-5,8-dihydro-l,8-naphthyridin-3-yl)-2-propenoate (10.0 mg, 24%): LCMS RT: 2.61 min, MH+: 412.3, R/ = 0.26 (1 :1 EtOAc:Hex). [228] Example 32:
(2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridin-3-yl)-2-propenoic acid
Figure imgf000079_0001
[229] To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-l-propenyl]-7-methyl-l -phenyl-l,8- naphthyridin-4(l/ )-one (10 mg, 0.025 mmol) in CH3CN (2.0 mL) was added IN NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo to afford (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-l ,8-naphthyridin-3-yl)-2- propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MH+: 398.3, R/ = 0.51 (EtOAc).
[230] Example 33:
3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridin-3-yl)propanoicacid
Figure imgf000079_0002
[231] To a stirred suspension of 2-anilino-6-[(£)-3-hydroxy-3-oxo-l-propenyl]-7-methyl-l- phenyl-l ,8-naphthyridin-4(l /)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-l ,8- naphthyridin-3-yl)propanoicacid (34.5 mg, 86 %): LCMS RT: 2.31 min, MH+: 400.4, R/ = 0.61 (4: l EtOAc:MeOH). [232] Example 34: 2-anilino-6,7-dimethyl-l-phenyl-l,8-naphthyridin-4(lH)-one
Figure imgf000080_0001
[233] Example 35: 2-anilino-7-ethyl-l-(3-methylphenyl)-l,8-naphthyridin-4(lH)-one
Figure imgf000080_0002
[234] A suspension of 2-anilino-6-bromo-7 -methyl- 1 -phenyl- l,8-naphthyridin-4(l/ )-one (203 mg, 0.5 mmol) in THF (10 mL) in an atmosphere of argon was cooled to -78 °C. A solution of n- BuLi in hexanes (1.0 mL, 1.6 mmol, 1.6 M) was added and the suspension was stirred for 10 min at 0 °C until it became a clear solution. Excessive Mel (0.2 mL, 3.2 mmol) was added, and the reaction was stirred for another 10 min. The reaction was quenched with saturated aqueous NH C1 (2.0 mL) and water (10 L) and the mixture was extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by prep-HPLC to afford 2- anilino-6,7-dimethyl-l-phenyl-l ,8-naphthyridin-4(lH)-one (55 mg, 32%): LCMS RT: 2.33 min, MH+: 342.4, R/ = 0.39 (EtOAc). 2-anilino-7-ethyl-l-(3-methylphenyl)-l ,8-naphthyridin-4(lH)- one (13.3 mg, 7.5%) was also obtained as a side product: LCMS RT: 2.54 min, MH+: 356.3, Rf = 0.40 (EtOAc). Other electrophiles such as aldehydes, carbon dioxide, disulfides, trifluoroacetates acid chlorides and other alkyl halides can also be used to quench the generated aryl lithium.
[235] Example 36:
Ethyl 7-anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2- carboxylate
Figure imgf000081_0001
[236] A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro- 1 ,8-naphthyridine-2- carboxylate (40.0 mg, 0.099 mmol) in anhydrous THF (10 L) in an atmosphere of argon was cooled to -78 °C. LiHMDS (5 mL, 5 mmol) was then added to the suspension, and the suspension was stirred for 2 h at 0 °C and then cooled to -78 °C and treated with CC12FCCIF2 (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0 °C before being quenched with saturated aqueous NH4C1 (2.0 mL) and water (10 mL) and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. Purification of the residue by prep-HPLC provided Ethyl 7-anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine-2-carboxylate (13.2 mg, 31%): LCMS RT: 2.80 min, MH+: 437.1, R = 0.78 (EtOAc).
[237] Example 37:
7-anilino-4-chloro-3-fluoro-N,N-diisopropyl-5-oxo-8-phenyl-5,8-dihydro-l,8-naphthyridine- 2-carboxamide
Figure imgf000081_0002
[238] LDA was made by adding n-BuLi (0.31 mL, 0.5 mmol, 1.6 M) to diisopropylamine (50 mg, 0.5 mmol) in THF (15 mL) at -15 °C. A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8- phenyl-5,8-dihydro- 1 ,8-naphthyridine-2-carboxyIate (40.0 mg, 0.915 mmol) in anhydrous THF ( 10 mL) in an atmosphere of argon was cooled to -78 °C. LDA was added and the suspension was stirred for 2 h at 0 °C and then cooled to -78 °C and treated with CC12FCC1F2 (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0 °C before being quenched with saturated aqueous NH4C1 (2.0 mL) and water (10 mL). The aqueous solution was extracted with EtOAc and the organic layer was dried over MgS04 and concentrated in vacuo. Purification of the residue by prep-HPLC provided 7-anilino-3-bromo-4-chloro-N,N-diisopropyl-5-oxo-8-phenyl-5,8-dihydro- l,8-naphthyridine-2-carboxamide (20 mg, 41 %): LCMS RT: 3.02 min, MH+: 493.3, R = 0.78 (EtOAc).
[239] Example 38:
2-[(4-Methylbenzyl)amino]-l-[3-(trifluoromethyl)phenyl]-l,8-naphthyridin-4(lH)-one
Figure imgf000082_0001
[240] A mixture of 2-amino-l-[3-(trifluoromethyl)phenyl]-1 ,8-naphthyridin-4(lH)-one (50 mg, 0.16 mmol), CsC03 (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80 °C in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH2C12 (3X), and the combined organic extracts were dried with Na2S04 and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150 x 20 mm I.D.; first run: 20-80% CH3CN in water, 1 1 min.; second run: 50-90% MeOH in water, 20 min.) to afford 2-[(4- Methylbenzyl)amino]-l-[3-(trifluoromethyl)phenyl]-l ,8-naphthyridin-4(lH)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH+: 410.2.
[241] The following specific examples are presented to illustrate the invention related to Formula (II) as described herein, but they should not be construed as limiting the scope of the invention in any way.
[242] Intermediate BA: 2,4-dichloro-6-methylnicotinic acid
Figure imgf000082_0002
[243] A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3- carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80 °C for 4 h. The mixture was acidified using 50% H2S04 and then filtered. The solid collected was washed with cold water and dried to give of 2,4-dichloro-6- methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2. [244] Intermediate BB: 3,3-dichloro-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-proρen-l-one Cl O Cl
[245] 2,4-Dichloro-6-methyInicotinic acid (8X.7 g, 43.0- mmol) was mixed with S0C12 (31 mL). The resulting mixture was heated to 80 °C for 2 h and concentrated in vacuo to give the acid chloride as yellow oil. The oil was then dissolved in CH2C12 (10 mL) and the solution was added to a cooled suspension of A1C1 (21.3 g, 160.0 mmol) in CH2C12 (50 mL) at 0 °C. After 2 h at 0 °C, vinylidene chloride (2.16 mL, 80.0 mmol) was added to the above suspension. The resulting mixture was then left to warm to room temperature and stirred overnight. The reaction mixture was poured into crushed ice and the resulting mixture was extracted with CH2C12. The combined organic layers were cooled to 0 °C and TEA (14.9 mL) was added. After 1 h of stirring, the organic layer was washed with 10% aqueous HCl (100 mL), water (200 mL), brine (100 mL), and dried over Na2S04. Solvents were removed in vacuo and the residue was purified by passing it through a pad of silica gel with 15% EtOAc in Hex as the eluent to provide 3,3-dichloro-l-(2,4- dichloro-6-methyl-3-pyridinyl)-2-propen-l-one (5.2 g, 46%): LCMS RT: 3.13 min, MH+: 284.6. Alternatively, the acid chloride could be prepared by using oxalyl chloride with a catalytic amount of DMF.
[246] Intermediate BC: 3,3-dianilino-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one
Figure imgf000083_0001
[247] A solution of 3,3-dichloro-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one (5.2 g, 18.0 mmol) in 1,4-dioxane (25 mL) was cooled to 0 °C and aniline (5.1 mL, 55.0 mmol) and TEA (7.7 mL, 55.0 mmol) were added dropwise. The reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The solvents were removed in vacuo. The residue was purified by passing it through a pad of silica gel with EtOAc:Hex (1 :5) as the eluent to provide 3,3-dianilino- l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one (7.1 g, 99%): LCMS RT: 3.06 min, MH+: 398.7. [248] Intermediates BAl , BB 1, BC1 , BA2, BB2, BC2 can be prepared in the same manner shown above for BA, BB and BC starting with the appropriate known starting nicotinic acid (Eur. J. Org. Chem. 2001, 1371).
[249] Intermediate B A 1 : 4,6-dichloronicotinic acid
Figure imgf000084_0001
[250] Intermediate BB 1 : 3,3-dichloro-l-(4,6-dichloro-3-pyridinyl)-2-propen-l-one
Figure imgf000084_0002
[251 ] Intermediate BC 1 : 3,3-dianilino-l-(4,6-dichloro-3-pyridinyl)-2-propen-l-one
Figure imgf000084_0003
[252] Intermediate BA2: 4,5-dichloronicotinic acid
Figure imgf000084_0004
[253] Intermediate BB2: 3,3-dichloro-l-(4,5-dichloro-3-pyridinyl)-2-propen-l-one
Figure imgf000085_0001
[254] Intermediate BC2: 3,3-dianilino-l-(4,5-dichloro-3-pyridinyl)-2-propen-l-one
Figure imgf000085_0002
[255] Example 39: 2-anilino-5-chloro-7-methyl-l-phenyI-l,6-naphthyridin-4(lH)-one
Figure imgf000085_0003
[256] A mixture of 3,3-dianilino-l-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80°C for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgS04, and concentrated in vcaco. Silica gel flash chromatography of the residue using 1 : 1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl-l-phenyl- l ,8-naphthyridin-4(l H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH+: 362 and 2-anilino-5- chloro-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one (68 mg, 75%): LCMS RT: 2.24 min, MH+: 362.3. Alternatively, the cyclization could be achieved by using other bases such as NaH and other aprotic solvents such as THF and DMF.
[257] Examples 40 and 41 can be prepared in the same manner as that for Example 39 above. [258] Example 40:
2-aniIino-7-chloro-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000086_0001
[259] Example 41:
2-anilino-8-chIoro-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000086_0002
[260] Example 42: 2-anilino-5-chloro-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000086_0003
[261] To a solution of 2-anilino-5-chloro-7-methyl-l -phenyl- l ,6-naphthyridin-4(lH)-one (80 mg, 0.22 mmol) in THF (3mL) was added Ni(dppp)Cl2 (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M , 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with IN HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgS0 , and concentrated in vacuo. Purification by reverse-phase preparative HPLC ( 10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-5,7-dimethyl-l-phenyl-l,6-naphthyridin- 4(lH)-one (31 mg, 40%): LCMS RT: 1.51 min, MH+: 342.4. [262] Example 43: 2-anilino-5-(dimethylamino)-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000087_0001
[263] A mixture of 2-anilino-5-chloro-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80 °C for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7- methyl-l-phenyl-l ,6-naphthyridin-4(lH)-one (74 mg, 91 %): LCMS RT: 1.86 min, MH+: 371.3
[264] Example 44: Ethyl[(2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridin-5-yl)sulfanyl]acetate
Figure imgf000087_0002
[265] A solution of 2-anilino-5-chloro-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one (200 mg, 0.55 mmol) in EtOH (10 mL) was added ethyl 2-mercaptoacetate (0.12 mL, 1.10 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, and dried over Na2S0 . Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl[(2-anilino-7- methyl-4-oxo-l-phenyl-l ,4-dihydro-l ,6-naphthyridin-5-yl)sulfanyl]acetate (120 mg, 49%): LCMS RT: 3.07 min, MH+: 446.2. [266] Example 45: [(2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridin-5-yl)sulfanyl]acetic acid
Figure imgf000088_0001
[267] Aqueous NaOH (2N, 1 mL) was added to a stirred solution of ethyI[(2-anilino-7-methyl-4- oxo-l-phenyl-l,4-dihydro-l,6-naphthyridin-5-yl)sulfanyl]acetate (100 mg, 0.23 mmol) in EtOH (8 mL) at room temperature. The mixture was allowed to stir for 4 h and was concentrated in vacuo. The reaction mixture was acidified with 1 N HCl and extracted with CH2C12. The organic layer was dried over MgS04 and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided [(2-anilino-7-methyl-4-oxo- 1 -phenyl- 1 ,4-dihydro- 1 ,6-naphthyridin-5-yl)sulfanyl]acetic acid (56 mg, 60%): LCMS RT: 2.61 min, MH+: 418.2.
[268] Example 46:
Ethyl N-(2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridin-5-yl)glycinate
Figure imgf000088_0002
[269] To a solution of 2-anilino-5-chloro-7-methyl-l -phenyl- 1 ,6-naphthyridin-4( 1 H)-one (80 mg, 0.22 mmol) in EtOH (8 mL) was added glycine ethyl ester hydrochloride (46 mg, 0.44 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 3 d. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl N-(2-anilino-7-methyl-4-oxo- l-phenyl-l,4-dihydro-l,6-naphthyridin-5-yl)glycinate (43 mg, 46%): LCMS RT: 2.16 min, MH+: 429.3.
[270] Example 47:
2-[(2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridin-5-yl)sulfanyl]-N- cyclopropylacetamide
Figure imgf000089_0001
[271] To a mixture of [(2-anilino-7-methyl-4-oxo-l -phenyl-l,4-dihydro-l,6-naphthyridin-5- yl)sulfanyl]acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH C12 (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH2C12, washed with 0.5N HCl, saturated aqueous NaHC03, brine and dried over Na2S04. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide 2-[(2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridin-5- yl)sulfanyl]-N-cyclopropylacetamide (13 mg, 59%): LCMS RT: 2.55 min, MH+: 457.1.
[272] Example 48: 2-anilino-7-methyl-l-phenyl-5-(2,2,2-trifluoroethoxy)-l,6-naphthyridin-4(lH)-one
Figure imgf000089_0002
[273] Trifluoroethanol (0.08 L, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1.1 mmol) in DMSO (4 mL) at 0 °C, and the mixture was heated at 60 °C for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5-chloro-7-methyl-l- phenyl-l ,6-naphthyridin-4(lH)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH2C12. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by a Biotage silica gel chromatography (2:1 EtOAc:Hex) to provide 2-anilino-7-methyl-l-phenyl-5-(2,2,2-trifluoroethoxy)-l,6-naphthyridin- 4(lH)-one (159 mg, 68%): LCMS RT: 2.65 min, MH+: 426.4. This transformation can be accomplished by using other aprotic solvents such as DMF, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.
[274] Example 49:
2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridine-5-carboxylic acid
Figure imgf000090_0001
[275] 2-Anilino-5-chloro-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one (1.0 g, 2.8 mmol), DPPP (64 mg, 0.15 mmol), Pd(OAc)2 (31 mg, 0.14 mmol), Cs2C03 (580 mg, 4.20 mmol) were dissolved in EtOH (10 mL) and DMF (10 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The flask was purged with CO for 5 min before it was heated to 70 °C. After 4 h the mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water, brine, and dried over Na2S04. Solvents were removed in vacuo and the residue was triturated with Et20 to give ethyl 2-anilino-7-methyl-4-oxo-l-phenyl- l,4-dihydro-l,6-naphthyridine-5-carboxylate (800 mg, 71 %). The ethyl ester was then dissolved in MeOH (5 mL), and THF (20 mL). To this stirring solution was added KOH (3N, 10 mL) and the mixture was stirred at room temperature for 6 h before it was extracted with Et20. The aqueous layer was acidified with 2N HCl to pH = 1 and the product precipitated out of the solution. The solid was filtered and dried to give 2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro- l,6-naphthyridine-5-carboxylic acid as a white solid (683 mg, 92%): LCMS RT: 1.75 min, MH+: 372.9. [276] Example 50:
2-anilino-N-methoxy-N,7-dimethyl-4-oxo-l-phenyl-l,4-dihydro-l,6 naphthyridine-5- carboxamide
Figure imgf000091_0001
[277] 2-anilino-7-methyl-4-oxo-l-phenyl-l,4-dihydro-l,6-naphthyridine-5-carboxylic acid (80 mg, 0.22 mmol), N,0-dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) were dissolved in CH2C12 (9 mL). To this solution was added TEA (120 uL, 0.88 mmol). The reaction was stirred for 1 h and was diluted with CH2C12, washed with 0.5N HCl, saturated NaHC03, and brine. The organic layer was collected, dried over Na2S04, and concentrated in vacuo. The solid obtained was triturated with Et20 and dried to give 2-anilino-N-methoxy-N,7-dimethyl-4-oxo-l-phenyl-l,4-dihydro-l,6 naphthyridine-5- carboxamide as a light yellow solid (50 mg, 55%): LCMS RT: 2.08 min, MH+: 414.9. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.
[278] Example 51 : 5-acetyl-2-anilino-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000091_0002
[279] 2-Anilino-/V-methoxy-tV,7-dimethyl-4-oxo-l -phenyl-l,4-dihydro-l ,6-naphthyridine-5- carboxamide (60 mg, 0.14 mmol) was suspended in THF (5 mL). To this stirring suspension at 0°C was added MeMgBr (0.19 mL, 0.56 mmol, 3M in Et20). The reaction was stirred at room temperature for 6 h and quenched with saturated aqueous NH C1, diluted with EtOAc, and washed with brine. The organic layer was collected, dried over Na2S04, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography using EtOAc as the eluent to provide 5- acetyl-2-anilino-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one as a light yellow solid (34 mg, 66%): LCMS RT: 2.20 min, MH+: 370.4.
[280] Example 52: 2-anilino-7-methyl-l-phenyl-5-(trifluoromethyl)-l,6-naphthyridin-4(lH)-one
Figure imgf000092_0001
[281] and Example 53: 7-methyl-2-[methyl(phenyl)amino]-l-phenyl-5-(trifluoromethyl)-l,6-naphthyridin-4(lH)-one
Figure imgf000092_0002
[282] A mixture of methyl fluorosulphonyldifluoroacetate (0.78 mL, 6.10 mmol) and 2-anilino- 5-chloro-7-methy 1-1 -phenyl- l ,6-naphthyridin-4(l H)-one (2.0 g, 5.50 mmol) in DMF (15 mL) was mixed with Copper(I) iodide (1.05 g, 5.50 mmol) at 80 °C for 6 h before the mixture was filtered and concentrated in vacuo. The residue was diluted with CH2C12, washed with water and brine, and dried over MgS04. Solvents were removed in vacuo and the residue was purified by Biotage silica gel chromatography using 1:1 EtOAc:Hex to provide 2-anilino-7-methyl-l-phenyl-5- (trifluoromethyl)-l,6-naphthyridin-4(lH)-one as a light yellow solid (477 mg 22%): LCMS RT: 2.68 min, MH+: 396.2. 7-Methyl-2-[methyl(phenyl)amino]-l-phenyl-5-(trifluoromethyl)-1 ,6- naphthyridin-4( l H)-one (270 mg, 12%) was also isolated: LCMS RT: 2.32 min, MH+: 410.4.
[283] Example 54: 2-anilino-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000093_0001
[284] To a flask containing 2-anilino-5-chloro-7 -methyl- 1 -phenyl- 1 ,6-naphthyridin-4( lH)-one (10 mg, 0.03 mmol) in EtOAc (2 L) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101 , 2 mg). The system was purged with H2 and left stirring at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7-methyl-l -phenyl- l,6-naphthyridin-4(lH)-one (8 mg, 91 %): LCMS RT: 1.22 min, MH+: 328.3.
[285] Example 55: 2-anilino-5-(4-methoxyphenyl)-7-methyl-l-phenyl-l,6-naphthyridin-4(lH)-one
Figure imgf000093_0002
[286] An 8-mL amber vial was charged with 2-anilino-5-chloro-7-methyl-l-phenyl-l,6- naphthyridin-4(lH)-one (72 mg, 0.20 mmol), 4-methoxyphenylboronic acid (36 mg, 0.24 mmol), Pd(OAc)2 (1 mg, 0.02 mmol), Ph3P (5 mg, 0.02 mmol), K2C03 (1 10 mg, 0.8 mmol, 2 M), and DME (2 mL). The mixture was heated to 90 °C 2 d. Water was added to the reaction mixture and it was extracted with CH2C12. The organic layer was dried over Na2S04. The residue after concentration in vacuo was triturated with Et20 to provide 2-anilino-5-(4-methoxyphenyl)-7- methyl-l-phenyl-l,6-naphthyridin-4(lH)-one (54 mg, 63%): LCMS RT: 1.92 min, MH+: 434.5.
[287] Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 1 A. Table 1A:
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
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Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
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Figure imgf000109_0001
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Figure imgf000120_0001
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Figure imgf000122_0001
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Figure imgf000127_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarized in Table IB. Table IB
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
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Figure imgf000148_0001
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Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Utilizing the above described procedures for intermediates and examples and Flow Diagrams I - XIN alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material. These compounds are summarized in Table IC. Table IC Example Structure
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 2A. Table 2A
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarized in Table 2B.
Table 2B
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
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Figure imgf000209_0001
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Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
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Figure imgf000236_0001
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Figure imgf000240_0001
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Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Utilizing the above described procedures for intermediates and examples, and Flow Diagrams I - XIV alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 2C
Table 2C
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
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Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Methods of Use
[288] 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 (LAD A) (Zimmet, et al., Diabetes Med. 1 1 :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 (Zimmet, et al., J Diab Comp, 11 : 60, 1997).
[289] 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. [290] 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 blood glucose levels, blood insulin levels, insulin sensitivity, and insulin secretion, 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 pancreatic 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.
[291] Thus, compounds of the invention may also be used in methods of the invention to activate or repair beta-cells in the pancreas. That is, the compounds of the present invention may be utilized to increase the number of pancreatic beta islet cells or to preserve or reduce the rate of loss of pancreatic beta islet cells by preventing or reducing apoptosis.
[292] 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. l):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 HIN infection.
[293] 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.
[294] The compounds of the invention may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR ligands (e.g., agonists, antagonists), insulin secretagogues, for example, sulfonylurea drugs and non-sulfonylurea secretagogues, - glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, insulin and insulin derivatives, and anti-obesity drugs. Such therapies may be administered prior to, concurrently with, or following administration of the compounds of the invention. Insulin and insulin derivatives include both long and short acting forms and formulations of insulin. PPAR ligands may include agonists and/or antagonists of any of the PPAR receptors or combinations thereof. For example, PPAR ligands may include ligands of PPAR-α, PPAR-γ, PPAR-δ or any combination of two or three of the receptors of PPAR. PPAR ligands include, for example, rosiglitazone, troglitazone, and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, tolbutamide, 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 PPAR-γ agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other thiazolidinedione and non-thiazolidinedione compounds; biguanides such as metformin and phenformin; protein tyrosine phosphatase- 1 B (PTP-1B) inhibitors; dipeptidyl peptidase IN (DPP-1N) inhibitors; and l lbeta-HSD inhibitors. Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of the invention include, for example, glucagon anatgonists and 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-1, GJP, PACAP, secretin, and derivatives thereof; nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide. For example, GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty -acid derivatized GLP-1 and exendin.
[295] 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-1 antagonists; neuropeptide Y5 inhibitors; Ciliary Νeurotrophic Factor and derivatives (e.g., Axokine); appetite suppressants, such as, for example, sibutramine (Meridia); and lipase inhibitors, such as, for example, orlistat (Xenical).
[296] 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, fatty acid lowering compounds (e.g., acipi ox); lipid lowering drugs (e.g., stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid derivatives. HMG-CoA reductase inhibitors include, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522. Fibric acid derivatives include, for example, clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil. Sequestrants include, for example, cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran. [297] Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors. Examples of additional anti- hypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e. g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
[298] 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.
Terms
[299] As used herein, various terms are defined below.
[300] 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.
[301] The term "subject" as used herein includes mammals (e.g., humans and animals).
[302] 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.
[303] 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.
[304] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product. [305] The term "prodrug" includes a compound that is a drug precursor that, following administration to a subject and subsequent absoφtion, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.
Pharmaceutical Compositions
[306] 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.
[307] 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.
[308] 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.
[309] 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 puφose 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. 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.
[310] 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.
[311 ] 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.
[312] 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.
[313] 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.
[314] 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 n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
[315] 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.
[316] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or inteφeritoneally, 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.
[317] 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. [318] 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.
[319] 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.
[320] 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.
[321] 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 puφose, 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.
[322] 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. [323] 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, incoφorated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[324] 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, incoφorated herein by reference.
[325] 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.
[326] 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.
[327] 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, CC1 F2, F2C1C-CC1F2 and CC1F3); 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, teφenes, 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).
[328] 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.
[329] 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.
[330] 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).
[331] 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
[332] 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 incoφorated by reference in their entirety.
[333] 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 Assays
Insulin Secretion from Dispersed Rat Islet Cells
[334] Islets of Langerhans, isolated from male Sprague-Dawley rats (200-250 g), are digested using collagenase. The dispersed islet cells are treated with trypsin, seeded into 96 V-bottom plates, and pelleted. The cells are then cultured overnight in media with or without compounds of this invention. The media is aspirated, and the cells are pre-incubated with Krebs-Ringer-HEPES buffer containing 3 mM glucose for 30 minutes at 37°C. The pre-incubation buffer is removed, and the cells are 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. A portion of the supernatant is removed and its insulin content was measured by SPA.
In Vivo Assays
Method for Measuring Blood Glucose Levels
[335] Male Wistar rats (270-330g) are fasted overnight and then given either vehicle or compound by oral gavage. Two or three hours later, the rats are given an intraperitoneal dose of glucose (2g/kg). The rats are tail-bled for glucose using a Glucometer (Bayer Coφoration, Mishawaka, IN) just prior to the glucose dose and 15, 30 and 60 minutes afterward. The area under the glucose curve is calculated by the trapezoidal method for both the vehicle and treated animals, and the percent reduction in the glucose AUC by the compound are calculated. A typical positive effect of the compound results in a 12-20% reduction in the AUC relative to the AUC of the vehicle-treated group. Compounds of present invention were found to have a blood glucose lowering effect in this in vivo assay. Method for Measuring Triglyceride Levels
[336] hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound once daily for 8 days. The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined. In each case, triglyceride levels are measured using a Technicon Axon Autoanalyzer (Bayer Coφoration, Tarrytown, NY).
Method for Measuring HDL- Cholesterol Levels
[337] To determine plasma HDL-cholesterol levels, hApoAl mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test compound for 7 days, and then bled again on day 8. Plasma is analyzed for HDL- cholesterol using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA).
Method for Measuring Total Cholesterol, HDL-Cholesterol, Triglycerides, and Glucose Levels
[338] In another in vivo assay, obese monkeys are bled, then orally dosed once daily with vehicle or test compound for 4 weeks, and then bled again. Serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides, and glucose using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA). Lipoprotein subclass analysis is performed by NMR spectroscopy as described by Oliver et al., (Proc. Natl. Acad. Sci. USA 98:5306-5311 , 2001).
Method for Measuring an Effect on Cardiovascular Parameters
[339] Cardiovascular parameters (e.g., heart rate and blood pressure) are also evaluated. SHR rats are orally dosed once daily with vehicle or test compound for 2 weeks. Blood pressure and heart rate are determined using a tail-cuff method as described by Grinsell et al., (Am. J. Hypertens. 13:370-375, 2000). In monkeys, blood pressure and heart rate are monitored as described by Shen et al., (J. Pharmacol. Exp. Therap. 278:1435-1443, 1996).
[340] 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.

Claims

What is claimed is:
1. A method of treating or preventing a disease or condition selected from the group consisting of diabetes (type 1 or type 2), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X, comprising administering to a subject an effective amount of a compound of formula (I)
Figure imgf000279_0001
(I) wherein
R1 is selected from alkyl of 1 -8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R1 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0),all of which may be substituted with l-3 of R 10.
R is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, NR"R12, C(=0)OR", C(=0)NHR", NHC(=0)R13, NHS(=0)2R13, S(=0)O.2R13, S(=0)2NHR", cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1 -8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1 -6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NR"R'2; or
R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or
R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0. and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, all of which may be substituted with 1-3 of R10;
R2 is selected from NR15R16, S(O)0.2R17, and OR17;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, A-R9, C(=0)R18, C(=0)NHR18, S(=0)2NHR18;
R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(=O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o_2 and O, all of which may be substituted with 1-3 of R10, or
R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1 -6 carbon atoms, or
R18 is A-R9;
R16 is selected from alkyl of 1 -8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R15 and R1 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1 -3 of R10;
R17 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, A-R9, or
R17 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o_2 and O, all of which may be substituted with 1-3 of R10;
R3 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0.2, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, all of which may be substituted with 1-3 of R,0, or
R3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NRI9R20, A-OR19, A-NR19R20, and A-R20; R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0_ 2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R'°;
R4 is selected from =0, =S, and OR21;
R21 is hydrogen, or
R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0. and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o.2 and O, all of which may be substituted with 1-3 of R10;
R5 and R6 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or
R5 and R6 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A- NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, or A-C(=0)NR24R25, or
R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1 -8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q- R29, Q-A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25;
Q is selected from O and S(=O)0.2;
R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or
R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R'°, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; 00 1 1 with the proviso for A(OR )-R that when R is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1 -3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3- 6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0. and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1 -6 carbon atoms, A(OR22)-R23, and A- R2 , or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2> and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or
R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R'°;
R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(=0)R24. C(=0)OR26, C(=0)NR25R30, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25, or
R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)-R23, and A- R23, or
R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=0)o_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R,0, or
R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o.2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10; R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(=0)R24, A-C(=0)OR24, A-C(=0)NR24R25, A-NR27R28, or
R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2, and O, all of which may be substituted with 1-3 of R10, or
R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R7 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or
R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, S(=O)0.2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A(OR22)-R23, A-R23. A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25 , S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, or A- C(=0)NR24R25, or
R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A- R 23 A(OR22)-R23, NR27R28, .29 29 A-NR27R28, A-Q-R , Q-R Q-A-NR24R25, C(=0)R; 2
Figure imgf000289_0001
A-C(=0)OR ,24 , and A-C(=0)NR ) 2"4DR25:'.; and pharmaceutically acceptable salts thereof.
2. A method of treating or preventing a disease or condition selected from the group consisting of diabetes (type 1 or type 2), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X, comprising administering to a mammal an effective amount of a compound of of the formula (II)
Figure imgf000289_0002
(II) wherein
R1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R1 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10; R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, NR"R12, C(=0)OR", C(=0)NHR", NHC(=0)R13, NHS(=0)2R13, S(=O)0.2R13, S(=0)2NHRn, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=0)o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R" and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NRnR12; or
R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or
R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, all of which may be substituted with 1-3 of R10;
with the proviso for R1 that when A is CH2, R9 is not optionally substituted biphenyl;
R2' is selected from NR,5R16, S(O)0-2R , and OR'7;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, A-R9, C(=0)R18, C(=0)NHR18, S(=0)2NHR18;
R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2 and O, all of which may be substituted with 1-3 of R10, or
R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
R18 is A-R9;
R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(=O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R17 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, A-R9, or
Rπ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(=O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o_2 and O, all of which may be substituted with 1-3 of R10;
R3 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0.2, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(0)o-2 and O, all of which may be substituted with 1-3 of R'°, or
R3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NRI9R20, A-OR19, A-NR,9R20, and A-R20; R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0.2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0. 2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0.2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with l-3 of R'°;
R4' is selected from =0, =S, and OR21;
R2' is hydrogen, or
R2' is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o_2 and O, all of which may be substituted with 1 -3 of R10;
R5 , R7 , and R8 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms, all of which may be substituted with 1 -3 of R10, or
R5 , R7 , and R8 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0. and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A- NR24R25, C(=0)R24, C(=0)0R24, C(=0)NR24R25, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, or A-C(=0)NR24R25, or
R5 , R7 , and R8 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q- R29, Q-R29, Q-A-NR24R25, C(=0)R24, C(=0)OR24, C(=0)NR24R25, A-C(=0)R24, A- C(=0)0R24, and A-C(=0)NR24R25;
Q is selected from O and S(=0)o-2;
R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of lr8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or
R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1 -4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1 -3 of R10. or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 -3 of R10; with the proviso for A(OR )-R * that when R is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1 -6 carbon atoms, and A-R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6- 10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3- 6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1 -3 heteroatoms selected from N, S(=0)o_2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)-R23, and A- R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R27 is selected from hydrogen, alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or
R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=0)o-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(=0)R24, C(=0)OR26, C(=0)NR25R30, S(=0)2R26, A-C(=0)R24, A-C(=0)OR24, and A-C(=0)NR24R25, or
R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=0)o-2, and O, all of which may be substituted with 1-3 of R10, or . R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1 -2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R'°;
R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)-R23, and A- R23, or
R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0.2, and O, all of which may be substituted with 1-3 of R10, or
R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=0)o-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(=O)0.2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R'°; R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(=0)R24, A-C(=0)OR24, A-C(=0)NR24R25, A-NR27R28, or
R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(=O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=O)0.2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(=O)0.2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(=0), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; and pharmaceutically acceptable salts thereof.
3. The method of claim 1 or 2, further comprising administering a dipeptidyl peptidase IV (DPP-IN) inhibitor in combination with the compound of formula (I) or (II).
4. The method of claim 1 or 2, further comprising administering one or more drug therapies selected from PPAR ligands, insulin sensitizers, sulfonylureas, insulin secretagogues, hepatic glucose output lowering compounds, α-glucosidase inhibitors, biguanides, protein tyrosine phosphatase- IB (PTP-1 B) inhibitors, l lbeta-HSD inhibitors, insulin or insulin derivatives in combination with the compound of formula (I) or (II).
5. The method of claim 4, wherein the PPAR ligand is a ligand of PPAR-oc, PPAR-γ, PPAR-δ, or any combination of two or three of the receptors of PPAR.
6. The method of claim 4, wherein the PPAR ligand is selected from troglitazone, pioglitazone, englitazone, MCC-555, and rosiglitazone.
7. The method of claim 4, wherein the sulfonylurea is selected from glyburide, glimepiride, chloφropamide, tolbutamide, and glipizide.
8. The method of claim 4, wherein the α-glucosidase inhibitor is selected from acarbose, miglitol, and voglibose.
9. The method of claim 4, wherein the biguanide is selected from metformin and phenformin.
10. The method of claim 4, wherein insulin is selected from long and short acting forms.
1 1. The method of claim 4, wherein the hepatic glucose output lowering compound is a glucagon anatgonist.
12. The method of claim 4, wherein the insulin secretagogue is selected from GLP-1, GIP, PACAP, secretin, and derivatives thereof; nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chloφropamide, and glipizide.
13. The method of claim 12, wherein the GLP-1 derivative is selected from fatty-acid derivatized GLP-1 and exendin.
14. The method of claim 1 or 2, further comprising administering an anti-obesity drug in combination with the compound of formula (I) or (II).
15. The method of claim 14, wherein the anti-obesity drug is selected from β-3 agonists, CB-1 antagonists, neuropeptide Y5 inhibitors, ciliary ncurotrophic factor and derivatives, appetite suppressants, and lipase inhibitors.
16. A method of treating or preventing lipid disorders in diabetic patients, comprising administering to a mammal an effective amount of a compound of formula (I) or (II) as described in claim 1 and 2, in combination with HMG-CoA reductase inhibitors, nicotinic acid, fatty acid lowering compounds, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, or fibric acid derivatives.
17. The method of claim 16, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522.
18. The method of claim 16, wherein the fibric acid derivative is selected from clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil.
19. The method of claim 16, wherein the bile acid sequestrant is selected from cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran.
20. A method of treating or preventing hypertension in diabetic patients, comprising administering to a mammal an effective amount of a compound of claim 1 or 2 as described in claim 1 and 2, in combination with β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, and nitrates.
21. The method of claim 20, wherein the calcium channel blocker is selected from diltiazem, verapamil, nifedipine, amlodipine, and mybefradil.
22. The method of claim 20, wherein the diuretic is selected from chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthahdone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, and spironolactone.
23. The method of claim 20, wherein the ACE inhibitor is selected from captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, and lisinopril.
24. The method of claim 20, wherein the AT- 1 receptor antagonist is selected from losartan, irbesartan, and valsartan.
25. The method of claim 20, wherein the ET receptor antagonist is selected from sitaxsentan and atrsentan.
26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II) as described in claim 1 and 2, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.
27. The pharmaceutical composition of claim 26, wherein said pharmaceutical agent is selected from the group consisting of PPAR ligands, insulin secretagogues, sulfonylurea drugs, α-glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, insulin and insulin derivatives, biguanides, protein tyrosine phosphatase-lB, dipeptidyl peptidase IV, 1 1 beta-HSD inhibitors, anti-obesity drugs, HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates.
28. The pharmaceutical composition of claim 26, wherein the PPAR ligand is a ligand of PPAR-α, PPAR-γ, PPAR-δ, or any combination of two or three of the receptors of PPAR.
29. The pharmaceutical composition of claim 26, wherein the PPAR ligand is selected from troglitazone, pioglitazone, englitazone, MCC-555, and rosiglitazone.
30. The pharmaceutical composition of claim 26, wherein the sulfonylurea is selected from glyburide, glimepiride, chloφropamide, tolbutamide, and glipizide.
31. The pharmaceutical composition of claim 26, wherein the α-glucosidase inhibitor is selected from acarbose, miglitol, and voglibose.
32. The pharmaceutical composition of claim 26, wherein the biguanide is selected from metformin and phenformin.
33. The pharmaceutical composition of claim 26, wherein insulin is selected from long and short acting forms.
34. The pharmaceutical composition of claim 26, wherein the hepatic glucose output lowering compound is a glucagon anatgonist.
35. The pharmaceutical composition of claim 26, wherein the insulin secretagogue is selected from GLP-1, GIP, PACAP, secretin, and derivatives thereof; nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
36. The pharmaceutical composition of claim 35, wherein the GLP-1 derivative is selected from fatty-acid derivatized GLP-1 and exendin.
37. The pharmaceutical composition of claim 26, wherein the anti-obesity drug is selected from β-3 agonists, CB- 1 antagonists, neuropeptide Y5 inhibitors, ciliary neurotrophic factor and derivatives, appetite suppressants, and lipase inhibitors.
38. The pharmaceutical composition of claim 26, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522.
39. The pharmaceutical composition of claim 26, wherein the fibric acid derivative is selected from clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil.
40. The pharmaceutical composition of claim 26, wherein the bile acid sequestrant is selected from cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran.
41. The pharmaceutical composition of claim 26, wherein the calcium channel blocker is selected from diltiazem, verapamil, nifedipine, amlodipine, and mybefradil.
42. The pharmaceutical composition of claim 26, wherein the diuretic is selected from chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthahdone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, and spironolactone.
43. The pharmaceutical composition of claim 26, wherein the ACE inhibitor is selected from captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, and lisinopril.
44. The pharmaceutical composition of claim 26, wherein the AT-1 receptor antagonist is selected from losartan, irbesartan, and valsartan.
45. The pharmaceutical composition of claim 26, wherein the ET receptor antagonist is selected from sitaxsentanand atrsentan.
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WO2005091857A3 (en) 2006-10-05
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