WO2006034512A2 - Phenyl-substituted quinoline and quinazoline compounds for the treatment of diabetes - Google Patents

Phenyl-substituted quinoline and quinazoline compounds for the treatment of diabetes Download PDF

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WO2006034512A2
WO2006034512A2 PCT/US2005/034867 US2005034867W WO2006034512A2 WO 2006034512 A2 WO2006034512 A2 WO 2006034512A2 US 2005034867 W US2005034867 W US 2005034867W WO 2006034512 A2 WO2006034512 A2 WO 2006034512A2
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mmol
inhibitors
cycloalkyl
diabetes
formula
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WO2006034512A3 (en
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David Cantin
Steven Magnuson
David Gunn
William Bullock
Jennifer Burke
Wenlang Fu
Ellalahewage Sathyajith Kumarasinghe
Sidney X. Liang
Jason Newcom
Herbert Ogutu
Alan Olague
Ming Wang
Philip Wickens
Zhonghua Zhang
Donald Bierer
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Bayer Pharmaceuticals Corporation
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to 2-phenyl-substituted quinoline and quinazoline compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.
  • Type 1 diabetes or insulin dependent diabetes mellitus (IDDM) arises when patients lack insulin-producing ⁇ -cells in their pancreatic glands.
  • IDDM insulin dependent diabetes mellitus
  • Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM)
  • IIDDM 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 ⁇ -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, metformin, and insulin.
  • Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose.
  • the drawbacks of insulin treatment include, for example, the need for drug injection, the potential for hypoglycemia, and weight gain.
  • cAMP cyclic adenosine monophosphate
  • 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.
  • the effect of cAMP is, however, glucose- dependent, that is, cAMP has little if any effects on insulin secretion 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 utilize the cAMP system to regulate insulin secretion in a glucose-dependent fashion ( Komatsu, et al., Diabetes 46:1928-1938, 1997).
  • Examples of such endogenous secretagogues include pituitary adenylate cyclase activating peptide (PACAP), vasoactive intestinal polypeptide (VIP), and glucagon-like peptide-1 (GLP-1).
  • PACAP pituitary adenylate cyclase activating peptide
  • VIP vasoactive intestinal polypeptide
  • GLP-1 glucagon-like peptide-1
  • new therapies to treat diabetes are needed.
  • new treatments to maintain normal (glucose-dependent) insulin secretion are needed.
  • Such new drugs should have the following characteristics: 1) dependency on glucose for promoting insulin secretion, that is, compounds that stimulate insulin secretion only in the presence of elevated blood glucose and therefore, low probability for hypoglycemia; 2) low primary and secondary failure rates; and 3) preservation of islet cell function.
  • Phosphodiesterases are a family of cAMP and/or cGMP-hydrolyzing enzymes that cleave 3',5'-cyclic nucleotide monophosphates to 5'-nucleotide monophosphates. PDEs are known to be involved in the regulation of the cAMP system.
  • PDE1 OA is a phosphodiesterase that hydrolyses cAMP and cGMP with K m values of approximately 0.1-7 ⁇ M (Fujishige, et al., J.
  • cGMP and cAMP are important second messengers that are involved in the regulation of vascular smooth muscle tone.
  • the PDE10 family comprises enzymes that are responsible for the degradation of cAMP and cGMP in various tissues (Fujishige, et al., J. Biol. Chem. 274:18438- 18445, 1999).
  • guanylate cyclases leads to increased intracellular cGMP levels and induces vasodilation.
  • GPCRs G protein-coupled receptors
  • adenylate cyclases generation of intracellular cAMP
  • vasodilation 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of 3',5'-cyclic nucleotides to their respective nucleoside 5 1 - monophosphates.
  • PDE10A likely plays a role in the cardiovascular system.
  • the compounds of the present invention may be used to inhibit PDE1 OA activity and thus, may be used to treat diseases and/or disorders such as diabetes, cardiovascular disorders, or PDE10A-related diseases and/or disorders.
  • the present invention relates to 2-phenyl-substituted quinoline and quinazoline compounds useful for the treatment of diabetes, including type 1 and type 2 diabetes. Additional methods of the invention include treatment of disorders related to diabetes, such as Syndrome X, impaired glucose tolerance, and impaired fasting glucose.
  • the present invention also relates to methods of treating gestational diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), and associated diabetic dyslipidemia and other diabetic complications, as well as hyperglycemia, hyperinsulinemia, dyslipidemia, hypertriglyceridemia, and insulin resistance.
  • the invention further relates to methods of stimulating insulin release from pancreatic cells in a mammal by administering an effective amount of a compound of the present invention.
  • This method of insulin release may be in response to an elevation of the concentration of glucose in the blood of a mammal.
  • the compounds of the present invention may also be administered in conjunction with other diabetes therapies, such as alpha-glucosidase inhibitors (e.g., acarbose), insulin sensitizers (e.g., thiazolidinediones), compounds that reduce hepatic glucose output (e.g., metformin), insulin secretagogues (e.g., sulfonylureas), ⁇ -3 agonists, and insulin.
  • the compounds of the present invention may be administered in conjunction with one or more weight reduction agents, such as orlistat, sibutramine, ⁇ -3 agonist, or CB-1 antagonist.
  • the compounds of the present invention may be administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, or an antihypertensive drug.
  • the compounds may be administered for the treatment of dementia or urogenital tract disorders.
  • Urogenital tract disorders include, but are not limited to, incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction, and hypertrophy of prostate.
  • compounds of the present invention may be administered for the treatment of cardiovascular disorders, such as hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke.
  • the invention provides 2-phenyI-substituted quinoline and quinazoline compounds of Formula (I)
  • X is a group selected from
  • Y is CR 7 or N
  • R 1 is:
  • R 3 is:
  • R 4 and R 4 which may be the same or different, are:
  • R 5 is:
  • R 6 is:
  • R 7 is:
  • aryl, heteroaryl, and heterocyclyl being optionally substituted at any available position by up to 3 independently selected R 8 groups, and optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl or heteroaryl ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein said fused ring may be optionally substituted at any available position by up to 3 independently selected R 8 groups;
  • R is selected from hydroxy
  • C 6 )alkoxy or a mono or bicyclic ring radical selected from the group consisting of: a) a phenyl optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and c) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R 9 groups;
  • n is 1, 2, 3, or 4;
  • p is 0, 1 , or 2;
  • the invention also provides 2-phenyl-substituted quinoline and quinazoline compounds of Formula (II)
  • X is a group selected from
  • R 1 is:
  • R 2 is:
  • R 3 is:
  • R 4 and R 4 ' which may be the same or different, are:
  • R 4 and R 4 can join to form a saturated (C 3 -C 6 )-cycloalkyl or a (C 3 - C 6 )heterocyclyl ring optionally substituted with:
  • R 5 is:
  • R 6 is:
  • R 8 is: hydroxy
  • (C 1 -C 6 )alkyl optionally substituted with halo, OH, S, NR 6 R 6 , (C 1 -C 6 ) kOXy, cycloalkyl, 67
  • a mono or bicyclic ring radical selected from the group consisting of: a) a phenyl optionally fused to a 5- or 6-membered cycloalkyl, or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and c) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N 1 O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R 9 groups;
  • R 10 is halo
  • Prefixes such as (C 1 -C 6 ) are used to indicate the respective number of carbon atoms, for example, in this case, 1 to 6 carbons.
  • halo means F, Cl, Br, or I.
  • (CrC ⁇ Jalkyl) means a straight or branched saturated hydrocarbon carbon chain of from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl, n-hexyl, and the like.
  • (C 2 -C 6 )alkenyl means a straight or branched unsaturated hydrocarbon carbon chain of from 2 to about 6 carbon atoms. Examples of such groups include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, 3-ethyl-2-butenyl, 4-hexenyl, and the like.
  • (CrC ⁇ Jhaloalkyl) means a (C 1 -C e )alkyl group substituted by 1 to 3 halogen atoms or fluorine up to the perfluoro level.
  • examples of such groups include, but are not limited to, trifluoromethyl, tetrafluoroethyl, 1 ,2-dichloropropyl, 5-bromopentyl, 6-iodohexyl, and the like.
  • (C 3 -C 6 )cycloalkyl or "(C 3 -C 8 )cycloalkyl” means a saturated carbocyclic ring system of from 3 to about 6 carbon atoms or from 3 to about 8 carbon atoms, respectively.
  • Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, and the like.
  • 5- to 6-membered cycloalkly means a saturated or patially unsaturated carbocyclic ring system of 5 or 6 carbon atoms, respectively.
  • groups include, but are not limited to, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
  • (C r C 6 )acyl means a (C r C 6 )alkyl group attached at the carbonyl carbon atom.
  • the radical is attached to the rest of the molecule at the carbonyl bearing carbon atom. Examples of such groups include, but are not limited to, acetyl, propionyl, n-butanoyl, 2-m ethyl pentantoyl, and the like.
  • thioaryl means an aryl group attached to a sulfur atom.
  • the S atom is the point of attachment of the thioaryl substituent to the rest of the molecule.
  • the term also includes the different oxidation states of sulfur (e.g., -SO-, -SO 2 -). Examples of such groups include, but are not limited to, thiophenyl, phenyl sulfoxide, phenyl sulfone, and the like.
  • (Ci-C 6 )alkoxy means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an O atom.
  • the O atom is the point of attachment of the alkoxy substituent to the rest of the molecule.
  • Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • (CrC 6 )thioalkyl means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an S atom.
  • the S atom is the point of attachment of the thioalkyl substituent to the rest of the molecule.
  • the term also includes the different oxidation states of sulfur (e.g., -SO-, -SO 2 -).
  • Such groups include, but are not limited to, methylthio, propylthio, hexylthio, ethylsulfoxide, methyl sulfone, and the like.
  • (CrC 6 )haloalkoxy means a (CrC ⁇ alkoxy group further substituted on C with 1 to 3 halogen atoms or fluorine up to the perfluoro level.
  • Such groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 3- chloropropoxy, 1-fluoro-2,2,-dichloroethoxy, and the like.
  • (C 3 -C 6 )cycloalkoxy means a (C 3 -C 6 )cycloalkyl group attached to an O atom.
  • the O atom is the point of attachment of the cycloalkoxy group with the rest of the molecule.
  • examples of such groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • phenoxy means an aryl group attached to an O atom.
  • the O atom is the point of attachment of the phenoxy group to the rest of the molecule.
  • aryl represents a mono- to bicyclic carbocyclic radical, which is aromatic at least in one ring, having generally 6 to 10 carbon atoms, illustratively representing phenyl and naphthyl.
  • heteroaryl represents an mono- or bicyclic radical, having generally 5 to 10 ring atoms from which up to 4 atoms may be selected from the group consisting of N, O, and S, which is aromatic at least in one ring.
  • the mono- or bicyclic radical can be attached to the rest of the molecule via a ring carbon atom or a ring nitrogen atom. If the radical represents a bicyclic, wherein one ring is aromatic and the other one is not, it can be attached at either ring.
  • Illustrative examples are thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothiophenyl, benzooxazolyl, benzothiaolyl, quinolinyl, isoquinolinyl, 1 ,3-benzodioxinyl, 1 ,4- benzodioxinyl, or benzodioxolyl.
  • heterocyclyl represents a mono- or bicyclic nonaromatic (saturated or partially saturated) radical having generally 3 to 10 ring atoms from which up to 3 atoms may be selected from the group consisting of N, O, and S.
  • the radical can be attached via a ring carbon atom or a ring nitrogen atom.
  • Illustrative examples are tetrahydrofuran-2-yl, pyrrolidin-2-yl, tetrahydropyridyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, perhydroazepinyl, dihydropyrano, pyrazolinyl, imidazolinyl, or dihydrofuryl,
  • the heteroaryl or heterocyclyl group When the heteroaryl or heterocyclyl group is attached to the rest of the molecule as a substituent, it becomes a radical.
  • the point of attachment of the radical may be from any available C or N atom of the ring to the rest of the molecule.
  • Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.
  • stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.
  • Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, 67
  • 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 present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability, and release time (see, e.g., "Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), Ed. Ansel, et al., Williams & Wilkins (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 ⁇ /-dealkylation, O- dealkylation, aliphatic hydroxylation, aromatic hydroxylation, ⁇ /-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation, and acetylation (see, e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), Ed. Molinoff, et al., McGraw-Hill (1996), which is hereby incorporated by reference).
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.
  • primary amides (VII) are prepared from acids of Formula (Vl) by conversion to the acid chloride using a chlorinating agent such as SOCI 2 , followed by exposure to ammonia. Subsequent reduction of the nitro group to the amine of Formula (VIII) is achieved through the use of a catalyst (e.g., Pd/C, Pd(OH) 2 ) under an atmosphere of hydrogen. Condensation of intermediate of Formula (VIII) with aldehydes of Formula (IX) in the presence of sodium hydrogen sulfite in a polar solvent such as /V,/V-dimethylacetamide affords quinazolones of Formula (X).
  • a catalyst e.g., Pd/C, Pd(OH) 2
  • R 7 H or alkyl
  • R 7 H or alkyl
  • Intermediate (XVIIb) can be prepared by the reaction of a substituted isatoic anhydride of Formula (XVIII) or a ⁇ /-hydroxysuccinimide ester of Formula (XIX) with a cyanoacetophenone of Formula (XX), together with a strong base such as sodium hydride.
  • intermediate (XXVI) is prepared by the reaction of a substituted isatoic anhydride of Formula (XVIII) with a cyanoacetate of Formula (XXV), together with a strong base such as sodium hydride. Conversion to a 2,4-dichlorosubstituted intermediate of Formula (XXVII) can be achieved by action of a chlorinating agent such as POCI 3 . Nucleophilic addition of the compound of Formula (III) in the presence of base provides the quinoline intermediate of Formula (XXVIII). Subsequent Suzuki coupling reaction with a boronic acid of Formula (XIII) or Formula (XIV) gives the compound of Formula (Ig) or Formula (Ih). Optional hydrolysis of Formula (Ig), for example, using aqueous sodium hydroxide, gives the corresponding acid compound of Formula (Ih).
  • Reaction Scheme 8 or may be prepared as illustrated in Reaction Schemes 8-15 below, beginning with Reaction Scheme 8 which illustrates the preparation of common intermediates of Formula (XXXV) and Formula (XXXVII). [069] Reaction Scheme 8
  • Reaction Scheme 9 illustrates the preparation of compounds of Formulae (U) and (Im) in
  • the compound of Formula (XXXVII) is esterified, for example, by reaction with MeI and a base, to provide the ester intermediate of Formula (XXXVIII).
  • This compound is then reduced to the primary alcohol (XXXIXa) with a suitable reducing agent such as DIBAL.
  • the alcohol can then be oxidized to the aldehyde of Formula (XL) under selective oxidizing conditions such as a Swern oxidation [DMSO, oxalyl chloride, and triethyl amine], and this intermediate can be used to prepare an alcohol of Formula (XXXIXb) by Grignard reaction with the reagent of Formula (XLI).
  • Either alcohol (XXXIXa) or (XXXIXb) may then be O-alkylated in base with an 2-halo ester of Formula (XXXII), to prepare the compound of Formula ( ⁇ i). Hydrolysis of (1 ⁇ ) in aqueous base provides the corresponding carboxylic acid compound of Formula (Im).
  • the intermediate carboxylic acid of Formula (XXXV) is esterified to the corresponding ester of Formula (XLIII), then reduced to the primary alcohol of Formula (XLIVa) with a selective reducing agent such as DIBAL.
  • Oxidation of (XLIVa) to the aldehyde of Formula (XLV) is accomplished with a selective oxidation, for example, under Swern conditions [DMSO 1 oxalyl chloride, and triethyl amine].
  • the aldehyde is then allowed to react with a Grignard reagent of Formula (XLI) to provide the alcohol of Formula (XLIVb), where R 4 is alkyl.
  • the carboxylic acid intermediate of Formula (XXXV) is coupled with an amino acid derivative of Formula (Ll) in the presence of a coupling agent such as EDCI.
  • the product, intermediate of Formula (LIl) may then be subjected to Suzuki coupling conditions using a boronic acid of Formula (XIII) or Formula (XIV) to give the compound of Formula (Ir) where R 3 is alkyl.
  • Hydrolysis of Formula (Ir) using aqueous base such as sodium hydroxide gives the acid compound of Formula (Is) where R 3 is H.
  • an alcohol intermediate of Formula (XLIV), described in Reaction Scheme 10 is converted to the corresponding chloro compound of Formula (XLVII).
  • This intermediate may be /V-alkylated with the amino acid derivative of Formula (Lib) or Formula (LIc), optionally in the presence of a base, to give the intermediate of Formula (LIII).
  • Suzuki coupling with the boronic acid derivative of Formula (XIII) or Formula (XIV) gives the compound of Formula (It) where R 3 is alkyl
  • hydrolysis of Formula (It) with aqueous base gives the compound of Formula (Iu) where R 3 is H.
  • a 4-halobenzoate of Formula (LIV) is transformed to the corresponding ketone of Formula (LV) using acetonitrile or dimethyl sulfone in THF in the presence of a strong base [e.g., NaH (rt to reflux), LiHMDS (-78 0 C to rt)].
  • Suzuki coupling with the boronic acid derivative of Formula (XIII) or Formula (XIV) gives the compound of Formula (XX).
  • the steps can be reversed where Suzuki coupling of halobenzoates of Formula (LIV) with boronic acid derivatives of Formula (XIlI) or Formula (XIV) gives the compound of Formula (LVI).
  • isatoic anhydrides of Formula (XVIII) can be obtained through oxidation of the isatins of Formula (XXXIII), for example, using peroxides such as H 2 O 2 or m- chloroperbenzoic acid.
  • isatoic anhydrides of Formula (XVIII) can be accessed from amino acids of Formula (LVII) using phosgene in the presence of a base such as Et 3 N.
  • n-hydroxysuccinimide esters of Formula (XIX) can be obtained by reaction of an amino benzoic acid of Formula (LVII) and reacting with n-hydroxysuccinimide under peptide-coupling conditions such as EDCI in DMF.
  • Celite ® brand of diatomaceous earth filtering agent registered trader of Celite Corporation cone concentrated d doublet dd doublet of doublet ddd doublet of doublet of doublet
  • Electron impact mass spectra were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source was maintained at 250 0 C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • LC-MS High pressure liquid chromatography-electrospray mass spectra
  • LC-MS High pressure liquid chromatography-electrospray mass spectra
  • a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization.
  • Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source.
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA.
  • ELSD Electrode L i ght Scattering Detector
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA.
  • Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate of 1.5 ml_/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration.
  • Agilent 1100 HPLC system The Agilent 1100 HPLC system was equipped with an Agilent
  • the HPLC column used was a Waters Sunfire (2.1 x 30 mm, 3.5 uM).
  • the eluents were A: water with 0.1 Formic acid and B: acetonitrile with 0.1% Formic acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and a final hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.
  • the reaction was heated (85 0 C) for 16 h and then cooled to rt.
  • the mixture was concentrated to dryness and then the residue was dissolved in methanol and acetonitrile.
  • This suspension was filtered through a C8 reverse phase extraction cartridge and the filtrate was concentrated to dryness.
  • the residue was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water to obtain 90 mg (58%) of the desired product.
  • amino benzamides can be prepared using the method described below.
  • the mixture was concentrated to dryness and the residue was dissolved in a mixture of methanol and DMSO.
  • the residue was purified by HPLC using a gradient elution from 10% to 90% acetonitrile in water to obtain 95 mg (43%) of the desired product.
  • the solid was added to phosphorous oxychloride (5 mL, 53.6 mmol), and the mixture was heated to reflux for 3 h. After cooling to rt, the reaction was quenched with ice and then the solution was adjusted to pH 7 using aqueous sodium hydroxide solution (1 N). The aqueous layer was extracted with dichloromethane (3 X 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel flash chromatography to obtain 1.55 g (27%) of the desired product.
  • the reaction was heated (85 0 C) for 16 h and then cooled to rt.
  • the mixture was concentrated to dryness and the residue was dissolved in a mixture of methanol and acetonitrile. This solution was filtered through a C8 reverse phase extraction cartridge and the filtrated was concentrated to dryness.
  • the residue was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water to obtain 100 mg (91%) of the desired product.
  • Example 93 was obtained as a solid (10 g, 70%) after drying under mechanical vacuum at 4O 0 C.
  • 1 H NMR 400 MHz, DMSO-c/ 6 ) 12.95 (s, 1 H), 7.86 (m, 2H), 7.75 (m, 5H); ES-MS m/z 343.2 [M+H] + , LCMS RT (min) 2.74. [163]
  • Example 94
  • the reaction mixture was heated at 15O 0 C for 12 min in a microwave reactor and then was cooled to rt. The mixture was then filtered. The filtrate was diluted with 2 mL DMSO then was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water with 0.1% TFA as modifier to obtain 4.8 mg (9.4%) of the desired product.
  • the mixture was filtered and the filtrate concentrated to dryness under reduced pressure.
  • the residue was purified by preparative HPLC (eluent: 10 to 100% acetonitrile in water [0.1% TFA]).
  • the fraction containing desired product was concentrated under reduced pressure and the pH of the resulting aqueous solution was adjusted to ⁇ 5.
  • the aqueous mixture was then extracted with ethyl acetate and the combined organic phases were dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give 15 mg of the desired product.
  • the organic solution was washed successively with K 2 CO 3 (10% aqueous solution), NH 4 CI (10% aqueous solution), and water, and the organic phase was dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure.
  • the residue was triturated with diethyl ether and dried under vacuum to give 1.2 g desired product. Additional amounts of Example 193 were recovered from the filtrate, which was concentrated under reduced pressure.
  • the residue was dissolved recrystallized from hexanes/ethyl acetate (50 ml_, 1 :1 mixture). The solid was collected by filtration and then dried under mechanical vacuum to give 900 mg of desired product.
  • the reaction mixture was filtered and the filtrate concentrated to dryness under reduced pressure.
  • the residue was purified by preparative HPLC (eluent: 10 to 100% acetonitrile in water [0.1% TFA]).
  • the fractions containing desired product were concentrated under reduced pressure, and the pH of the resulting aqueous solution was adjusted to ⁇ 5.
  • the aqueous mixture was then washed with ethyl acetate, and the solid from resulting aqueous suspension was collected by filtration. The solid was washed with water and then dried under mechanical vacuum at 4O 0 C to give 23 mg of the desired product.
  • Example 199 (1.1 g) as a solid, which was used in the next step without further purification.
  • Example 200 (470 mg) as a solid that was used in the next step without further purification.
  • Example 201
  • the reaction was heated (80°C) for 16 h and then cooled to it The mixture was filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative HPLC using an elution gradient from 25-75% acetonitriie in water to afford 37 mg (32%) of the desired product.
  • the reaction was heated (70°C) for 17 h and then cooled to rt.
  • the mixture was concentrated to dryness and the residue was dissolved in a mixture of DMSO and MeOH.
  • the crude mixture was purified by HPLC using a gradient elution from 10% to 90% acetonitrile in H 2 O to obtain 44 mg (40%) of the desired product.
  • Examples 221 and 222 were prepared using the procedures of Example 208 and 209, respectively.
  • the starting materials ethyl N-[2-(4-bromo-2-methylphenyl)-3-cyanoquinolin-4-yl]-beta- alaninate, was prepared using the methods described for the preparation of Examples 93-95.
  • Example 289 were recovered after concentration of the filtrate under reduced pressure and purification of the residue by silica gel flash chromatography (10 to 50% ethyl acetate in hexane) to give an additional 300 mg of Example 289.
  • the resultant suspension was stirred at rt under nitrogen for 1.5 h and then evaporated under reduced pressure.
  • the residue was diluted with dichloromethane (20 ml_), washed with water (20 r ⁇ L), dried over sodium sulfate and evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography using a gradient of 20-50% ethyl acetate/hexanes to afford 302 mg (70%) of desired product.
  • the reaction was stirred at rt and then diluted with water (80 mL).
  • the product was extracted with ethyl acetate (3 x 20 mL) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography using 25% ethyl acetate/hexanes to afford 273 mg (45%) of desired product.
  • the mixture was diluted with ethyl acetate (50 ml_) and then successively washed with water (50 ml_) and 1 N aqueous sodium hydroxide solution (30 ml_), dried over sodium sulfate, and concentrated to dryness.
  • the residue was purified by HPLC using a gradient of 25-75% acetonitrile in water to afford 167 mg (34%) of the desired product.

Abstract

The invention relates to 2-phenyl-substituted quinoline and quinazoline compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.

Description

PHENYL-SUBSTITUTED QUINOLINE AND QUINAZOLINE COMPOUNDS FOR THE TREATMENT OF DIABETES
[001] This application claims benefit of U.S. Provisional Application Serial No. 60/612,601 ; filed on September 23, 2004, the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[002] The invention relates to 2-phenyl-substituted quinoline and quinazoline compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.
BACKGROUND OF THE INVENTION
[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 and type 2. Type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing β-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired β-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 β-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, metformin, and insulin.
[005] Over time, more than one-third of all type 2 diabetic subjects lose their response to oral agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment include, for example, the need for drug injection, the potential for hypoglycemia, and weight gain.
[006] Another strategy for diabetes therapy is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion. 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. The effect of cAMP is, however, glucose- dependent, that is, cAMP has little if any effects on insulin secretion 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.
[007] Endogenous secretagogues utilize the cAMP system to regulate insulin secretion in a glucose-dependent fashion (Komatsu, et al., Diabetes 46:1928-1938, 1997). Examples of such endogenous secretagogues include pituitary adenylate cyclase activating peptide (PACAP), vasoactive intestinal polypeptide (VIP), and glucagon-like peptide-1 (GLP-1). [008] The use of such endogenous secretagogues to treat diabetes has some drawbacks. For instance, the peptidyl nature of these compounds requires that they be administered by injection. Additionally, the effects of the endogenous secretagogues are short-lived because of the short half-life of the peptides.
[009] Because of the problems with current treatments, new therapies to treat diabetes are needed. In particular, new treatments to maintain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: 1) dependency on glucose for promoting insulin secretion, that is, compounds that stimulate insulin secretion only in the presence of elevated blood glucose and therefore, low probability for hypoglycemia; 2) low primary and secondary failure rates; and 3) preservation of islet cell function.
[010] The present invention provides a novel treatment for diabetes and related disorders by focusing on regulation of the cAMP signaling system by inhibition of phosphodiesterase 10A (PDE10A). Phosphodiesterases (PDEs) are a family of cAMP and/or cGMP-hydrolyzing enzymes that cleave 3',5'-cyclic nucleotide monophosphates to 5'-nucleotide monophosphates. PDEs are known to be involved in the regulation of the cAMP system. Specifically, PDE1 OA is a phosphodiesterase that hydrolyses cAMP and cGMP with Km values of approximately 0.1-7 μM (Fujishige, et al., J. Biol. Chem. 274:18438-18445, 1999; Soderling, et al., Proc. Natl. Acad. Sci. 96:7071-7076, 1999; Loughney, et al., Gene 234:109-117, 1999).
[011] By inhibiting PDE1 OA activity, intracellular levels of cAMP are increased thereby increasing the release of insulin-containing secretory granules and therefore, increasing insulin secretion. Thus, compounds that are PDE1 OA inhibitors are useful for the treatment for diabetes and related disorders.
[012] In addition, expression of PDE10 can be detected in the heart (Loughney, et al., Gene 234:109-117, 1999; Kotera, et al., Biochem. Biophy. Res. Comm. 261:551-557, 1999), and cGMP and cAMP are important second messengers that are involved in the regulation of vascular smooth muscle tone. The PDE10 family comprises enzymes that are responsible for the degradation of cAMP and cGMP in various tissues (Fujishige, et al., J. Biol. Chem. 274:18438- 18445, 1999). The activation of soluble and membrane bound guanylate cyclases leads to increased intracellular cGMP levels and induces vasodilation. The stimulation of various G protein-coupled receptors (GPCRs) which are expressed in vascular smooth muscle cells (e.g., adrenomedullin and CGRP receptors) induces the activation of adenylate cyclases, generation of intracellular cAMP, and produces vasodilation. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of 3',5'-cyclic nucleotides to their respective nucleoside 51- monophosphates. Thus, PDE10A likely plays a role in the cardiovascular system.
[013] The compounds of the present invention may be used to inhibit PDE1 OA activity and thus, may be used to treat diseases and/or disorders such as diabetes, cardiovascular disorders, or PDE10A-related diseases and/or disorders. SUMMARY OF THE INVENTION
[014] The present invention relates to 2-phenyl-substituted quinoline and quinazoline compounds useful for the treatment of diabetes, including type 1 and type 2 diabetes. Additional methods of the invention include treatment of disorders related to diabetes, such as Syndrome X, impaired glucose tolerance, and impaired fasting glucose. The present invention also relates to methods of treating gestational diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), and associated diabetic dyslipidemia and other diabetic complications, as well as hyperglycemia, hyperinsulinemia, dyslipidemia, hypertriglyceridemia, and insulin resistance.
[015] The invention further relates to methods of stimulating insulin release from pancreatic cells in a mammal by administering an effective amount of a compound of the present invention. This method of insulin release may be in response to an elevation of the concentration of glucose in the blood of a mammal.
[016] The compounds of the present invention may also be administered in conjunction with other diabetes therapies, such as alpha-glucosidase inhibitors (e.g., acarbose), insulin sensitizers (e.g., thiazolidinediones), compounds that reduce hepatic glucose output (e.g., metformin), insulin secretagogues (e.g., sulfonylureas), β-3 agonists, and insulin. Furthermore, the compounds of the present invention may be administered in conjunction with one or more weight reduction agents, such as orlistat, sibutramine, β-3 agonist, or CB-1 antagonist. Finally, in another embodiment, the compounds of the present invention may be administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, or an antihypertensive drug.
[017] In one aspect of the invention, the compounds may be administered for the treatment of dementia or urogenital tract disorders. Urogenital tract disorders include, but are not limited to, incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction, and hypertrophy of prostate. In another aspect of the invention, compounds of the present invention may be administered for the treatment of cardiovascular disorders, such as hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke.
DETAILED DESCRIPTION OF THE INVENTION
[018] The invention provides 2-phenyI-substituted quinoline and quinazoline compounds of Formula (I)
Figure imgf000005_0001
(I)
wherein
X is a group selected from
Figure imgf000005_0002
Y is CR7 or N;
R1 is:
• H,
• (CrC6)alkyl,
• (C3-C6)cycloalkyl,
• (CrC6)alkoxy,
• (C3-C6)cycloalkoxy,
• (CrC6)thioalkyl,
• halo,
• (CrC6)haloalkyl,
• (CTCeJhaloalkoxy,
• CN, or
• NR6R6; R2 is:
• H1
• (Ci-C6)alkyl optionally substituted with (C3-C6)cycloalkyl,
• (C3-C6)cycloalkyl,
• (C1-C6)alkoxy optionally substituted with (C3-C6)cycloalkyl,
• (C3-C6)cycloalkoxy,
• (CrC6)thioalkyl,
• halo,
• (CrC6)haloalkyl,
• (CrC6)haloalkoxy,
• NR6R6,
• (CrCgJacyl, or
• (C3-C6)cycloalkyl;
R3 is:
• H,
• (Ci-C6)alkyl, or
• (C3-C6)cycloalkyl;
R4 and R4 , which may be the same or different, are:
• H,
• (CrC6)haloalkyl,
• (C3-C6)cycloalkyl,
• (CrC6)alkoxy,
• (C3-C6)cycloalkoxy,
• (Ci-C6)haloalkoxy, or
• (CrC6)alkyl optionally substituted with aryl, heteroaryl, OH, CN, or NR6R6, or, when taken together, R4 and R4' can join to form a saturated (C3-C6)-cycloalkyl or a (C3- C6)heterocyclyl ring optionally substituted with:
• (Ci-C6)haloalkyl,
• (C3-C6)cycloalkyl,
• (CrC6)alkoxy,
• (C3-C6)cycloalkoxy,
• (CrCβJhaloalkoxy, or
• (CrC6)alkyl optionally substituted with aryl, heteroaryl, OH1 CN, or NR6R6;
R5 is:
• H,
• aryl,
• heteroaryl, or
• (CrC6)alkyl optionally substituted with an aryl or heteroaryl group;
R6 is:
• H,
• (d-C6)alkyl,
• (C3-C6)cycloalkyl, or
• (CrC6)haloalkyl;
R7 is:
• H,
• (C3-C6)alkyl,
• (CrC^cycloalkyl,
• (CrC6)thioakyl,
• halo, or
• CN; Z is:
H1
(d-CβJalkyl,
(C3-C6)cyc!oalkyl,
(CrC6)alkoxy,
(CrC6)thioalkyl, halo,
(CrC6)haloalkyl,
(C3-C6)cycloalkoxy,
CN,
• thioaryl,
• (C2-C6)alkenyl optionally substituted with aryl, heteroaryl, heterocyclyl, (C3- C6)cycloalkyl, (CrC6)haloalkyl, or halo,
• aryl,
• heteroaryl, or
• heterocyclyl,
wherein said aryl, heteroaryl, and heterocyclyl being optionally substituted at any available position by up to 3 independently selected R8 groups, and optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl or heteroaryl ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein said fused ring may be optionally substituted at any available position by up to 3 independently selected R8 groups;
R is selected from hydroxy,
SH, formyl, halo,
CN,
NO2,
SiMe3,
C(=O)OH,
C(=O)-O(CrC6)alkyl, • C(=O)-O-(C3-C6)cycloalkyl,
• (CrC6)acyl,
• C(=O)-(C3-C6)cycloalkyl,
• C(=O)-aryl,
• C(=O)-heteroaryl,
• NR6R6,
• C(=O)NR6R6,
• C(=S)NR6R6,
• (CrC6)alkyl optionally substituted with halo, OH, NR6R6, (CrC6)alkoxy, cycloalkyl, CN,
or
Figure imgf000009_0001
wherein Q is CH2, O, S, NR 60 DR6 , or aryl,
(d-C6)haloalkyl,
(CrC6)alkoxy optionally substituted with (C3-C6)cycloalkyl, heteroaryl, or aryl,
(Ci-CeOthioalkyl,
(C2-C6)alkenyl,
(C1-C6)haloalkoxy,
(C3-C8)cycloalkyl,
(C3-C8)cycloalkoxy, phenoxy optionally substituted on the phenyl ring with halo, (CrC^alkyl, or (C1-
C6)alkoxy, or a mono or bicyclic ring radical selected from the group consisting of: a) a phenyl optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and c) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R9 groups;
R9 Is:
• halo,
• hydroxy,
• oxo,
• CN, • (d-CeJalkyl optionally substituted with halo, OH, NR6R6, or (C1-C6JaIkOXy,
• (CrC6)haloalkyl,
• (C1-C6JaIkOXy,
• (CrC6)thioalkyl,
• (C1-C6)IIaIOaIkOXy,
• (C3-C8)cycloalkyl,
• (C3-C8)cycloalkoxy,
• (CrCβ)acyl,
• C(=O)OH,
• CH2C(=O)OH,
• NR6R6,
• C(=O)NR6R6,
• C(=O)O(C1-C6)alkyl, and
• C(=0)0(C3-C6)cycloalkyl;
m is O, 1 , 2, or 3; n is 1, 2, 3, or 4; p is 0, 1 , or 2;
or pharmaceutically acceptable salts and esters thereof;
with the proviso that when X is
Figure imgf000010_0001
v m 2 and m = 0, then Y is C-R7 and R7 is CN or
SO2(CrC6)alkyl.
[019] The invention also provides 2-phenyl-substituted quinoline and quinazoline compounds of Formula (II)
Figure imgf000011_0001
(H)
X is a group selected from
Figure imgf000011_0002
R1 is:
• H,
• (Ci-Cβ)alkyl,
• (C3-C6)cycloalkyl,
• (C1-C6)alkoxy,
• (C3-C6)cycloalkoxy,
• (CrCβJthioalkyl,
• halo,
• (C1-C6)haloalkyl,
• (Ci-C6)haloalkoxy, or
• CN;
R2 is:
• H,
• (Ci-Cβ)alkyl optionally substituted with (C3-C6)cycloalkyl,
• (C3-Cβ)cycloalkyl,
• (C1-C6JaIkOXy optionally substituted with (C3-C6)cycloalkyl,
• (C3-C6)cycloalkoxy, • (C1-C6)IhJOaIkYl,
• halo,
• (d-C6)haloalkyl,
• (C1-C6)haloalkoxy,
• NR6R6,
• (C1-C6JaCyI, or
• (C3-C6)cycloalkyl;
R3 is:
• H,
• (d-Ce)alkyl, or
• (C3-C6)cycloalkyl;
R4 and R4', which may be the same or different, are:
• H,
• (Ci-C6)haloalkyl,
• (C3-C6)cycloalkyl,
• (C1-C6JaIkOXy,
• (C3-C6)cycloalkoxy,
• (CrC6)haloalkoxy, or
• (d-C6)alkyl optionally substituted with aryl, heteroaryl, OH, CN or NR6R6;
or, when taken together, R4 and R4 can join to form a saturated (C3-C6)-cycloalkyl or a (C3- C6)heterocyclyl ring optionally substituted with:
• (C1-C6)haloalkyl,
• (C3-C6)cycloalkyl,
• (C1-C6JaIkOXy,
• (C3-C6)cycloalkoxy,
• (d-C6)haloalkoxy, or • (CrC6)alkyl optionally substituted with aryl, heteroaryl, OH, CN, or NR6R6;
R5 is:
• H,
• aryl,
• heteroaryl, or
• (CrC6)alkyl optionally substituted with an aryl or heteroaryl group;
R6 is:
• H,
• (CrC6)alkyl,
• (C3-C6)cycloalkyl, or
• (CrC6)haloalkyl;
R8 is: hydroxy,
SH, formyl, halo,
CN,
NO2,
SiMe3,
C(=O)OH,
C(=O)-O(CrC6)alkyl,
C(=O)-O-(C3-C6)cycloalkyl,
(CrC6)acyl,
C(=O)-(C3-C6)cycloalkyl,
C(=O)-aryl,
C(=O)-heteroaryl,
NR6R6,
C(=O)NR6R6,
C(=S)NR6R6,
(C1-C6)alkyl optionally substituted with halo, OH, S, NR6R6, (C1-C6) kOXy, cycloalkyl, 67
CN, or
Figure imgf000014_0001
wherein Q is CH2, O, NR6R6, or aryl,
• (CrC6)haloalkyl,
• (CrC6)alkoxy optionally substituted with (C3-C6)cycloalkyl, heteroaryl, or aryl,
• (CrC6)thioalkyl,
• (C2-C6)alkenyl,
• (C1-C6)haloalkoxy,
• (C3-C8)cycloalkyl,
• (C3-C8)cycloalkoxy,
• phenoxy optionally substituted on the phenyl ring with halo, (CrC6)alkyl, or (C1- Ce)alkoxy, or
• a mono or bicyclic ring radical selected from the group consisting of: a) a phenyl optionally fused to a 5- or 6-membered cycloalkyl, or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and c) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N1 O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R9 groups;
R9 Is:
• halo,
• hydroxy,
• oxo,
• CN1
• (CrC6)alkyl optionally substituted with halo, OH, NR6R6, or (C1-C6)^kOXy,
• (C1-C6)haloalkyl,
• (C1-C6)^kOXy1
• (CrCeJthioalkyl,
• (CrC^haloalkoxy,
• (C3-C8)cycloalkyl,
• (C3-C8)cycloalkoxy,
• (C1-C6JaCyI1
• C(=0)0H, • CH2C(=O)OH,
• NR6R6,
• C(=O)NR6R6,
• C(=O)O(C1-C6)alkyl, or
• C(=O)O(C3-C6)cycloalkyl;
R10 is halo;
m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; p is O, 1 , or 2; q is 1 , 2 or 3; or pharmaceutically acceptable salts and esters thereof.
[020] The terms identified above have the following meaning throughout:
[021] Prefixes such as (C1-C6) are used to indicate the respective number of carbon atoms, for example, in this case, 1 to 6 carbons.
[022] The term "halo" means F, Cl, Br, or I.
[023] The term "(CrCβJalkyl" means a straight or branched saturated hydrocarbon carbon chain of from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl, n-hexyl, and the like.
[024] The term "(C2-C6)alkenyl" means a straight or branched unsaturated hydrocarbon carbon chain of from 2 to about 6 carbon atoms. Examples of such groups include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, 3-ethyl-2-butenyl, 4-hexenyl, and the like.
[025] The term "(CrCβJhaloalkyl" means a (C1-Ce)alkyl group substituted by 1 to 3 halogen atoms or fluorine up to the perfluoro level. Examples of such groups include, but are not limited to, trifluoromethyl, tetrafluoroethyl, 1 ,2-dichloropropyl, 5-bromopentyl, 6-iodohexyl, and the like.
[026] The terms "(C3-C6)cycloalkyl" or "(C3-C8)cycloalkyl" means a saturated carbocyclic ring system of from 3 to about 6 carbon atoms or from 3 to about 8 carbon atoms, respectively. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, and the like.
[027] The term "5- to 6-membered cycloalkly" means a saturated or patially unsaturated carbocyclic ring system of 5 or 6 carbon atoms, respectively. Examples of such groups include, but are not limited to, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
[028] The term "(CrC6)acyl" means a (CrC6)alkyl group attached at the carbonyl carbon atom. The radical is attached to the rest of the molecule at the carbonyl bearing carbon atom. Examples of such groups include, but are not limited to, acetyl, propionyl, n-butanoyl, 2-m ethyl pentantoyl, and the like.
[029] The term "thioaryl" means an aryl group attached to a sulfur atom. The S atom is the point of attachment of the thioaryl substituent to the rest of the molecule. The term also includes the different oxidation states of sulfur (e.g., -SO-, -SO2-). Examples of such groups include, but are not limited to, thiophenyl, phenyl sulfoxide, phenyl sulfone, and the like.
[030] The term "(Ci-C6)alkoxy" means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an O atom. The O atom is the point of attachment of the alkoxy substituent to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
[031] The term "(CrC6)thioalkyl" means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an S atom. The S atom is the point of attachment of the thioalkyl substituent to the rest of the molecule. The term also includes the different oxidation states of sulfur (e.g., -SO-, -SO2-). Such groups include, but are not limited to, methylthio, propylthio, hexylthio, ethylsulfoxide, methyl sulfone, and the like.
[032] The term "(CrC6)haloalkoxy" means a (CrC^alkoxy group further substituted on C with 1 to 3 halogen atoms or fluorine up to the perfluoro level. Such groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 3- chloropropoxy, 1-fluoro-2,2,-dichloroethoxy, and the like.
[033] The term "(C3-C6)cycloalkoxy" means a (C3-C6)cycloalkyl group attached to an O atom. The O atom is the point of attachment of the cycloalkoxy group with the rest of the molecule. Examples of such groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
[034] The term "phenoxy" means an aryl group attached to an O atom. The O atom is the point of attachment of the phenoxy group to the rest of the molecule.
[035] The term "aryl" represents a mono- to bicyclic carbocyclic radical, which is aromatic at least in one ring, having generally 6 to 10 carbon atoms, illustratively representing phenyl and naphthyl.
[036] The term "heteroaryl" represents an mono- or bicyclic radical, having generally 5 to 10 ring atoms from which up to 4 atoms may be selected from the group consisting of N, O, and S, which is aromatic at least in one ring. The mono- or bicyclic radical can be attached to the rest of the molecule via a ring carbon atom or a ring nitrogen atom. If the radical represents a bicyclic, wherein one ring is aromatic and the other one is not, it can be attached at either ring. Illustrative examples are thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothiophenyl, benzooxazolyl, benzothiaolyl, quinolinyl, isoquinolinyl, 1 ,3-benzodioxinyl, 1 ,4- benzodioxinyl, or benzodioxolyl. [037] The term "heterocyclyl" represents a mono- or bicyclic nonaromatic (saturated or partially saturated) radical having generally 3 to 10 ring atoms from which up to 3 atoms may be selected from the group consisting of N, O, and S. The radical can be attached via a ring carbon atom or a ring nitrogen atom. Illustrative examples are tetrahydrofuran-2-yl, pyrrolidin-2-yl, tetrahydropyridyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, perhydroazepinyl, dihydropyrano, pyrazolinyl, imidazolinyl, or dihydrofuryl,
[038] When the heteroaryl or heterocyclyl group is attached to the rest of the molecule as a substituent, it becomes a radical. The point of attachment of the radical may be from any available C or N atom of the ring to the rest of the molecule.
[039] The term "optionally substituted" means that, unless indicated otherwise, the moiety so modified may have from one to up to the number of the substituents indicated, provided the resulting substitution is chemically feasible as recognized in the art. Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. When there are two or more substituents on any moiety, each substituent is chosen independently of the other substituent so that, accordingly, the substituents can be the same or different.
Alternative Forms Of Novel Compounds
[040] 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.
[041] The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.
[042] 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, 67
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, /V-hydroxybutyric, salicylic, galactaric, and galacturonic acid, and combinations thereof.
[043] Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.
[044] The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides, and sulfonamides.
[045] The present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability, and release time (see, e.g., "Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), Ed. Ansel, et al., Williams & Wilkins (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 Λ/-dealkylation, O- dealkylation, aliphatic hydroxylation, aromatic hydroxylation, Λ/-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation, and acetylation (see, e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), Ed. Molinoff, et al., McGraw-Hill (1996), which is hereby incorporated by reference).
General Preparative Methods
[046] In general, the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.
[047] Additionally, sensitive or reactive groups on a compound of Formula (I) may need to be protected and deprotected during any of the above methods for forming esters. Protecting groups in general may be added and removed by conventional methods well known in the art (see, e.g., T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).
[048] The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific X moiety, and the specific substituents possible at various locations on the molecule, all play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.
[049] For example, compounds of Formula (Ia) and (Ib), where Y = N and X is
Figure imgf000019_0001
Figure imgf000019_0005
, can be prepared by the general method illustrated in Reaction
Scheme 1.
[050] Reaction Scheme 1
Figure imgf000019_0002
(IVa) (IVb)
1. base, Pd catalyst
Figure imgf000019_0003
where X =
Figure imgf000019_0004
[051] In this Reaction Scheme, a readily available dichloroquinazoline compound of Formula (IVa) is allowed to react with a nucleophile of Formula (111) in the presence of a base, to provide the intermediate of Formula (IVb). Compound (IVb) is then subjected to a Suzuki coupling reaction with a boronic ester derivative of Formula (V), using a Pd catalyst such as Pd(dppf)CI2 and a base such as K2CO3. The product as formed is Formula (Ia), and can converted to the Formula (Ib) acid by hydrolysis with aqueous base. [052] A supplementary method for the preparation of compounds of Formula (Ic) and (Id) where Y = N and X is
Figure imgf000020_0001
\ X(CR4R41)-CO2R3
, is described in Scheme 2.
)53] Reaction Scheme 2
Figure imgf000020_0002
[054] In Reaction Scheme 2, primary amides (VII) are prepared from acids of Formula (Vl) by conversion to the acid chloride using a chlorinating agent such as SOCI2, followed by exposure to ammonia. Subsequent reduction of the nitro group to the amine of Formula (VIII) is achieved through the use of a catalyst (e.g., Pd/C, Pd(OH)2) under an atmosphere of hydrogen. Condensation of intermediate of Formula (VIII) with aldehydes of Formula (IX) in the presence of sodium hydrogen sulfite in a polar solvent such as /V,/V-dimethylacetamide affords quinazolones of Formula (X). Conversion to a 4-chlorosubstituted intermediate of Formula (Xl) by action of a chlorinating agent such as SOCI2 is followed by nucleophilic addition of the compound of Formula (III) in the presence of base provides the quinoline of Formula (XII). When Z is halo, Suzuki coupling reaction of (XII) with a boronic acids of Formula (XIII) or (XIV) gives compounds of Formula (Ic) and (Id). Optional hydrolysis of (Ic), for example, using aqueous sodium hydroxide, gives the corresponding acid compound of Formula (Id).
[055] A method useful for the preparation of compounds of Formula (Ie) and Formula (If) where Y = CR7 and X is
Figure imgf000021_0001
>P
^ (CR4R4) -CO R3 or m 2 , is shown in Reaction Schemes 3-5.
[056] Reaction Scheme 3
Figure imgf000021_0002
R7= H or alkyl R7= H or alkyl
Figure imgf000021_0003
[057] In Reaction Scheme 3, the 2-(4-halophenyl)-4-hydroxyquinoline intermediates (XVIIa) and (XVIIb) are prepared. The preparation of intermediate (XVIIa), where R7 is H or alkyl, is accomplished by reaction of the ketoester of Formula (XV) with an aniline of Formula (XVI), and addition of an acidic catalyst such as p-toluenesulfonic acid. Intermediate (XVIIb) can be prepared by the reaction of a substituted isatoic anhydride of Formula (XVIII) or a Λ/-hydroxysuccinimide ester of Formula (XIX) with a cyanoacetophenone of Formula (XX), together with a strong base such as sodium hydride.
[058] Reaction Scheme 4
Figure imgf000022_0001
Where:
Ar= aryl
Het = heteroaryl
X =
Figure imgf000022_0002
[059] In Reaction Scheme 4, either intermediate of Formula (XVIIa) or Formula (XVIIb) is converted to the corresponding by aryl using Suzuki coupling reaction of a boronic acid of Formula (XIII) or Formula (XIV) to give compounds of Formula (XXI). Conversion to a 4- chlorosubstituted intermediate of Formula (XXII) can be effected by action of a chlorinating agent such as POCI3. Nucleophilic addition of the compound of Formula (III) in the presence of base provides compounds of Formula (Ie). Optional hydrolysis of (Ie), for example, using aqueous sodium hydroxide or a strong acid, gives the corresponding acid compound of Formula (If). [060] Reaction Scheme 5
Figure imgf000023_0001
Figure imgf000023_0002
[061] In Reaction Scheme 5, either intermediate of Formula (XVlIa) or Formula (XVIIb) is converted to a 4-chlorosubstituted intermediate of Formula (XXIII) by action of a chlorinating agent such as POCI3. Nucleophilic addition of the compound of Formula (III) in the presence of base provides the quinoline intermediate of Formula (XXIV). Suzuki coupling reaction of (XXIV) with a boronic acid of Formula (XIII) or (XIV) gives the compound of Formula (Ie) or (If). Optional hydrolysis of (Ie), for example, using aqueous sodium hydroxide or a strong acid, gives the corresponding acid compound of Formula (If).
[062] A supplementary route to the above method, useful for preparation of compounds of Formula (Ig) and Formula (Ih) where Y = CR7 and X is
Figure imgf000023_0003
>P X(CR4R4')-CO2R3 or , is shown in Reaction Scheme 6. [063] Reaction Scheme 6
Figure imgf000024_0001
(XVIlI) (XXVI) (XXVlI)
Figure imgf000024_0002
[064] In Reaction Scheme 6, intermediate (XXVI) is prepared by the reaction of a substituted isatoic anhydride of Formula (XVIII) with a cyanoacetate of Formula (XXV), together with a strong base such as sodium hydride. Conversion to a 2,4-dichlorosubstituted intermediate of Formula (XXVII) can be achieved by action of a chlorinating agent such as POCI3. Nucleophilic addition of the compound of Formula (III) in the presence of base provides the quinoline intermediate of Formula (XXVIII). Subsequent Suzuki coupling reaction with a boronic acid of Formula (XIII) or Formula (XIV) gives the compound of Formula (Ig) or Formula (Ih). Optional hydrolysis of Formula (Ig), for example, using aqueous sodium hydroxide, gives the corresponding acid compound of Formula (Ih).
[065] A supplementary route to the above method, useful for preparation of compounds of
Formula (Ii) and Formula (Ij), where Y = CR7 and X is
Figure imgf000024_0003
is shown in Reaction Scheme 7. [066] Reaction Scheme 7
Figure imgf000025_0001
Lg = Cl, Br, I
X = -(CR4R4')ffCO2R3
[067] In Reaction Scheme 7, acid of Formula (XXIX) is exposed to a chlorinating agent such as SOCI2 or (COCI)2, followed by treatment with a source of ammonia to give and amide of Formula (XXX). Subsequent Hoffmann-type rearrangement using BTIB or NaOBr affords A- aminoquinolines of Formula (XXXI). Treatment of a compound of Formula (XXXI) with an appropriately substituted electrophile of Formula (XXXII) in the presence of base provides compounds of Formula (Ii). Optional hydrolysis of Formula (Ii), for example, using aqueous sodium hydroxide, gives the corresponding acid compound of Formula (Ij).
[068] Compounds of Formula (I) in which X is
Figure imgf000025_0002
or
Figure imgf000025_0003
may be prepared as illustrated in Reaction Schemes 8-15 below, beginning with Reaction Scheme 8 which illustrates the preparation of common intermediates of Formula (XXXV) and Formula (XXXVII). [069] Reaction Scheme 8
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0004
Figure imgf000026_0003
Ar = aryl, Het = heteroaryl
[070] As illustrated in Reaction Scheme 8, preparation of compounds where Y = CR7 is accomplished by reaction of an isatin compound of Formula (XXXIII) with ketone of Formula (XXXIV) in the presence of a base such as potassium hydroxide to give the 2-(4- bromophenyl)quinoline-4 carboxylic acid of Formula (XXXVa). Preparation of the of 2-(4- bromophenyl)quinazoline-4 carboxylic acid of Formula (XXXVb) where Y = N, is accomplished by reaction of isatin (XXXIII) with a benzoyl chloride of Formula (XXXVI) and base, followed by quenching with ammonia. Either intermediate (XXXVa) or (XXXVb) is then allowed to undergo Suzuki coupling with a boronic acid of Formula (XIII) or Formula (XIV) under standard conditions to provide the compounds of Formula (XXXVIIa) [(XXXVII) where Y = CR7] and (XXXVIIb) [(XXXVIII) where Y = N]. Compounds of Formula (XXXV) and (XXXVII) can be used to prepare compounds of the invention as further described below in Reaction Schemes 9-12.
[071] Reaction Scheme 9 illustrates the preparation of compounds of Formulae (U) and (Im) in
Figure imgf000026_0005
which X = from intermediate (XXXVII). [072] Reaction Scheme 9
Figure imgf000027_0001
[073] In Reaction Scheme 9, the compound of Formula (XXXVII) is esterified, for example, by reaction with MeI and a base, to provide the ester intermediate of Formula (XXXVIII). This compound is then reduced to the primary alcohol (XXXIXa) with a suitable reducing agent such as DIBAL. The alcohol can then be oxidized to the aldehyde of Formula (XL) under selective oxidizing conditions such as a Swern oxidation [DMSO, oxalyl chloride, and triethyl amine], and this intermediate can be used to prepare an alcohol of Formula (XXXIXb) by Grignard reaction with the reagent of Formula (XLI). Either alcohol (XXXIXa) or (XXXIXb) may then be O-alkylated in base with an 2-halo ester of Formula (XXXII), to prepare the compound of Formula (\i). Hydrolysis of (1^) in aqueous base provides the corresponding carboxylic acid compound of Formula (Im).
[074] Compounds of Formulae (U) and (Im) [ (I) in which X =
Figure imgf000028_0001
can also by the route illustrated in Reaction Scheme 10.
[075] Reaction Scheme 10
Figure imgf000029_0001
Figure imgf000029_0002
[076] In Reaction Scheme 10, the intermediate carboxylic acid of Formula (XXXV) is esterified to the corresponding ester of Formula (XLIII), then reduced to the primary alcohol of Formula (XLIVa) with a selective reducing agent such as DIBAL. Oxidation of (XLIVa) to the aldehyde of Formula (XLV) is accomplished with a selective oxidation, for example, under Swern conditions [DMSO1 oxalyl chloride, and triethyl amine]. The aldehyde is then allowed to react with a Grignard reagent of Formula (XLI) to provide the alcohol of Formula (XLIVb), where R4 is alkyl. Either alcohol intermediate (XLIVa) or (XLIVb) is then alkylated with a 2-haloester of Formula (XXXII) in the presence of base, to give the intermediate of Formula (XLVI). Suzuki coupling of (XLVI) with the boronic acid of Formula (XIII) or Formula (XIV) provides compounds of Formula (l£) where R3 is alkyl. Optional hydrolysis of (l£), for example, under aqueous basic conditions, give the corresponding acid of Formula (Im) where R3 is H.
[077] A supplementary method for the synthesis of compounds of Formula (In) when Y = C-R7
and X = /X[CR R ]m-CO2R3 j-m _ 2] js described in scheme 11.
[078] Reaction Scheme 11
Figure imgf000030_0001
[079] In Reaction Scheme 11 , conversion of intermediate of Formula (XXXIXa) to the corresponding halide of Formula (XLVII) is effected using halogenating reagents such as CBr4ZPPh3. Homologation to compounds of Formula (XLVlII) can then be achieved through the addition of a malonate unit in the presence of a strong base such as NaH in a polar solvent such as DMF. Decarboxylation of intermediate of Formula (XLVIII) can be achieve through hydrolysis of the esters in aqueous base, followed by a treatment with aqueous acid (e.g., HCI) at reflux to provide compounds of Formula (In).
[080] A supplementary method for the synthesis of compounds of Formula (lo) and Formula (Ip)
when Y = CR7 and X = X[CR R Jm-CO2R3 [m _ 2] is described in Reaction Scheme 12. [081] Reaction Scheme 12
Figure imgf000031_0001
[082] In Reaction Scheme 12, coupling of intermediate of Formula (XXII) with an appropriately substituted acrylate of Formula (XLIX) can be effected using Heck-type conditions, for example, using Pd2(dba)3, Cy2Nme, P(J-Bu)3 in dioxane. Subsequent reduction of the olefin of compounds of Formula (L) can be achieved using a catalyst (e.g., Pd/C, Pd(OH)2) under an atmosphere of hydrogen. Optionally, hydrolysis of Formula (lo) in aqueous base provides the corresponding carboxylic acid compound of Formula (Ip).
[083] A supplementary method for the synthesis of compounds of Formula (Iq) when Y = CR7
and X 1] is described in Reaction Scheme 13.
Figure imgf000031_0003
[084] Reaction Scheme 13
Figure imgf000031_0002
[085] The halogenated intermediate (XLVlI) can be carbonylated using a catalyst (e.g., RhCI(COD)) in the presence of Kl and formic acid under an atmosphere of carbon monoxide to provide compounds of Formula (Iq) [086] Compounds of Formula (Ir) and Formula (Is) [(I) where X =
Figure imgf000032_0001
can be prepared from intermediate of Formula (XXXV) from Reaction
Scheme 8 by the method illustrated in Reaction Scheme 14.
[087] Reaction Scheme 14
Figure imgf000032_0002
Ar = aryl, Het = heteroaryl
[088] In Reaction Scheme 14, the carboxylic acid intermediate of Formula (XXXV) is coupled with an amino acid derivative of Formula (Ll) in the presence of a coupling agent such as EDCI. The product, intermediate of Formula (LIl), may then be subjected to Suzuki coupling conditions using a boronic acid of Formula (XIII) or Formula (XIV) to give the compound of Formula (Ir) where R3 is alkyl. Hydrolysis of Formula (Ir) using aqueous base such as sodium hydroxide gives the acid compound of Formula (Is) where R3 is H.
[089] Compounds of Formula (It) and Formula (Iu)1 [(I) where X is
Figure imgf000032_0003
can be prepared from intermediates of
Formula (XLIV) from Reaction Scheme 10, by the general method illustrated in Reaction Scheme 15. [090] Reaction Scheme 15
Figure imgf000033_0001
Figure imgf000033_0002
[091] In this Reaction Scheme, an alcohol intermediate of Formula (XLIV), described in Reaction Scheme 10, is converted to the corresponding chloro compound of Formula (XLVII). This intermediate may be /V-alkylated with the amino acid derivative of Formula (Lib) or Formula (LIc), optionally in the presence of a base, to give the intermediate of Formula (LIII). Suzuki coupling with the boronic acid derivative of Formula (XIII) or Formula (XIV) gives the compound of Formula (It) where R3 is alkyl, and hydrolysis of Formula (It) with aqueous base gives the compound of Formula (Iu) where R3 is H.
[092] Compounds of Formula (Iv) and Formula (Iw) [(I) in which X =
Figure imgf000033_0003
can also by the route illustrated in Reaction Scheme 16. [093] Reaction Scheme 16
Figure imgf000034_0001
Lg = Cl, Br1
[094] In Reaction Scheme 16, 4-hydroxyquinolines of Formula (XVIIb) is reacted with an electrophile of Formula (XXXII) to produce compounds of Formula (Iv). Hydrolysis of Formula (Ir) with aqueous base gives the acid compound of Formula (Iw) where R is H.
[095] The starting materials for the preparations described above can be obtained from commercial sources or prepared by using methods known to one skilled in the art. As an example, schemes 17-19 describe the synthesis of some common intermediates.
[096] Reaction Scheme 17
Figure imgf000034_0002
[097] In this Reaction Scheme, a 4-halobenzoate of Formula (LIV) is transformed to the corresponding ketone of Formula (LV) using acetonitrile or dimethyl sulfone in THF in the presence of a strong base [e.g., NaH (rt to reflux), LiHMDS (-78 0C to rt)]. Suzuki coupling with the boronic acid derivative of Formula (XIII) or Formula (XIV) gives the compound of Formula (XX). Optionally, the steps can be reversed where Suzuki coupling of halobenzoates of Formula (LIV) with boronic acid derivatives of Formula (XIlI) or Formula (XIV) gives the compound of Formula (LVI). Then, reacting Formula (LVI) with acetonitrile or dimethyl sulfone in THF in the presence of a strong base [e.g., NaH (rt to reflux), LiHMDS (-780C to rt)] affords compounds of Formula (XX). [098] Reaction Scheme 18
Figure imgf000035_0001
[099] In this reaction Scheme, isatoic anhydrides of Formula (XVIII) can be obtained through oxidation of the isatins of Formula (XXXIII), for example, using peroxides such as H2O2 or m- chloroperbenzoic acid. Alternatively, isatoic anhydrides of Formula (XVIII) can be accessed from amino acids of Formula (LVII) using phosgene in the presence of a base such as Et3N.
[100] Reaction Scheme 19
Figure imgf000035_0002
[101] In Reaction Scheme 19, n-hydroxysuccinimide esters of Formula (XIX) can be obtained by reaction of an amino benzoic acid of Formula (LVII) and reacting with n-hydroxysuccinimide under peptide-coupling conditions such as EDCI in DMF.
Abbreviations and Acronyms
[102] A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry, this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
[103] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87. [104] When the following abbreviations are used throughout this disclosure, they have the following meaning:
Ac acetyl
AcOH acetic acid am u atomic mass unit aq aqueous atm atmosphere
Bu butyl
BTIB [Bis(trifluoroacetoxy)iodo]benzene
GDI carbonyl diimidazole
Celite® brand of diatomaceous earth filtering agent, registered trader of Celite Corporation cone concentrated d doublet dd doublet of doublet ddd doublet of doublet of doublet
DIBAL diisobutylaluminum hydride
DME dimethyoxyethane
DMF Λ/,/V-dimethyl formamide
DMSO dimethylsulfoxide
DMSO-cfe dimethylsulfoxide-dβ dppf 1 ,1 '-bis(diphenylphosphino)ferrocene
EDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
El electron impact ionization
EI-MS electron impact - mass spectrometry equiv equivalent
ES - MS electrospray mass spectrometry
Et ethyl
Et2O diethyl ether
Et3N triethylamine
EtOAc ethyl acetate
EtOH ethanol
Ex example g gram
GC-MS gas chromatography - mass spectrometry h hour(s)
Hex hexanes
1H NMR proton nuclear magnetic resonance
HOAT 1 -hydroxy-7-aza-benzotriazole HOBT 1 -hydroxybenzotriazole
HPLC high-performance liquid chromatography
HPLC ES-MS high-performance liquid chromatography-electrospray mas spectroscopy
KOSu potassium fert-butoxide
L liter
LCMS liquid chromatography / mass spectroscopy
LHMDS lithium bis(trimethylsilyl)amide m multiplet
M molar mL milliliter m/∑ mass over charge
Me methyl
MeCN acetonitrile
MeOH methanol mg milligram
MHz megahertz min minute(s) mmol millimole mol mole mp melting point
MS mass spectrometry
N normal
NaOAc sodium acetate
NMM 4-methylmorpholine
1H NMR proton nuclear magnetic resonance
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(O)
Pd(OAc)2 palladium acetate
Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
Pd/C palladium on carbon
Pd(dppf)CI2 [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
Ph phenyl ppm parts per million
Pr propyl psi pounds per square inch q quartet qt quintet
Rf TLC retention factor rt room temperature
RT retention time (HPLC) S singlet t triplet
TBAF tetrabutylammonium fluoride
TBDMS terf-butyldimethylsilyl
TBDMSCI ferf-butyldimethylsilyl chloride
TBS terf-butyldimethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS tetramethylsilane v/v volume per unit volume vol volume w/w weight per unit weight
General Experimental Methods
[105] Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentration under reduced pressure" refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (0C). Thin layer chromatography (TLC) was performed on EM Science pre-coated glass-backed silica gel 60 A F-254 250 μm plates. Column chromatography (flash chromatography) was performed using 32-63 micron, 60 A, silica gel pre¬ packed cartridges (on a Biotage or ISCO system) or using glass column and air pressure. Purification using preparative reversed-phase HPLC chromatography were accomplished using a Gilson 215 system, typically using a YMC Pro-C18 AS-342 (150 x 20 mm I. D.) column. Typically, the mobile phase used was a mixture of water (A) and MeCN (B). The water could be mixed or not with 0.1% TFA. A typical gradient was:
Figure imgf000038_0001
[106] Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 μM coating; 30 m x 0.25 mm). The ion source was maintained at 2500C and spectra were scanned from 50-800 amu at 2 sec per scan. [107] High pressure liquid chromatography-electrospray mass spectra (LC-MS) were obtained using either a: a) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes. b) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate of 1.5 ml_/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration. c) Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped with an Agilent
1100 autosampler, quaternary pump, and a diode array. The HPLC column used was a Waters Sunfire (2.1 x 30 mm, 3.5 uM). The HPLC eluent was directly coupled with a 1 :4 split to a Finnigan LTQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 50-1000 amu using a variable ion time according to the number of ions in the source in either positive or negative ion mode. The eluents were A: water with 0.1 Formic acid and B: acetonitrile with 0.1% Formic acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and a final hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.
[108] Routine one-dimensional NMR spectroscopy was performed on 300/400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.05 ppm for acetone-d6, 2.49 ppm for DMSO-Cf6, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CD2CI2 and 7.26 ppm for CDCI3 for 1H spectra.
[109] By using these above described methods, the compounds of the invention may be prepared. The following specific examples are presented to further illustrate the invention described herein, but they should not be construed as limiting the scope of the invention in any way. [110] Example 1 Preparation of ethyl ΛM2-chloroquinazolin-4-yl)qlvcinate
Figure imgf000040_0001
[111] A mixture of 2,4-dichloroquinazoline (360 mg, 1.81 mmol), ethyl glycinate hydrochloride (303 mg, 2.17 mmol), and triethylamine (1.26 ml_, 9 mmol) in ethanol (5 ml_) was heated (700C) for 16 h. The mixture was cooled to rt, concentrated to dryness, and the residue was purified by silica gei flash chromatography using 40-100% ethyl acetate in hexanes followed by 0-5% methanol in dichloromethane to obtain 540 mg (98%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.13-8.09 (m, 1 H), 7.85-7.79 (m, 1 H), 7.67-7.64 (m, 1 H), 7.58-7.53 (m, 1 H), 4.32 (s, 2 H), 4.24 (q, 2 H), 1.28 (t, 3 H); ES-MS m/z 266.2 [M+H]+, LCMS RT (min) 2.41.
[112] The following intermediates were prepared using the procedure of Example 1 and substituting for the appropriate starting materials.
[113] Table 1
Figure imgf000040_0002
[114] Example 5
Preparation of ethyl Λ/-r2-(2'-methoxybiphenyl-4-yl)quinazolin-4-yllglvcinate
Figure imgf000041_0001
[115] To a solution of ethyl Λ/-(2-chloroquinazolin-4-yl)glycinate (Example 1 , 100 mg, 0.38 mmol), [1,1 '-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (30.7 mg, 0.04 mmol), and 2-(2'-methoxybiphenyl-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.175 g, 0.56 mmol) in degassed toluene and dioxane (4:1 , 1.25 mL) was added with aqueous sodium carbonate solution (2 M, 0.25 mL). The reaction was heated (850C) for 16 h and then cooled to rt. The mixture was concentrated to dryness and then the residue was dissolved in methanol and acetonitrile. This suspension was filtered through a C8 reverse phase extraction cartridge and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water to obtain 90 mg (58%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.37-8.30 (m, 3 H), 8.08-7.99 (m, 2 H), 7.82-7.76 (m, 3 H), 7.42-7.36 (m, 2 H), 7.13-7.03 (m, 2 H), 4.62 (s, 2 H), 4.27 (q, 2 H), 3.83 (s, 3 H), 1.29 (t, 3 H); ES-MS m/z 414.3 [M+H]+, LCMS RT (min) 3.03.
[116] The following compounds were prepared using the procedure of Example 1 and substituting for the appropriate starting materials.
[117] Table 2
Figure imgf000041_0002
Figure imgf000042_0002
[118] Example 9 Preparation of Λ/-r2-(2'-methoxybiphenyl-4-yl)quinazolin-4-yllqlvcine
Figure imgf000042_0001
[119] To a solution of ethyl Λ/-[2-(2'-methoxybiphenyl-4-yl)quinazolin-4-yl]glycinate (Example 5, 0.10 g, 0.24 mmol) in ethanol (1 mL) was added lithium hydroxide monohydrate (51 mg, 1.21 mmol) and water (1 mL). The resulting mixture was stirred overnight at it The mixture was adjusted to pH 5 using hydrochloric acid (2 N) and then concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 80% acetonitrile in water to afford 40 mg (43%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.38-8.32 (m, 3 H), 8.08-7.97 (m, 2 H), 7.80-7.74 (m, 3 H), 7.43-7.37 (m, 2 H), 7.15-7.04 (m, 2 H), 4.55 (s, 2 H), 3.84 (s, 3H); ES-MS m/z 386.3 [M+Hf, LCMS RT (min) 2.78.
[120] The following compounds were prepared using the procedure of Example 9 and substituting for the appropriate starting materials. 67
[121] Table 3
Figure imgf000043_0001
[122] Example 13 Preparation of 2-(4-bromophenyl)-3H-quinazolin-4-one
Figure imgf000043_0002
[123] A solution of 2-aminobenzamide (5.00 g, 36.7 mmol), 4-bromobenzaldehyde (6.79 g, 36.7 mmol), and sodium hydrogen sulfite (3.90 g, 37.5 mmol), in Λ/,Λ/-dimethylacetamide (100 mL) was heated (15O0C) for 2 h. An additional amount of sodium hydrogen sulfite (3.90 g, 37.5 mmol) was added to the reaction and the reaction mixture was heated (150°C) for an additional 2 h. The reaction was cooled to rt and was poured over ice water (800 mL). The mixture was allowed to warm to rt and the resulting precipitate was collected by filtration and washed with water. After air drying, the crude material was recrystallized from ethanol to obtain 6.54 g (59%) of the desired product. 1H NMR (300 MHz, DMSO-cfe) δ 12.59 (s, 1 H), 8.15-8.08 (m, 3 H), 7.85-7.80 (m, 1 H), 7.77-7.71 (m, 3 H), 7.55-7.49 (m, 1 H); ES-MS m/z 301.2 [M+H]+, LCMS RT (min) 2.86.
[124] When not commercially available, the amino benzamides can be prepared using the method described below.
[125] Example 14
Preparation of 5-f luoro-2-nitrobenzamide
Figure imgf000044_0001
[126] A solution of 5-fluoro-2-nitrobenzoic acid (5.00 g, 27.0 mmol) and thionyl chloride (59.1 ml_, 810.3 mmol) in 1 ,4-dioxane (50 ml_) was heated to reflux for 16 h. After cooling to rt, the reaction was concentrated to dryness. Toluene (100 ml_) was added to the residue and the mixture was again concentrated to dryness. The residue was dissolved in 1 ,4-dioxane (50 mL) and ammonia gas was bubbled into the solution. The reaction was sealed and was stirred at rt for 2 h. The resulting solid was collected by filtration, but dissolved upon washing with water. The filtrate was concentrated under reduced pressure to remove volatiles and the remaining aqueous mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine (1x) and were dried over sodium sulfate and evaporated to obtain 4.83 g (97%) of the desired product. 1H NMR (300 MHz, DMSO-Cf6) 68.13 (br s, 1 H), 8.11-8.05 (m, 1 H), 7.77 (br s, 1 H), 7.52-7.44 (m, 2 H).
[127] Example 15
Preparation of 2-amino-5-fluorobenzamide
Figure imgf000044_0002
[128] To a dry flask purged with N2 was added 10% Pd/C (483 mg) followed by 5-fluoro-2- nitrobenzamide (Example 14, 4.83 g, 26.2 mmol) as a solution in ethanol (130 mL). The mixture was stirred under an H2 atmosphere for 5 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford 4.03 g (99%) of the desired product. 1H NMR (300 MHz, DMSO-CZ6) δ 7.75 (br s, 1 H), 7.45-7.29 (m, 1 H), 7.18 (br s, 1 H), 7.10-6.93 (m, 1 H), 6.74-6.58 (m, 1 H), 6.43 (br s, 2H); ES-MS m/z 155.0 [M+Hf, LCMS RT (min) 0.27.
[129] The following compound was prepared using the procedure of Examples 13-15 and substituting for the appropriate starting materials. [130] Table 4
Figure imgf000045_0002
[131] Example 17 Preparation of 2-(4-bromophenyl)-4-chloroquinazoline
Figure imgf000045_0001
[132] A suspension of 2-(4-bromophenyl)-3H-quinazolin-4-one (Example 13, 3.00 g, 9.96 mmol), thionyl chloride (8.72 mL, 119 mmol), and Λ/,Λ/-dimethylformamide (0.19 mL, 2.49 mmol) in chloroform (90 mL) was heated to reflux for 17 h. After cooling to rt, the reaction was concentrated to dryness. The residue was dried under mechanical vacuum to obtain 3.37 g (100%) of the desired product, which contained trace impurities. 1H NMR (300 MHz, DMSO-cfe) δ 8.40-8.36 (m, 2 H), 8.28-8.24 (m, 1 H), 8.12-8.09 (m, 2 H), 7.87-7.81 (m, 1 H), 7.79-7.74 (m, 2 H); ES-MS m/z319.2 [M+H]+, LCMS RT (min) 4.65.
[133] The following compound was prepared using the procedure of Example 17 and substituting for the appropriate starting materials.
[134] Table 5
Figure imgf000045_0003
[135] Example 19 Preparation of ethyl /V-r2-(4-bromophenvπquinazolin-4-yll-beta-alaninate
Figure imgf000046_0001
[136] A mixture of 2-(4-bromophenyI)-4-chloroquinazoline (Example 17, 500 mg, 1.56 mmol), ethyl beta-alaninate (1.20 g, 7.82 mmol), and triethylamine (1.1 ml_, 7.82 mmol) in 2-propanol (10 ml_) was heated (800C) in a sealed pressure reaction flask for 4 h. The mixture was cooled to rt and was concentrated to dryness. The residue was partitioned between EtOAc/H2O. The layers were separated and the organic was further washed with H2O (3x), brine (1x) and was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 600 mg (95%) of the desired product. 1H NMR (300 MHz, DMSOd6) δ 8.45 (t, J=5A, 1 H), 8.41-8.36 (m, 2 H), 8.19 (d, J=8.1 , 1 H), 7.77-7.71 (m, 2 H), 7.70-7.64 (m, 2 H), 7.51-7.44 (m, 1 H), 4.02 (q, J=I. Q, 2H), 3.89 (q, J=6.8, 2H), 2.78 (t, J=6.8, 2 H), 1.12 (t, J=IJQ, 3H); ES-MS m/z 400.5 [M+H]+, LCMS RT (min) 2.50.
[137] The following compounds were prepared using the procedures of Example 19 and substituting for the appropriate starting materials.
Figure imgf000046_0002
034867
Figure imgf000047_0002
[139] Example 24
Preparation of ethyl /V-r2-(2'-ethoxybiphenyl-4-yl)quinazolin-4-yl1-beta-alaninate
Figure imgf000047_0001
[140] To a solution containing ethyl Λ/-[2-(4-bromophenyl)quinazolin-4-yl]-beta-alaninate (Example 19, 200 mg, 0.50 mmol), [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (40.8 mg, 0.050 mmol), and (2-ethoxyphenyl)boronic acid (249 mg, 1.50 mmol) in degassed DME (1.75 mL) was added aqueous sodium carbonate solution (2 M, 0.75 ml_). The reaction was heated (7O0C) for 16 h and then cooled to rt. The mixture was concentrated to dryness and the residue was dissolved in a mixture of methanol and DMSO. The residue was purified by HPLC using a gradient elution from 10% to 90% acetonitrile in water to obtain 95 mg (43%) of the desired product. 1H NMR (300 MHz, DMSO-cfe) δ 8.51-8.46 (m, 2 H), 8.41 (t, J=5.2, 1 H), 8.20 (d, J=8.1 , 1 H), 7.75 (d, J=3.8, 2 H), 7.63 (d, J=8.5, 2 H), 7.49-7.43 (m, 1 H), 7.38-7.29 (m, 2 H), 7.10 (d, J=8.1 , 1 H), 7.05-6.99 (m, 1 H), 4.10-4.00 (m, 4H), 3.92 (q, J=Ql, 2H), 2.81 (t, J=6.7, 2H), 1.30 (t, J=6.8, 3H), 1.14 (t, J=IA, 3H); ES-MS m/z 442.4 [M+H]+, LCMS RT (min) 3.14.
[141] The following compounds were prepared using the procedure of Example 24 and substituting for the appropriate starting materials.
[142] Table 7
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0002
[143] Example 45
Preparation of ΛH2-(2'-ethoxybiphenyl-4-vQquinazolin-4-vπ-beta-alanine
Figure imgf000052_0001
[144] To a solution of ethyl Λ/-[2-(2'-ethoxybiphenyl-4-yl)quinazolin-4-yl]-beta-alaninate (Example 24, 95 mg, 0.22 mmol) in MeOH (2 mL) and THF (0.5 mL) was added aqueous sodium hydroxide solution (1 N, 0.24 mL). The resulting mixture was heated (400C) for 16 h. The mixture was cooled to rt was evaporated to remove volatiles. The remaining aqueous mixture was further diluted with H2O was adjusted to pH 5 using hydrochloric acid (1 N). The resulting precipitate was collected by filtration and dried in vacuoto afford 58 mg (31%) of the desired product. 1H NMR (300 MHz, DMSO-Cf6) δ 8.45 (d, J=8.3, 2 H), 8.37-8.29 (m, 1 H), 7.92-7.80 (m, 2 H), 7.71 (d, J=7.4, 2 H), 7.63-7.53 (m, 1 H), 7.41-7.30 (m, 2 H), 7.12 (d, J=8.3, 1 H), 7.07-7.00 (m, 1 H), 4.08 (q, J=6.8, 2H), 3.98-3.90 (m, 2H), 2.79 (t, J=6.8, 2H), 1.30 (t, J=6.8, 3H); ES-MS m/z 414.2 [M+H]+, LCMS RT (min) 2.45.
[145] The following compounds were prepared using the procedure of Example 45 and substituting for the appropriate starting materials.
[146] Table 8
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0002
[147] Example 61 Preparation of 2-(4-bromophenvO-4-chloroquinoline
Figure imgf000056_0001
[148] A solution of aniline (1.65 mL, 18.2 mmol), ethyl 3-(4-bromophenyl)-3-oxopropanoate (4.92 g, 18.2 mmol), and 4-toluenesulfonic acid monohydrate (172.6 mg, 0.91 mmol), in toluene (5 mL) heated to reflux for 4 h. The reaction was cooled to rt and concentrated to dryness. The residue was dissolved in diphenyl ether (35 mL) and heated (2250C) for 1h. The reaction mixture was cooled to rt and then diluted with hexanes (50 mL). The resulting precipitate was collected by filtration using hexanes to wash. The solid was added to phosphorous oxychloride (5 mL, 53.6 mmol), and the mixture was heated to reflux for 3 h. After cooling to rt, the reaction was quenched with ice and then the solution was adjusted to pH 7 using aqueous sodium hydroxide solution (1 N). The aqueous layer was extracted with dichloromethane (3 X 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel flash chromatography to obtain 1.55 g (27%) of the desired product. 1H NMR (300 MHz, CD2CI2) δ 8.32 (d, 1 H), 8.27 (d, 1 H), 8.19-8.09 (m, 2 H), 8.05 (s, 1 H)1 7.90-7.80 (m, 1 H), 7.75-7.65 (m 3 H); ES-MS m/z 320.2 [M+2]+, LCMS RT (min) 4.27. [149] Example 62 Preparation of ethyl Λ/-r2-(4-bromophenv0quinolin-4-vπ-beta-alaninate
[150] A melt of 2-(4-bromophenyl)-4-chloroquinoline (Example 61 , 1.19 g, 3.74 mmol) and ethyl beta-alaninate (1.30 g, 11.2 mmol) was heated (165°C) for 3 h. The mixture was cooled to rt and the residue was dissolved in a mixture of ethyl acetate and ethanol (1 :1 , 50 ml_). The solution was concentrated to dryness, and the residue was purified by silica gel flash chromatography using a gradient elution from 20% to 100% ethyl acetate in hexanes followed by 0-10% methanol in dichloromethane to obtain 680 mg (46%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.36 (d, 1 H), 8.02-7.81 (m, 6 H), 7.74-7.68 (m, 1 H), 7.12 (s, 1 H), 4.14 (q, 2 H), 3.96 (t, 2 H), 2.88 (t, 2H), 1.22 (t, 3H); ES-MS m/z 399.1 [M+Hf, LCMS RT (min) 2.42.
[151] The following compounds were prepared using the procedures of Examples 61-62 and substituting for the appropriate starting materials.
[152] Table 9
Figure imgf000057_0002
Figure imgf000058_0002
[153] Example 65
Preparation of ethyl ΛH2-(2'-ethoxybiphenyl-4-yl)quinolin-4-yll-beta-alaninate
Figure imgf000058_0001
[154] To a solution containing ethyl Λ/-[2-(4-bromophenyl)quinolin-4-yl]-beta-alaninate (Example 62, 100 mg, 0.25 mmol), [1 ,1'-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (10.2 mg, 0.013 mmol), and (2-ethoxyphenyl)boronic acid (83 mg, 0.50 mmol) in degassed toluene and dioxane (4:1 , 1.25 ml_) was added aqueous sodium carbonate solution (2 M, 0.25 mL). The reaction was heated (850C) for 16 h and then cooled to rt. The mixture was concentrated to dryness and the residue was dissolved in a mixture of methanol and acetonitrile. This solution was filtered through a C8 reverse phase extraction cartridge and the filtrated was concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water to obtain 100 mg (91%) of the desired product. 1H NMR (300 MHz1 CD3OD) δ 8.38 (d, 1 H), 8.04-7.93 (m, 4 H), 7.85-7.81 (m, 2 H), 7.74-7.69 (m, 1 H), 7.40-7.33 (m, 2 H), 7.16 (s, 1 H), 7.10-7.02 (m, 2 H), 4.19-4.05 (m, 4H), 3.98 (t, 2H), 2.89 (t, 2H), 1.35(t, 3H), 1.22 (t, 3H); ES-MS m/z441.2 [M+H]+, LCMS RT (min) 2.81.
[155] The following compounds were prepared using the procedure of Example 65, and substituting for the appropriate starting materials. 56] Table 10
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
[157] Example 79
Preparation of ΛH2-(2'-ethoxybiphenyl-4-yl)quinolin-4-vH-beta-alanine
Figure imgf000062_0001
[158] To a solution of ethyl Λ/-[2-(2'-ethoxybiphenyl-4-yl)quinolin-4-yI]-beta-alaninate (Example 65, 0.10 g, 0.23 mmol) in ethanol (1 ml_) was added lithium hydroxide monohydrate (48 mg, 1.14 mmol) and water (1 mL). The resulting mixture was stirred overnight at rt. The mixture was adjusted to pH 5 using hydrochloric acid (2 N) and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 80% acetonitrile in water to afford 75 mg (80%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.37 (d, 1 H), 8.04-7.93 (m, 4 H), 7.84-7.81 (m, 2 H), 7.73-7.67 (m, 1 H), 7.39-7.32 (m, 2 H), 7.17 (s, 1 H), 7.10-7.02 (m, 2 H), 4.08 (q, 2 H), 3.96 (t, 2 H), 2.88 (t, 2 H), 1.35 (t, 3 H); ES-MS m/z 413.4 [M+H]+, LCMS RT (min) 2.67.
[159] The following compounds were prepared using the procedure of Example 79 and substituting for the appropriate starting materials.
[160] Table 11
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0002
[161] Example 93 Preparation of 2-(4-bromophenyl)-6-fluoro-4-hvdroxyquinoline-3-carbonitrile
Figure imgf000065_0001
[162] A suspension of NaH (1.3 g, 52.4 mmol) in THF (150 ml.) was refluxed at 650C, and ethyl 4-bromobenzoate 10.0 g, 43.7 mmol) was added, followed by the slow addition of CH3CN (5.4 g, 130.9 mmol) (H2 evolution). The reaction mixture was then refluxed for 4 h, cooled to rt, and 6- fluoro-2H-3,1-benzoxazine-2,4(1 H)-dione (7.9 g, 43.7 mmol) was added. The reaction mixture was refluxed for 16 h (precipitate appears) and then cooled to rt. Water (1 L) was added, and the pH was adjusted to ~ 6 using HCI (1 N solution in water). After stirring for 30 min, the solid was collected by filtration and rinsed with water. Example 93 was obtained as a solid (10 g, 70%) after drying under mechanical vacuum at 4O0C. 1H NMR (400 MHz, DMSO-c/6) 12.95 (s, 1 H), 7.86 (m, 2H), 7.75 (m, 5H); ES-MS m/z 343.2 [M+H]+, LCMS RT (min) 2.74. [163] Example 94
Preparation of 2-(4-bromophenyl)-6-fluoro-4-chloroquinoline-3-carbonitrile
Figure imgf000066_0001
[164] A solution of 2-(4-bromophenyl)-6-fluoro-4-hydroxyquinoline-3-carbonitrile (Example 93, 12.0 g, 35.0 mmol) in POCI3 (150 ml_, 1.6 mol) was refluxed at 10O0C for 4 h. The reaction mixture was then cooled to rt and POCI3 was removed at reduced pressure. Ice water (500 mL) was added, and the mixture was stirred while slowly adding NaHCO3 until pH 7.5, causing a precipitate to form. The solid was collected by filtration and dried under mechanical vacuum at 350C to afford Example 94 as a solid (12.0 g, 95%). 1H NMR (400 MHz, DMSO-c/6) 8.30 (m, 1 H), 8.10 (m, 1 H), 8.00 (m, 1 H), 7.88 (d, 2H), 7.80 (d, 2H); ES-MS m/z 363.1 [M+H]+, LCMS RT (min) 3.94.
[165] Example 95
Preparation of fert-butyl ΛH2-(4-bromophenvπ-3-cvano-6-fluoroquinolin-4-yl1-D-alaninate
Figure imgf000066_0002
[166] To a suspension of 2-(4-bromophenyl)-6-fluoro-4-chloroquinoIine-3-carbonithle (Example 94, 12.0 g, 33.2 mmol) and ferf-butyl D-alaninate hydrochloride (9.0 g, 49.8 mmol) in DMSO (350 mL) was added Et3N (20.2 g, 199.1 mmol) at O0C. The reaction mixture was stirred at rt for 72 h. The reaction mixture was poured onto 1 L ice water, and extracted with 2 x 250 mL CH2CI2. Combined organic phases were washed with water (2 x 500 mL), then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography to provide the title as a foam (11.8 g, 76%). 1H NMR (400 MHz, DMSO-d6) 8.40 (d, 1 H), 7.95 (m, 1 H), 7.70 (m, 6H), 5.15 (m, 1 H), 1.62 (d, 3H), 1.40 (s, 9H); ES-MS m/z 471.9 [M+H]+, LCMS RT (min) 3.56. [167] Example 96
Preparation of 2-r3-cvano-2-(3'.4'dichloro-biphenvI-4-yl)-6-fluoro-quinolin-4-ylaminol- propionic acid
Figure imgf000067_0001
[168] To a 5 ml_ microwave reaction vessel with stirring bar, tert-butyl Λ/-[2-(4-bromopheny!)-3- cyano-6-fluoroquinoiin-4-yl]-D-alaninate (Example 95, 50 mg, 0.106 mmol), [1 ,1 '- bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (5 mg, 0.007 mmol), 3,4-dichloro-benzene boronic acid (40.6 mg, 0.213 mmol), K2CO3 (0.5 ml_, 2 M solution in water) and N1N- dimethylacetamide (2 mL) were added. The reaction mixture was heated at 15O0C for 12 min in a microwave reactor and then was cooled to rt. The mixture was then filtered. The filtrate was diluted with 2 mL DMSO then was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water with 0.1% TFA as modifier to obtain 4.8 mg (9.4%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.44 (d, 1 H), 8.07 (s, 1 H), 8.03-7.98 (m, 1 H), 7.92-7.83 (m, 4 H), 7.83-7.73 (m, 4 H), 5.20 (q, 1 H), 1.65 (d, 3 H); ES-MS m/z 480.06 [M+H]+, LCMS RT (min) 3.71.
[169] The above procedure can cause the partial racemization (30-40%) of the chiral center. When needed, the enantiomers could be separated using chiral HPLC. Below are described typical HPLC conditions that are useful for the separation of enantiomers:
a) Preparative chiral HPLC:
Column Chiralpak AD H 50 X 500 (10 micron)
Eluent: 10 to 25% /-propanol (0.1% TFA) in hexanes over 28 minutes at 150 mL/min
b) Chiral HPLC analytical:
Column Chiralpak AD-H 20 X 250 (10 micron)
Eluent 20 to 65% isopropanol (0.1% ethane sulfonic acid) in hexanes over
15 minutes at 1 mL/min .
Column oven: 400C [170] The following compounds were prepared using the procedure of Example 93-96 and substituting for the appropriate starting materials.
[171] Table 12
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000079_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
[172] Example 185
Preparation of methyl N-r2-(4-bromophenyl)-3-cvano-6-fluoroquinolin-4-yll-
D-alaninate
Figure imgf000086_0001
[173] To a solution 2-(4-bromophenyl)-6-chloro-4-fluoroquinoline-3-carbonitrile (Example 94, 1.0 g, 2.77 mmol) and methyl D-alaninate hydrochloride (1.16 g, 8.30 mmol) in DMF (20 mL) was added TEA (2.31 mL, 16.59 mmol), and the solution mixture was stirred at rt for 60 h. The reaction was concentrated under vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed successively with NH4Ci (10% aqueous solution), K2CO3 (10% aqueous solution), and water and the organic solution was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 10% to 100% ethyl acetate in hexane) to give 857 mg of desired product. 1H NMR (400 MHz, acetone-cfe) δ 8.16 (dd, 1 H), 8.01 (dd, 1 H), 7.80 (d, 2H), 7.71 (d, 2H), 7.69-7.66 (m, 1 H), 7.069 (d, 1 H), 5.42-5.39 (m, 1 H), 3.76 (s, 3H), 1.76 (d, 3H); ES-MS m/z [M+H]+ 428.1 , 430.1 , LCMS RT (min) 3.11.
[174] Example 186
Preparation of N-r2-(4-bromophenvD-3-cyano-6-fluoroquinolin-4-vπ-D-alanine
Figure imgf000086_0002
[175] To a solution of methyl N-[2-(4-bromophenyl)-3-cyano-6-fluoroquinolin-4-yl]- D-alaninate (Example 185, 500 mg, 1.17 mmol) in water (10 mL), methanol (5 mL), and THF (10 mL) was added LiOH (84 mg, 3.5 mmol), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in water. The pH of aqueous mxiture was adjusted to ~ 5 using HCI (5N aqueous solution) and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to give 460 mg of the desired product. 1H NMR (400 MHz, acetone-c/6) 58.15 (dd, 1 H), 8.01 (dd, 1 H), 7.08 (d, 2H), 7.72 (d, 2H), 7.69-7.67 (m, 1 H),5.43 (q, 1 H), 1.79 (d, 3H); ES-MS m/z [M+H]+ 414.1 , 416.1 , LCMS RT (min) 2.71.
[176] Example 187
Preparation of N-{3-cvano-6-fluoro-2-r4-(2-methoxypyridin-3-yl)phenyriquinolin-
4-vlVD-alanine
Figure imgf000087_0001
[177] To a solution of N-[2-(4-bromophenyl)-3-cyano-6-fluoroquinolin-4-yl]-D-alanine (Example 186, 60 mg, 0.14 mmol), tetrakis( triphenylphosphine) palladium(O) (8.4 mg, 0.01 mmol), and (2- methoxypyridin-3-yl)boronic acid (44.3 mg, 0.29 mmol) in degassed DMF (1 mL) was added sodium carbonate (2 M aqueous solution, 0.22 mL, 0.44 mmol). The reaction was heated by a microwave reactor (1500C ) for 15 min and then cooled to rt. The mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (eluent: 10 to 100% acetonitrile in water [0.1% TFA]). The fraction containing desired product was concentrated under reduced pressure and the pH of the resulting aqueous solution was adjusted to ~ 5. The aqueous mixture was then extracted with ethyl acetate and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 15 mg of the desired product. 1H NMR (400 MHz, DMSO-c/6) δ 8.42 (dd, 1 H), 8.20 (dd, 1 H), 7.95 (dd, 1 H ), 7.83 (dd, 1 H), 7.81 (d, 2H), 7.767.74 (m, 1 H), 7.68 (d, 2H), 7.12 (dd, 1 H), 5.27- 5.23 (m, 1 H), 1.65 (d, 3H); ES-MS m/z [M+H]+ 443.2, LCMS RT (min) 2.63.
[178] The following compounds were prepared using the procedure of Example 185-187 and substituting for the appropriate starting materials.
[179] Table 13
Figure imgf000088_0001
[180] Example 193
Preparation of ethyl 4-{r2-(4-bromophenylV3-cvano-6-fluoroquinolin- 4-vπaminoTbutanoate
Figure imgf000089_0001
[181] To a solution 2-(4-bromophenyI)-6-chloro-4-fluoroquinoIine-3-carbonitrile (Example 94, 2.0 g, 5.53 mmol) and ethyl 4-aminobutanoate hydrochloride (2.78 g, 16.6 mmol) in DMF (100 ml_) was added TEA (4.63 ml_, 33.2 mmol) and the solution was stirred at rt for 16 h. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed successively with K2CO3 (10% aqueous solution), NH4CI (10% aqueous solution), and water, and the organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and dried under vacuum to give 1.2 g desired product. Additional amounts of Example 193 were recovered from the filtrate, which was concentrated under reduced pressure. The residue was dissolved recrystallized from hexanes/ethyl acetate (50 ml_, 1 :1 mixture). The solid was collected by filtration and then dried under mechanical vacuum to give 900 mg of desired product. 1H NMR (400 MHz, acetone-de) δ 8.08 (dd, 1 H), 7.97 (dd, 1 H), 7.79 (d, 2H), 7.71 (d, 2H), 7.76-7.62 (m, 1 H), 7.37 (t, 1 H), 4.11-4.01 (m,4H ), 2.56 (t, 2H), 2.22-2.15 (m, 2H), 1.19 (t, 2H).
[182] Example 194
Preparation of 4-({3-cvano-6-fluoro-244-(4-methoxypyridin-3-vQphenyriquinolin-
4-vHamino)butanoic acid
Figure imgf000089_0002
[183] To a solution of ethyl 4-{[2-(4-bromophenyl)-3-cyano-6-fluoroquinolin-4-yl]amino}butanoate (Example 193, 80 mg, 0.18 mmol), tetrakis(triphenylphosphine) palladium(O) (10.1 mg, 0.01 mmol) and (4-methoxypyridin-3-yl)boronic acid (107.2 mg, 0.70 mmol) in degassed DMF (4.5 ml.) was added sodium carbonate (2 M aqueous solution, 0.35 mL, 0.70 mmol). The reaction was heated using a microwave reactor (15O0C) for 15 min and then cooled to rt. The reaction mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (eluent: 10 to 100% acetonitrile in water [0.1% TFA]). The fractions containing desired product were concentrated under reduced pressure, and the pH of the resulting aqueous solution was adjusted to ~ 5. The aqueous mixture was then washed with ethyl acetate, and the solid from resulting aqueous suspension was collected by filtration. The solid was washed with water and then dried under mechanical vacuum at 4O0C to give 23 mg of the desired product. 1H NMR (400 MHz, DMSO-Cf6) δ 12.16 (s, 1 H), 8.52 (d, 1 H), 8.49 (s, 1 H), 8.29 (dd, 1 H), 8.02 (t, 1 H), 7.96 (dd, 1 H), 7.81 (d, 2H), 7.70-7.69 (m, 1 H), 7.65 (d, 2H ), 7.27 (d, 1 H), 3.93 (s, 3H), 3.87 (q, 2H), 2.38 (t, 2H), 2.03-1.99 (m, 2H); ES-MS m/z [M+H]+ 457.3, LCMS RT (min) 1.89.
[184] The following compounds were prepared using the procedure of Example 193-194 and substituting for the appropriate starting materials.
Figure imgf000090_0001
[186] Example 199 Preparation of 2-(4-bromophenyl)-7-methoxyquinolin-4-ol
Figure imgf000091_0001
[187] A mixture of ethyl 4-(bromobenzoyl)acetate (2.50 g, 9.22 mmol), m-anisidine (1.14 g, 9.22 mmol), and 4-toluenesulfonic acid monohydrate (88 mg, 0.46 mmol) in toluene (6 ml_) was heated (110°C) for 4 h. The mixture was cooled to rt and was concentrated to dryness under reduced pressure. The residue was dissolved in diphenyl ether (15 mL) and was heated (225°C) for 2 h. The mixture was cooled to rt and the solid was collected by filtration and rinsed with hexanes. The solid was triturated using dichloromethane and was dried under mechanical vacuum to afford Example 199 (1.1 g) as a solid, which was used in the next step without further purification. ES-MS m/z 330.3 [M+H]+, LCMS RT (min) 2.87.
[188] Example 200 Preparation of 2-(4-bromophenvD-4-chloro-7-methoxyquinoline
Figure imgf000091_0002
[189] A mixture of 2-(4-bromophenyl)-7-methoxyquino!in-4-ol (Example 199, 500 mg, 1.51 mmol) and phosphorous oxychioride (2.8 mL, 30.3 mmol) was heated (1050C) for 16 h. The mixture was cooled to rt and allowed to stand for 60 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in dichloromethane (25 mL). The ice water was added and the pH was adjusted to ~7 using potassium carbonate. The mixture was allowed to warm to rt and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Example 200 (470 mg) as a solid that was used in the next step without further purification. ES-MS m/z 348.3 [M+H]+, LCMS RT (min) 4.46. [190] Example 201
Preparation of ethyl 1-r2-(4-bromophenvπ-7-methoχyquinolin-4-yllpiperidine-4-carboxylate
Figure imgf000092_0001
[191] A mixture of 2-(4-bromophenyl)-4-chloro-7-methoxyquinoline (Example 200, 470 mg, 1.35 mmol), ethyl isonipecotate (1.06 g, 6.74 mmol), and hydrochloric acid (1 N, 0.13 ml_, 0.13 mmol) in 1-butanol (5 mL) was heated (1200C) for 16 h. The crude reaction mixture was concentrated to dryness and the residue was purified by preparative HPLC using a gradient elution from 25-75% acetonitrile in water to afford 107 mg (17%) of the desired product. 1H NMR (300 MHz, DMSO-Cf6) δ 8.16 (d, 2 H), 7.85 (d, 1 H), 7.69 (d, 2 H), 7.34 (d, 1 H), 7.32 (s, 1 H), 7.14 (dd, 1 H), 4.11 (q, 2 H), 3.90 (s, 3 H), 3.56 (d, 2 H), 2.97 (t, 2 H), 2.55-2.65 (m, 1 H), 1.99-2.09 (m, 2 H), 1.84-1.97 (m, 2 H), 1.22 (t, 3 H); ES-MS m/z 469.3 [MH-H]+, HPLC RT (min) 3.11.
[192] Example 202
Preparation of ethyl 1-r2-(2'-ethoxybiphenyl-4-yl)-7-methoxyquinolin-4-vnpiperidine-4- carboxylate
Figure imgf000092_0002
[193] To a stirred solution of ethyl 1-[2-(4-bromophenyI)-7-methoxyquinoiin-4-yl]piperidine-4- carboxylate (Example 201 , 107 mg, 0.23 mmol), 2-ethoxybenzeneboronic acid (114 mg, 0.68 mmol), and sodium carbonate (72 mg, 0.68 mmol) in DME (1.8 mL) and water (0.8 mL) was added [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (19 mg, 0.02 mmol). The reaction was heated (80°C) for 16 h and then cooled to it The mixture was filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative HPLC using an elution gradient from 25-75% acetonitriie in water to afford 37 mg (32%) of the desired product. 1H NMR (300 MHz, DMSOd6) δ 8.24 (d, 2 H), 7.86 (d, 1 H), 7.65 (d, 2 H), 7.29-7.40 (m, 2H), 7.28-7.41 (m, 2H), 7.08-7.16 (m, 2 H), 7.03 (t, 1 H), 4.03-4.16 (m, 4 H), 3.91 (s, 3 H), 2.56-2.62 (m, 1 H), 2.40-2.46 (m, 4 H), 2.01-2.07 (m, 2 H), 1.86-2.00 (m, 2 H), 1.30 (t, 3 H), 1.23 (t, 3 H); ES-MS m/z 511.4 [M+H]+, HPLC RT (min) 3.45.
[194] Example 203
Preparation of 1-r2-(2'-ethoxybiphenyl-4-yl)-7-methoxyquinolin-4-vπpiperidine-4-carboxylic acid
Figure imgf000093_0001
[195] A mixture of ethyl 1-[2-(2'-ethoxybiphenyl-4-yl)-7-methoxyquinolin-4-yl]piperidine-4- carboxylate (Example 202, 37 mg, 0.072 mmol) and aqueous sodium hydroxide solution (1 N, 0.72 ml.) in methanol (0.5 mL) and THF (0.1 mL) was heated (400C) in a sealed tube for 4 h. The mixture was cooled to rt and was concentrated to dryness. The residue was dissolved in water (2 mL), and the solution was adjusted to pH 7 using and aqueous hydrogen chloride solution (1 N). The resulting solid was collected by filtration and was dried to afford 30 mg (84%) of the desired product. 1H NMR (300 MHz, DMSO-c/6) δ 8.09 (d, 2 H), 7.88 (d, 1 H), 7.66 (d, 2 H), 7.35- 7.51 (m, 2 H), 7.24-7.35 (m, 2 H), 7.15 (d, 1 H), 7.06 (d, 1 H), 6.98 (dd, 1 H), 4.00 (q, 2 H), 3.87 (s, 3 H), 2.50-2.61 (m, 1 H), 2.40-2.46 (m, 4 H), 1.99 (d, 2 H), 1.76-1.89 (m, 2 H)1 1.24 (t, 3 H); ES-MS m/z 483.5 [M+H]+, HPLC RT (min) 2.80.
[196] Example 204
Preparation of butyl 1-r2-(2'-formylbiphenyl-4-yl)-7-methoxyquinolin-4- vπpiperidine-4-carboxylate
Figure imgf000093_0002
[197] To a stirred solution of butyl 1 -[2-(4-bromophenyl)-7-methoxyquinolin-4-yl]piperidine-4- carboxylate (prepared similarly to the method described for Example 201 , 188 mg, 0.38 mmol), 2- formyphenylboronic acid (170 mg, 1.13 mmol), and sodium carbonate (120 mg, 1.13 mmol) in DME (2.8 ml_) and water (0.6 ml_) was added [1 ,1'-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (31 mg, 0.04 mmol). The reaction was heated (800C) for 16 h and then cooled to rt. The mixture was filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was washed with water (50 mL) and brine (50 ml_), dried over sodium sulfate, and concentrated to dryness to afford 103 mg (52%) of the desired product, which was used in the next step without purification. ES-MS m/z 523.4 [M+H]+, HPLC RT (min) 3.44.
[198] Example 205
Preparation of butyl 1-r2-(2'-morpholin-4-ylmethyllbiphenyl-4-v0-7-methoxyquinolin-4- yllpiperidine-4-carboxylate
Figure imgf000094_0001
[199] To a stirred solution of butyl 1-[2-(2'-formylbiphenyl-4-yl)-7-methoxyquinolin-4-yl]piperidine- 4-carboxylate (Example 204, 103 mg, 0.20 mmol) and morpholine (17 mg, 0.20 mmol) in CH2CI2 (2.5 mL) was added sodium triacetoxyborohydride (125 mg, 0.59 mmol). The reaction was stirred at rt for 4 h. The mixture was partitioned between H2O (25 mL) and CH2CI2 (25 mL). The layers were separated and the organic was dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative HPLC using an elution gradient from 25-75% acetonitrile in water to afford 100 mg (85%) of the desired product. ES-MS m/z 594.6 [M+H]+, HPLC RT (min) 2.54.
[200] Example 206
Preparation of H2-(2'-morpholin-4-ylmethyllbiphenyl-4-yl)-7-methoxyquinolin-4- yllpiperidine-4-carboxylic acid
Figure imgf000095_0001
[201] A mixture of butyl 1-[2-(2'-morpholin-4-ylmethyllbiphenyI-4-yl)-7-methoxyquinolin-4- yl]piperidine-4-carboxyIate (Example 205, 100 mg, 0.17 mmol) and aqueous sodium hydroxide solution (1 N, 0.17 mL) in methanol (0.5 mL) and THF (0.1 mL) was heated (400C) in a sealed tube for 3 h. The mixture was cooled to rt and was concentrated to dryness. The residue was dissolved in water (2 mL) and the solution was adjusted to pH 7 using aqueous hydrogen chloride solution (1 N). The resulting solid was collected by filtration and was purified using a preparative TLC (eluent: 95:5 CH2CI2/Me0H) to afford 31 mg (35%) of the desired product. 1H NMR (300 MHz, DMSO-dg) δ 12.28 (s, 1 H), 8.26 (d, J = 8.3, 2H), 7.86 (d, J = 9.3, 1 H), 7.56 (d, J= 8.3, 2 H), 7.53-7.47 (m, 1 H), 7.40 (s, 1H), 7.38-7.32 (m, 4 H), 7.32-7.28 (m, 1 H), 7.14 (dd, J= 2.6, 9.3, 1 H), 3.92 (s, 3 H), 3.61-3.49 (m, 5H), 3.41 (s, 2H), 2.98 (t, J= 10.3, 2 H), 2.29 (m, 4 H), 2.10-2.00 (m, 2 H), 1.99-1.85 (m, 2 H); ES-MS m/z 538.4 [M+H]+, HPLC RT (min) 2.49.
[202] Example 207
Preparation of ethyl ΛH2-(4-bromophenyl)-6-fluoroquinolin-4-vπ-beta-alaninate
Figure imgf000095_0002
[203] A melt of 2-(4-bromophenyl)-4-chloro-6-fluoroquinoline [prepared using methods similar to the one used to synthesized Example 61] (400 mg, 1.19 mmol) and ethy! beta-alaninate (975 mg, 8.32 mmol) was heated (165°C) for 4 h. The mixture was cooled to rt, and the residue was partitioned between CH2CI2 (100 mL) and H2O (100 mL). The layers were separated and the organic was further washed with H2O (2 x 100 mL) and brine (50 mL). The organic was dried over sodium sulfate, and concentrated to dryness to obtain 350 mg (71%) of the desired product as a pale yellow solid, which contained trace impurities. 1H NMR (300 MHz, DMSOd6) δ 8.15 (d, J = 9.3, 2 H), 8.01 (dd, J= 3.0, 10.9, 1 H), 7.88 (dd, J = 6.0, 9.3, 1 H), 7.67 (d, J= 8.4, 2 H), 7.49-7.55 (m, 1 H), 7.16 (t, J= 5.3, 1 H), 7.01 (s, 1 H), 4.07 (q, J = 6.8, 2H), 3.66 (q, J = 6.8, 2H), 2.75 (t, J = 6.8, 2H), 1.16 (t, J= 6.8, 3H); ES-MS m/z 417.1 [M]+, LCMS RT (min) 2.51.
[204] Example 208
Preparation of ethyl Λ/-r2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yll-beta-alaninate
Figure imgf000096_0001
[205] To a solution containing ethyl Λ/-[2-(4-bromophenyl)-6-fluoroquinolin-4-yl]-beta-alaninate (Example 207, 100 mg, 0.24 mmol), [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (19.6 mg, 0.024 mmol), and (2-ethoxyphenyl)boronic acid (119 mg, 0.72 mmol) in degassed DME (1.50 ml_) was added aqueous sodium carbonate solution (2 M, 0.36 ml_). The reaction was heated (70°C) for 17 h and then cooled to rt. The mixture was concentrated to dryness and the residue was dissolved in a mixture of DMSO and MeOH. The crude mixture was purified by HPLC using a gradient elution from 10% to 90% acetonitrile in H2O to obtain 44 mg (40%) of the desired product. 1H NMR (300 MHz, DMSO-Cf6) δ 8.22 (d, J = 8.1 , 2 H)1 8.02 (dd, J = 2.3, 10.7, 1 H), 7.90 (dd, J = 9.1 , 5.7, 1 H), 7.63 (d, J = 8.0, 2 H), 7.48-7.55 (m, 1 H), 7.28-7.38 (m, 2 H), 7.17-7.07 (m, 2 H), 7.07-6.98 (m, 2H), 4.12-4.01 (m, 4H), 3.68 (q, J = 6.1 , 2H), 2.77 (t, J= 6.1 , 2H), 1.30 (t, J = 6.1 , 3H), 1.17 (t, J= 6.1 , 3H).
[206] Example 209
Preparation of ΛH2-(2'-ethoxybiphenyl-4-vO-6-fluoroquinolin-4-vπ-beta-alanine
Figure imgf000096_0002
[207] A mixture of ethyl Λ/-[2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl]-beta-alaninate (Example 208, 43 mg, 0.094 mmol) and aqueous sodium hydroxide solution (1 N, 0.19 mL) in methanol (2 mL) was heated (500C) for 1 h. The mixture was cooled to rt and was concentrated to dryness. The residue was dissolved in water (2 mL) and the solution was adjusted to pH 6 using an aqueous solution of hydrogen chloride (1 N). The resulting solid was collected by filtration and was dried to afford 30 mg (74%) of the desired product. 1H NMR (300 MHz, DMSO-Cf6) δ 12.30 (s, 1 H), 8.17 (d, J = 8.5, 2 H), 8.14-8.05 (m, 1 H), 7.97-7.89 (m, 1 H), 7.64 (d, J = 8.5, 2 H), 7.62-7.51 (m, 1 H), 7.36-7.26 (m, 2 H), 7.12-6.97 (m, 3 H), 4.05 (q, J= 6.7, 2 H), 3.70-3.62 (m, 2 H), 2.70 (t, J= 6.8, 2 H), 1.28 (t, J= 6.8, 3 H); ES-MS m/z 431.2 [M+H]+, HPLC RT (min) 2.68.
[208] The following compounds were prepared using the procedure of Example 207-209 and substituting for the appropriate starting materials.
[209] Table 15
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
*Note: Examples 221 and 222 were prepared using the procedures of Example 208 and 209, respectively. The starting materials, ethyl N-[2-(4-bromo-2-methylphenyl)-3-cyanoquinolin-4-yl]-beta- alaninate, was prepared using the methods described for the preparation of Examples 93-95.
**Note: The starting material for the synthesis of Examples 223 and 224, ethyl 4-{[2-(4-bromophenyl)-6- fluoro-3-(methylsulfonyl)quinolin-4-yl]amino}butanoate, was prepared following the procedures used for the preparation of Examples 93 [substituting dimethyl sulfone for acetonitrile] to Example 95.
[210] Example 225
Preparation of N-r2-(4-bromophenyl)quinazolin-4-yll-beta-aIanine
Figure imgf000101_0001
[211] A mixture of ethyl Λ/-[2-(4-bromophenyl)quinolin-4-yl]-beta-alaninate (Example 62, 2.70 g, 6.76 mmol) and aqueous sodium hydroxide solution (1 N, 10.1 mL) in methanol (50 mL) and THF (10 mL) was heated (500C) for 16 h. The mixture was cooled to rt and was concentrated to dryness. The residue was dissolved in water (50 mL) and the solution was adjusted to pH 7 using aqueous hydrogen chloride solution (1 N). The resulting solid was collected by filtration. The solid was triturated with hot EtOH and was allowed to cool to rt. The solid was collected by filtration and was dried to afford 2.25 g (90%) of the desired product with trace impurities. 1H NMR (300 MHz, DMSO-Cf6) δ 8.18-8.12 (m, 3 H), 7.85-7.73 (m, 2 H), 7.69-7.63 (m, 2 H), 7.63-7.57 (m, 1 H), 7.41- 7.35 (m, 1 H), 6.98 (s, 1 H), 3.59 (t, J = 6.9, 2 H), 2.61 (t, J= 6.9, 2 H); ES-MS m/z 371.4 [M]+, HPLC RT (min) 2.71.
[212] Example 226
Preparation of ΛH2-(2'-formylbiphenyl-4-yl)quinolin-4-yll-beta-alanine
Figure imgf000101_0002
[213] To a solution containing N-[2-(4-bromophenyl)quinolin-4-yl]-beta-alanine (Example 225, 250 mg, 0.67 mmol), [1 ,1'-bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (55 mg, 0.07 mmol), and (2-formylphenyl)boronic acid (302 mg, 2.02 mmol) in degassed DME (5.0 mL) was added aqueous sodium carbonate solution (2 M, 1.01 mL). The reaction was heated (700C) for 6 h and then cooled to rt. The mixture was filtered through a pad of Celite® using ethyl acetate to rinse, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC using an elution gradient from 25-75% acetonitrile in water followed by trituration with ethyl acetate to afford 82 mg (31%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO--/e) δ 9.95 (s, 1 H), 8.33 (d, J = 8.2, 2 H), 8.19 (d, J = 8.2, 1 H), 7.94 (d, J = 8.2, 1 H), 7.84 (d, J = 8.2,
1 H), 7.78 (t, J = 8.2, 1 H), 7.66-7.54 (m, 5H), 7.41 (t, J = 7.2, 1 H), 7.31-7.23 (m, 1 H), 7.07 (s, 1 H),3.74-3.61 (m, 2 H), 2.72 (t, J = 7.5, 2 H); ES-MS m/z 397.3 [M+H]+, HPLC RT (min) 2.30.
[214] The following compounds were prepared using the procedures of Examples 225-226 and substituting the appropriate starting materials.
[215] Table 16
Figure imgf000102_0002
[216] Example 229
Preparation of Λ/-r2-(2'morpholin-4-ylmethylbiphenyl-4-yl)quinolin-4-yll-beta-alanine
Figure imgf000102_0001
[217] To a stirred solution of Λ/-[2-(2'-formylbiphenyl-4-yl)quinoIin-4-yl]-beta-alanine (Example 226, 66 mg, 0.17 mmol) and morpholine (30 mg, 0.35 mmol) in CH2CI2 (3 mL) was added sodium triacetoxyborohydride (212 mg, 1.0 mmol). The reaction was stirred at rt for 16 h. The mixture was partitioned between H2O (25 mL) and CH2CI2 (25 mL). The layers were separated and the organic was washed with H2O (15 mL), and brine (30 mL), dried over sodium sulfate, and concentrated to dryness. The solid was triturated with ethyl acetate and dried to afford 50 mg (62%) of the desired product. 1H NMR (300 MHz1 DMSO-Cf6) δ 8.22 (d, J= 8.4, 2 H), 8.03 (d, J = 7.5, 2 H), 7.83 (d, J = 7.5, 1 H), 7.60 (t, J= 8.4, 1H), 7.56-7.48 (m, 4H), 7.42-7.27 (m, 5 H), 6.99 (s, 1 H), 3.57-3.47 (m, 6 H), 2.38 (t, J= 6.2, 2 H), 2.34-2.25 (m, 4H), ; ES-MS m/z 468.3 [M+H]+, HPLC RT (min) 1.88.
[218] Example 230
Preparation of 3-(4-bromophenyl)-3-oxopropanenitrile
Figure imgf000103_0001
[219] A suspension of NaH (1.3 g, 52.4 mmol) in THF (50 ml.) was refluxed at 750C, and ethyl 4- bromobenzoate (10.0 g, 42.8 mmol) was added, followed by the slow addition of CH3CN (5.3 g, 128 mmol) (H2 evolution). The reaction mixture was then refluxed for 16 h and cooled to rt. The excess base was quenched by adding water (10 mL), after which the organic solvent was removed under reduced pressure, and the resulting aqueous mixture was washed with EtOAc. Acidification of the aqueous solution using acetic acid caused the formation of a precipitate, which was collected by filtration. After drying under mechanical vacuum, Example 230 was obtained as a solid (9.4 g, 98%). ES-MS: did not ionize, LCMS RT (min) 2.65.
[220] Example 231
Preparation of 2-(4-bromophenyl)-6-fluoro-4-hvdroxyquinoline-3-carbonitrile
Figure imgf000103_0002
[221] To a solution of 3-(4-bromophenyl)-3-oxopropanenitrile (Example 230, 3.37 g,
15.04 mmol) in THF (100 mL) was added a 60% mineral oil suspension of sodium hydride (0.72 g,
18.05 mmol) in an ice-water bath. After the gaseous evolution had ceased, 6-fluoro-2H-3,1- benzoxazine-2,4(1 H)-dione was added and the resultant mixture was refluxed under nitrogen for 2 h. The reaction mixture was then cooled (O0C) and quenched with water (5 mL). THF was evaporated under reduced pressure and a precipitate formed in the remaining aqueous layer. The solid was filtered, washed with water (5 mL) and dried to afford 4.34 g (84%) of product. 1H NMR (400 MHz, DMSO-Cf6) δ 12.90 (bs, 1 H), 7.88-7.83 (m, 2 H), 7.79-7.73 (m, 4 H), 7.70-7.65 (m, 1 H); ES-MS m/z 343.3 [MH-H]+, LCMS RT (min) 2.79. [222] Example 232
Preparation of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-4-hvdroxyαuinoline-3- carbonitrile
Figure imgf000104_0001
[223] A mixture of 2-(4-bromophenyI)-6-fluoro-4-hydroxyquinoline-3-carbonitrile (Example 231 , 4.32 g, 12.59 mmol), 2-ethoxyphenylboronic acid (2.51 g, 15.11 mmol), PdCI2(dppf)«CH2Cl2 (0.38 g, 0.63 mmol), and sodium carbonate (4.00 g, 37.77 mmol) in water (20 ml_) and dioxane (60 mL) was heated (110 0C) under nitrogen for 48 h. After cooling to rt, the solvents were evaporated under reduced pressure and water (50 mL) was added. The pH of the aqueous mixture was adjusted to 7 using HCI (2N aqueous solution). The resulting solid was collected by vacuum filtration and dried to afford 4.72 g (97%) of the product. 1H NMR (400 MHz, DMSOd6) δ 12.96 (bs, 1 H), 7.81-7.70 (m, 6 H), 7.58-7.57 (m, 1 H), 7.37-7.33 (m, 2 H), 7.14-7.12 (m, 1 H), 7.06-7.032 (m, 1 H), 4.09 (q, 2 H), 1.31 (t, 3 H); ES-MS m/z 385.2 [M+H]+, LCMS RT (min) 3.33.
[224] Example 233
Preparation of 4-chloro-2-(2'-ethoxybiphenyl-4-vD-6-fluoroquinoline-3- carbonitrile
Figure imgf000104_0002
[225] A mixture of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-4-hydroxyquinoline-3-carbonitrile (Example 232, 4.71 g, 12.25 mmol) and POCI3 (30 mL, 322 mmol) was refluxed for 16 h. After cooling to rt, the POCI3 was evaporated under reduced pressure. The residue was mixed with water (100 mL,) and then the resulting precipitate was collected and washed with a small amount of ethyl acetate (20 mL) to give 3.27 g (66%) of the product. 1H NMR (400 MHz, CDCI3) δ 8.15- 8.11 (m, 1 H)1 7.93-7.90 (m, 2 H), 7.84-7.82 (m, 1 H), 7.68-7.66 (m, 2 H), 7.62-7.57 (m, 1 H), 7.32- 7.29 (m, 1 H), 7.27-7.22 (m, 1 H), 6.98-6.94, (m, 1 H), 6.92-6.90 (m, 1 H), 4.00 (q, 2 H), 1.31 (t, 3
H); ES-MS m/z 403.1 [M+H]+, LCMS RT (min) 4.55. [226] Example 234
Preparation of N-r3-cvano-2-f2'-ethoxybiphenyl-4-vπ-6-fluoroquinolin-4-vnqlycine
Figure imgf000105_0001
[227] A mixture of 4-chloro-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinoline-3-carbonitrile (Example 233, 50.0 mg, 0.12 mmol), 2-aminoacetic acid (glycine, 18.6 mg, 0.26 mmol), and triethylamine (0.1 ml_, 0.75 mmol) in DMF (1.4 mL) was heated (100°C) under nitrogen for 16 h, and then cooled to it The crude mixture was purified by preparative HPLC using a gradient of 20 - 80% acetonitrile in water over 8 min to yield 11.2 mg (20%) of the product. 1H NMR (400 MHz, DMSO- d6) δ 13.07 (bs, 1 H), 8.48 (bs, 1 H), 8.24-8.21 (m, 1 H), 7.99-7.95 (m, 1 H), 7.79-7.75 (m, 3 H), 7.67-7.65 (m, 2 H), 7.38-7.32 (m, 2 H), 7.12-7.11 (m, 1 H), 7.06-7.02 (m, 1 H), 4.61 (d, 2 H), 4.08 (q, 2 H), 1.30 (t, 3 H); ES-MS m/z 442.2 [M+H]+, LCMS RT (min) 2.76.
[228] The following compounds were prepared using the procedures of Example 230-234 and substituting the appropriate starting materials.
[229] Table 17
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
[230] Example 250
Preparation of ethyl N-[3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl]-beta- alaninate
Figure imgf000109_0001
[231] To a solution of 4-chloro-2-(2'-ethoxybiphenyl-4-yl)-6-fIuoroquinoline-3-carbonitrile (Example 233, 100 mg, 0.25 mmol) and beta alanine ethyl ester chloride (76.3 mg, 0.50 mmol) in DMF (5 ml_) was added triethylamine (0.21 mL, 1.50 mmol). The reaction was stirred at rt for 30 min and then the reaction was diluted with water (50 mL). The product was extracted with ethyl acetate (3 x 15 mL) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 25% ethyl acetate/hexanes to afford 119 mg (99%) of desired product. 1H NMR (300 MHz DMSO- d6) δ 8.23 (dd, 1 H), 7.92 (dd, 1 H), 7.87 (br s, 1 H), 7.82-7.62 (m, 5 H), 7.39-7.30 (m, 2 H), 7.13-7.08 (m, 1 H), 7.03 (ddd, 1 H), 4.12-4.00 (m, 6 H), 2.86 (t, 2 H), 1.30 (t, 3 H), 1.12 (t, 3 H); ES-MS m/z 484.2 [M+H]+, LCMS RT (min) 3.11.
[232] Example 251
Preparation of N-r3-cvano-2-f2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yll-beta-alanine
Figure imgf000110_0001
[233] To a solution of ethyl N-[3-cyano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl]-beta- alaninate (Example 250, 90 mg, 0.19 mmol) in THF (6 ml_) was added a solution of lithium hydroxide (22 mg, 0.93 mmol) in water (2 mL). The reaction was stirred at rt for 1 h and then diluted with water (15 mL). The product was extracted with ethyl acetate (3 x 10 mL) and the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 25% ethyl acetate/hexanes to afford 66 mg (79%) of desired product. 1H NMR (300 MHz, DMSO- d6) δ 8.60 (br s, 1 H), 8.17 (dd, 1 H), 7.89 (dd, 1 H), 7.80-7.74 (m, 2 H), 7.70-7.60 (m, 3 H)1 7.39-7.30 (m, 2 H), 7.11 (d, 1 H), 7.03 (ddd, 1 H), 4.11-4.00 (m, 4 H), 2.64 (t, 2 H), 1.30 (t, 3 H); ES-MS m/z 456.3 [MH-H]+, LCMS RT (min) 2.77.
[234] The following compounds were prepared using the procedures of Example 250-251 and substituting the appropriate starting materials.
[235] Table 18
Figure imgf000111_0002
[236] Example 254
Preparation of 1 -f r3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-f luoroquinolin-4- Vl]amino}cvclopentanecarboxvlic acid
Figure imgf000111_0001
[237] To a solution of 4-chloro-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinoline-3-carbonitrile (Example 233, 160 mg, 0.397 mmol) in dimethylacetamide (4 ml_) was added 1 -amino cyclopentanecarboxylic acid (154 mg, 1.2 mmol) and triethylamine (240 mg, 2.4 mmol). The reaction was stirred for 20 min at 1500C, and thereafter subjected to preparative HPLC purification using a gradient elution from 10% to 100% acetonitrile in water (0.1% TFA) to obtain 38 mg (19%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.35 (dd, 1 H), 7.99 (m, 1 H), 7.85-7.76 (m,
5 H), 7.42-7.32 (m, 2 H), 7.18-7.02 (m, 2 H), 4.08 (q, 2 H), 2.77- 2.45 (m, 4 H), 2.08 - 1.92 (m, 4 H), 1.35 (t, 3 H); ES-MS m/z 496.3 [MH-H]+, LCMS RT (min) 2.97.
[238] The following compounds were prepared using the procedures of Example 254 and substituting the appropriate starting materials.
[239] Table 19
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0002
[240] Example 265
Preparation of Λ/-r6-chloro-3-cvano-2-(2'-ethoxybiphenyl-4-yl)quinolin-4-yl1-D-alanine
Figure imgf000114_0001
[241] To a solution of 4,6-dichloro-2-(2'-ethoxybiphenyl-4-yl)quinoline-3-carbonitrile (100 mg, 0.238 mmol) [prepared using a similar method used to prepare Example 233 but starting from 5- chloroisatin] dissolved in DMSO (5 ml_) was added D-alanine (64 mg, 0.715 mmol) and triethylamine (0.2 mL, 1.43 mmol). The reaction mixture was stirred at rt for 24 h and then directly subjected to preparative HPLC purification. The desired fractions were combined, evaporated, free-based with aqueous sodium bicarbonate, and extracted with methylene chloride. Removal of the solvents under reduced pressure yielded 13 mg of Λ/-[6-chloro-3-cyano-2-(2'-ethoxybiphenyl-4- yl)quinolin-4-yl]-D-alanine. 1H NMR (400 MHz, acetone-c/6) δ 8.60 (s, 1 H), 8.12 (d, 1H), 7.96 (d, 2H), 7.90 (d, 1H), 7.75 (d, 2H), 7.42-7.35 (m, 2 H), 7.16-7.06 (m, 2 H), 5.41-5.66 (m, 1 H), 4.12 (q, 2H), 1.83 (d, 3H), 1.39 (t, 3H); ES-MS m/z 472.2 [M+H]+, LCMS RT (min) 3.21.
[242] The following compounds were prepared using the procedures of Example 265 and substituting the appropriate starting material. [243] Table 20
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
[244] Example 283 Preparation of 2,5-dioxocyclopentyl 2-amino-4.5-difluorobenzoate
Figure imgf000119_0001
[245] To a solution of 2-amino-4,5-difluorobenzoic acid (2.89 mmol, 500 mg) and N- hydroxysuccinimide (5.78 mmol, 665 mg) in DMF (100 ml_) was added EDCI (4.33 mmol, 830 mg), and the mixture was stirred for 18 h at rt. The mixture was filtered, and the filtrate was diluted with water (200 mL) and extracted with ethyl acetate (150 ml_). The combined organic phase was dried over Na2SO4. Evaporation of the solvent yielded the product, a sticky brown solid. This was triturated with ethyl acetate to give a light-brown solid, 2,5-dioxocyclopentyl 2-amino-4,5- difluorobenzoate. 1H NMR (400 MHz, acetone-d6): δ 2.97 (s, 4H), 6.71 (br s, 2H), 6.81- 6.84 (m, 1 H), 7.75- 7.80 (m, 1 H).
[246] Example 284
Preparation of N-r3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6,7-difluoroquinolin-4-yll-D-alanine
Figure imgf000119_0002
[247] To a suspension of NaH (48 mg, 1.2 mmol, 60% dispersion in mineral oil) in THF (25 mL) was added a solution of 3-(2'-ethoxybiphenyl-4-yl)-3-oxopropanenitrile (prepared using the methods described for the preparation of Examples 230 and 288, 265 mg, 1.0 mmol) in THF (5 mL). After stirring for 5 min, a solution of 2,5-dioxocyclopentyl 2-amino-4,5-difluorobenzoate (Example 283, 297 mg, 1.1 mmol) in THF (2 mL) was added drop-wise. The reaction mixture was then stirred at 650C for 16 h, cooled to rt and then filtered. The organic solvent was then removed under reduced pressure. Water was added to the residue and the pH of the resulting solution was adjusted to 6, giving rise to a precipitate. The solid, 2-(2'-ethoxybiphenyl-4-yl)-6,7-difluoro-4- hydroxyquinoline-3-carbonitrile (260 mg, 64%) was isolated by filtration, dried under mechanical vacuum and used in the next step without further purification.
[248] A solution of 2-(2'-ethoxybiphenyl-4-yl)-6,7-difluoro-4-hydroxyquinoline-3-carbonitrile (150 mg, 0.373 mmol) in POCI3 (20 mL) was stirred at 8O0C for 6 h. The reaction mixture was cooled to rt, and POCI3 was removed under reduced pressure. The flask containing the residue was placed in an ice-bath and NaOH (1 N aqueous solution) was slowly added while stirring until pH ~7 was reached. Methylene chloride and water were added to the mixture, and the organic phase was separated, dried (Na2SO4), filtered, and concentrated under reduced to give 4-chloro-2- (2'-ethoxybiphenyl-4-yl)-6,7-difluoroquinoline-3-carbonitrile (124 mg, 79%) as a solid.
[249] To a solution of 4-chloro-2-(2'-ethoxybiphenyl-4-yl)-6,7-difluoroquinoline-3-carbonitrile (75 mg, 0.169 mmoi) dissolved in DMSO (5 ml_) was added D-aianine (45 mg, 0.508 mmol), and thethylamine (0.14 mL, 1.02 mmol). The reaction mixture was stirred at rt for 24 h and then directly subjected to preparative HPLC purification. The desired fractions were combined, evaporated, free-based using aqueous sodium bicarbonate, and extracted with methylene chloride. Removal of the solvent under reduced pressure yielded Λ/-[3-cyano-2-(2'-ethoxybiphenyl- 4-yl)-6,7-difluoroquinolin-4-yl]-D-alanine (20 mg). 1H NMR (400 MHz, DMSO-c/6) δ 8.60 -8.52 (m, 1 H), 7.88 - 7.82 (m, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.38 - 7.32 (m, 2H), 7.13-7.05 (d, 1 H), 7.01- 6.96 (m, 1 H), 5.11-5.06 (m, 1 H), 4.14 (q, 2H), 1.64 (d, 3H), 1.32 (t, 3H); ES-MS m/z 474.2 [M+H]+, LCMS RT (min) 3.38.
[250] The following compounds were prepared using the procedures of Example 283-284 and substituting the appropriate starting materials.
Figure imgf000120_0002
[252] Example 286 Preparation of ethyl 4-bromo-2-f luorobenzoate
Figure imgf000120_0001
[253] To a solution 4-bromo-2-fluorobenzoic acid (5 g, 22.8 mmol) in EtOH (40 mL) was added of cone H2SO4 (1 ml_) and the reaction mixture was refluxed for 16 h. The reaction mixture was cooled to rt, ethyl acetate (10OmL) was added and the organic phase was washed successively with KHCO3 (10% aqueous solution) and water. The organic phase was then dried (Na2SO4), filtered, and concentrated under reduced pressure to give Example 286 as an oil (5.6 g). 1H NMR (400 MHz, Acetone-dβ) δ 7.89-787 (m,1 H), 7.56-7.53 (m, 2H), 5.36 (q, 2H), 1.37 (t, 3H).
[254] Example 287
Preparation of 3-(4-bromo-2-fluorophenyl)-3-oxopropanenitrile
Figure imgf000121_0001
[255] To a solution LHMDS (38 mL, 1 M solution) in THF (40 mL) cooled to -780C, was added acetonitrile (2.1 mL, 40.5 mmol) drop-wise. The reaction was stirred at -780C for 60 min, and a solution of ethyl 4-bromo-2-fluorobenzoate (Example 286, 5 g, 20.2 mmol) in THF (10 mL) was added. The reaction mixture was left to warm to rt over 16 h. Then, NH4CI (50 mL, 10% aqueous solution) was added, and the organic solvent was removed under reduced pressure. The resulting aqueous suspension was filtered, and the filter cake was washed successively with water and ether, and then dried under mechanical vacuum at 4O0C to give the desired product (4.4 g). EI-MS m/z [M+H]+ 241.2, GCMS RT 12.64 min.
[256] Example 288
Preparation of 3-(2'-ethoxy-3-fluorobiphenyl-4-yl)-3-oxopropanenitrile
Figure imgf000121_0002
[257] To a solution of 3-(4-bromo-2-fluorophenyl)-3-oxopropanenitrile (Example 287, 2.2 g, 9.1 mmol), (2-ethoxyphenyl)boronic acid (2.27 g, 13.5 mmol), and PdCI2(dppb) (27.4 mg, 0.045 mmol) in DMF (65 mL), was added Na2CO3 (13.6 mL, 27.3 mmol, 2 M solution in water). The solution was degassed by passing a flow of N2 through the solution for 10 min. The reaction mixture was stirred at 8O0C overnight under N2, and cooled to rt and then filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel flash chromatography (10 to 50% ethyl acetate in hexane) to give the desired product (2.5 g). ES-MS m/z [M-H]", 282.0, LCMS RT 5.07 (min).
[258] Example 289
Preparation of 2-(2'-ethoxy-3-fluorobiphenyl-4-vπ-6-fluoro-4-hvdroxyquinoline-
3-carbonitrile
Figure imgf000122_0001
[259] To a solution of 3-(2'-ethoxy-3-fluorobiphenyl-4-yl)-3-oxopropanenitrile (Example 288, 1.0 g, 3.53 mmol) and 6-fluoro-2H-3,1-benzoxazine-2,4(1 H)-dione (767 mg, 4.24 mmol) in THF (20 L), was added NaH (169 mg, 4.24 mmol, 60% dispersion in mineral oil). The solution was stirred at 500C over 16 h. The reaction mixture was cooled to rt and NH4CI (40 L, 10% aqueous solution) was added. The mixture was extracted with ethyl acetate (2X), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate, and then dried under mechanical vacuum to give the desired product (600 g). Additional amounts of Example 289 were recovered after concentration of the filtrate under reduced pressure and purification of the residue by silica gel flash chromatography (10 to 50% ethyl acetate in hexane) to give an additional 300 mg of Example 289. 1H NMR (400 MHz, DMSOd6) δ 7.80-7.60 (m, 6H), 7.43 (dd, 1H), 7.39-7.37 (m, 1 H), 7.15 (d, 1H), 7.06 (t, 1 H), 4.12 (q, 2H), 1.32 (t, 3H); m/z [M+H]+ 403.2, LCMS RT (min) 3.26.
[260] Example 290
Preparation of 4-chloro-2-(2'-ethoxy-3-fluorobiphenyl-4-vπ-6-fluoroquinoline-
Figure imgf000122_0002
[261] A solution of 2-(2'-ethoxy-3-fluorobiphenyl-4-yl)-6-fluoro-4-hydroxyquinoline-3-carbonitrile (Example 289, 900 mg, 2.24 mmol) in POCI3 (25 mL) was stirred at 950C for 4 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (50 ml_) and NaHCO3 (50 mL, saturated aqueous solution), and the mixture was stirred for 15 min. The organic layer was separated, washed successively with NaHCO3 (2X, saturated aqueous solution) and water. The organic phase was then dried (Na2SO4), filtered, and concentrated under reduced pressure to give 922.7 mg of the desired product. 1H NMR (400 MHz, DMSO-c/e) δ 8.32 (dd, 1), 8.13 (dd, 1H), 8.08-8.03 (m, 1H), 7.75 (t, 1 H), 7.62-7.58 m, 2H), 7.45 (dd, 1 H), 7.40-7.37 (m, 1 H), 7.15 (d, 1 H), 7.06 (t, 1 H); ES-MS m/z [M+KT, 421.1 ; LCMS RT (min) 4.33.
[262] Example 291
Preparation of N-r3-cvano-2-(2'-ethoxy-3-fluorobiphenyl-4-yl)-6-fluoroquinolin-
4-yll-D-alanine
Figure imgf000123_0001
[263] To a solution of 4-chloro-2-(2'-ethoxy-3-fluorobiphenyl-4-yl)-6-fluoroquinoline-3-carbonitrile (Example 290, 80 mg, 0.19 mmol) and D-alanine (50.8 mg, 0.57 mmol) in DMSO (3 mL) was added TEA (0.16 mL, 1.14 mmol). The solution was stirred at rt for 16 h, then filtered and the filtrate concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (eluent: 10% to 90% acetonitrile in water containing 0.1 % TFA). The desired fractions were combined, evaporated, free-based using an aqueous solution of sodium bicarbonate, and extracted with methylene chloride. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue further was purified by Biotage to give 25.9 mg of desired product. 1H NMR (400 MHz, acetone-d6) δ 8.03 (dd, 1 H), 7.95- 7.94 (br, 1 H), 7.68-7.63 (m, 2H), 7.56-7.45 (m, 3H), 7.39-7.35 (m, 1 H), 7.13 (dd,1H), 7.07 (td, 1 H), 5.25-5.23 (m, 1 H), 4.14 (q, 2H), 1.73 (d, 3H), 1.38 (t, 3H); ES-MS m/z [M+H]+ 474.2, LCMS RT (min) 3.27.
[264] The following compounds were prepared using the procedures of Example 286-291 and substituting the appropriate starting materials.
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0002
[266] Example 307
Preparation of 2-(4-bromophenyl)-6-fluoro-3-methylquinoline-4-carboxylic acid
Figure imgf000126_0001
[267] A mixture of 5-fluoroisatin (5.00 g, 30.2 mmol), 4-bromopropiophenone (7.1O g, 33.3 mmol), and potassium hydroxide (19.3 g, 90.6 mmol) in ethanol (60 mL) was heated (8O0C) for 16 h. The reaction was allowed to cool to rt and was concentrated to dryness. The residue was dissolved in water (200 mL), and the mixture was washed with diethyl ether (2 x 200 mL). The aqueous layer was cooled (O0C) and acidified to pH 1 using concentrated hydrochloric acid. The resulting precipitate was collected by filtration to afford 11.8 g of the crude desired product, which was used in the next synthetic step without further purification. If needed, purification of the product can be effected by trituration using methanol. 1H NMR (300 MHz, DMSO-cfe) δ 8.12-8.08 (m, 1 H), 7.71-7.66 (m, 3 H), 7.57-7.54 (m, 2 H), 7.47-7.44 (m, 1 H), 2.37 (s, 3 H); ES-MS m/z 362.2 [M+H]+, HPLC RT (min) 2.45.
[268] Example 308
Preparation of 2-(2'-ethoxybiphenyl-4-v0-6-fluoro-3-methylquinoline-4- carboxylic acid
Figure imgf000127_0001
[269] A mixture 2-(4-bromophenyl)-6-fluoro-3-methylquinoline-4-carboxylic acid (Example 307, 500 mg, 1.39 mmol), 2-ethoxybenzeneboronic acid (345 mg, 2.08), sodium carbonate (294 mg, 2.78 mmol) and [1 ,4-bis(diphenylphosphino)butane]-palladium(ll) dichloride (42 mg, 0.07 mmol) in DMF (5 mL) and water (1 mL) was heated (12O0C) for 16 h. The mixture was cooled to rt, and filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was poured into water (20 mL), the resulting white precipitate collected by filtration, and then triturated with dichloromethane to afford the desired product (302 mg, 54%). 1H NMR (400 MHz, DMSO-αfe) δ 8.13 (dd, 1 H), 7.65-7.73 (m, 5 H), 7.46 (dddd, 1 H), 7.32-7.39 (m, 2 H), 7.13 (d, 1 H), 7.04 (dddd, 1 H), 4.09 (q, 2 H), 1.31 (t, 3 H); ES-MS m/z 402.3 [M+H]+, HPLC RT (min) 3.41
[270] Example 309
Preparation of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxamide
Figure imgf000127_0002
[271] A solution of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxylic acid (Example 308, 3.00 g, 7.47 mmol) in thionyl chloride (3 mL) was refluxed for 2.5 h. After cooling to rt, the excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in dichloromethane (5.4 mL) and cooled (O0C). Triethylamine (0.3 mL, 2.17 mmol) and 2M ammonia in methanol (2.7 ml_, 5.4 mmol) were added. The resultant suspension was stirred at rt under nitrogen for 1.5 h and then evaporated under reduced pressure. The residue was diluted with dichloromethane (20 ml_), washed with water (20 rπL), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 20-50% ethyl acetate/hexanes to afford 302 mg (70%) of desired product. 1H NMR (400 MHz, DMSO-Cf6) δ 8.26 (bs, 1 H), 8.11-8.08 (m, 2 H), 7.70-7.60 (m, 5 H), 7.44-7.32 (m, 3 H), 7.13-7.11 (m, 1 H)1 7.06-7.02 (m, 1 H), 4.09 (q, 2 H), 2.44 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 401.3 [M+H]+, LCMS RT (min) 3.16.
[272] Example 310
Preparation of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-amine
Figure imgf000128_0001
[273] A mixture of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxamide (Example 309, 296 mg, 0.74 mmol) and [bis(trifluoroacetoxy)iodo]benzene (476.8 mg, 1.11 mmol) in acetonitrile (5.9 mL) and water (1.5 ml.) was stirred at rt for 16 h. The organic solvents were evaporated under reduced pressure and the residue was purified by preparative HPLC using a gradient of 10 - 90% acetonitrile in water over 8 min to yield 252.0 mg (70%) of desired product. 1H NMR (400 MHz, DMSO-cfe) δ 8.92 (bs, 1 H), 8.42-8.38 (m, 1 H), 8.33 (bs, 1 H), 8.02-7.98 (m, 1 H), 7.91-7.86 (m, 1 H), 7.79-7.77 (m, 2 H), 7.69-7.67 (m, 2 H), 7.40-7.35 (m, 2 H), 7.16-7.14 (m, 1 H), 7.08-7.04 (m, 1 H), 4.11 (q, 2 H), 2.17 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 373.3 [M+H]+, LCMS RT (min) 2.67.
[274] Example 311
Preparation of ethyl N-r2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-vnqlvcinate
Figure imgf000128_0002
[275] A mixture of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methy!quinolin-4-amine (Example 310, 79.0 mg, 0.21 mmol), ethyl bromoacetate (2.0 ml_, 18 mmol), and potassium carbonate (46.9 mg, 0.34 mmol) was heated (1500C) under nitrogen for 16 h. The reaction was diluted with ethyl acetate (15 mL) and washed with water (15 ml_). The aqueous wash was extracted with dichloromethane (15 mL) and then the combined organic layers were dried (sodium sulfate) filtered and evaporated under reduced pressure. The residue was purified by HPLC using a gradient of 20 - 80% of acetonitrile in water over 8 min to yield 42.3 mg (43%) of desired product. 1H NMR (400 MHz, DMSO-Cf6) δ 9.32 (bs, 1 H), 8.66 (bs, 1 H), 8.53-8.50 (m, 1 H), 8.21-8.17 (m, 1 H), 8.01- 7.96 (m, 1 H), 7.80-7.78 (m, 2 H), 7.41-7.35 (m, 3 H), 7.16-7.14 (m, 1 H), 7.08-7.05 (m, 1 H), 4.14- 4.06 (m, 4 H), 3.60 (s, 2 H), 1.96 (s, 3 H), 1.29 (t, 3 H), 1.12 (t, 3 H); ES-MS m/z 459.3 [Mn-H]+, LCMS RT (min) 2.90.
[276] Example 312
Preparation of N-re-te'-ethoxybiphenvM-vO-β-fluoro-S-metriylquinolin-
4-yllqlycine
Figure imgf000129_0001
[277] A mixture of ethyl N-[2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-yl]glycinate (Example 311 , 42.0 mg, 0.09 mmol) and lithium hydroxide (11.0 mg, 0.46 mmol) in water (1.0 mL) and THF (5.0 mL) was stirred at rt for 16 h. The reaction was evaporated under reduced pressure and the residue was suspended in water (5 mL). The pH of the mixture was adjusted to 3 using 2N hydrochloric acid. The resulting precipitate was filtered, washed with water and dried to afford 26.3 mg (67%) of the product. 1H NMR (400 MHz, DMSO-d6) δ 8.42-8.39 (m, 1 H), 7.96-7.87 (m, 2 H), 7.75-7.64 (m, 3 H), 7.43-7.33 (m, 4 H), 7.14-7.11 (m, 1 H), 7.06-7.03 (m, 1 H), 4.09 (q, 2 H), 3.31 (s, 2 H), 1.92 (s, 3 H), 1.30 (t, 3 H); ES-MS m/z 431.3 [MH-H]+, LCMS RT (min) 2.56. [278] Example 313
Preparation of 2-(4-bromophenyl)-6-fluoro-3-methvlquinolin-4-ol
Figure imgf000130_0001
[279] A solution of methyl 2-amino-5-fluoro-benzoate (1.00 g, 5.91 mmol), 4'- bromopropiophenone (1.26 g, 5.91 mmol), and 4-toluenesulfonic acid monohydrate (112.4 mg, 0.59 mmol) in diphenyl ether (4 ml.) was flushed with nitrogen for 5 min and then heated (1200C) for 4 days. The mixture was cooled to rt and a yellow precipitate formed. The mixture was diluted with ethyl acetate (10 mL) and then the solid was filtered and dried to give 0.65 g (33%) of desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.74 (bs, 1 H), 7.79-7.71 (m, 3 H), 7.66-7.63 (m, 1 H), 7.56-7.50 (m, 3 H), 1.88 (s, 3 H); ES-MS m/z 332.4 [M+H]+, LCMS RT (min) 2.80.
[280] Example 314
Preparation of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-ol
Figure imgf000130_0002
[281] A mixture 2-(4-bromophenyl)-6-fluoro-3-methylquinolin-4-ol (Example 313, 0.62 g, 1.87 mmol), 2-ethoxyphenylboronic acid (0.37 g, 2.24 mmol), PdCI2(dppf)«CH2Cl2 (152.4 mg, 0.18 mmol), and sodium carbonate (0.59 g, 5.60 mmol) in water (3 mL) and dioxane (9 mL) was heated at reflux under nitrogen for 3 h. The reaction mixture was cooled to rt and dioxane was evaporated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and evaporated under reduced pressure. The solid was triturated with ethyl acetate to yield 0.42 g (60%) of desired product. 1H NMR (400 MHz, DMSO-cfe) δ 11.78 (bs, 1 H), 7.76-7.66 (m, 4 H), 7.59-7.51 (m, 3 H), 7.38-7.33 (m, 2 H), 7.14-7.12 (m, 1 H), 7.07-7.03 (m, 1 H), 4.10 (q, 2 H), 1.95 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 374.2 [M+H]+, LCMS RT (min) 3.27. [282] Example 315
Preparation of 4-chloro-2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline
Figure imgf000131_0001
[283] A solution of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-ol (Example 314, 410.0 mg, 1.10 mmol) in POCI3 (2 mL) was heated at refluxed for 15 h. Excess POCI3 was evaporated under reduced pressure and the residue was suspended in water (10 mL). The mixture was stirred vigorously for 15 min and then the resulting solid was filtered and dried to give 0.43 g (100%) of desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.13 (m, 1 H), 7.92-7.89 (m, 1 H), 7.78-7.73 (m, 1 H), 7.68-7.63 (m, 4 H), 7.39-7.32 (m, 2 H), 7.13-7.11 (m, 1 H), 7.06-7.02 (m, 1 H), 4.09 (q, 2 H), 2.57 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 392.2 [M+H]+, LCMS RT (min) 4.71.
[284] Example 316
Preparation of ethyl 4-fr2-(2'-ethoxybiphenyl-4-vD-6-f luoro-3-methylquinolin-4-
VliaminoTbutanoate
Figure imgf000131_0002
[285] A mixture of 4-chloro-2-(2'-ethoxybipheny!-4-yl)-6-fluoro-3-methylquinoline (Example 315, 150.0 mg, 0.38 mg), ethyl 4-aminobutyrate hydrochloride (1.09 g, 6.51 mmol), tin(IV) chloride (0.10 g, 0.38 mmol), and triethylamine (0.91 mL, 6.51 mmol) was heated (1300C) under nitrogen for 16 h. The mixture was purified by HPLC using a gradient of 20 - 60% of acetonitrile in water over 8 min to yield 93.0 mg (50%) of desired product. 1H NMR (400 MHz, DMSO-Cf6) δ 8.38-8.34 (m, 1 H), 8.08 (bs, 1 H), 8.04-8.00 (m, 1 H), 7.91-7.86 (m, 1 H), 7.80-7.78 (m, 2 H), 7.70-7.68 (m, 2 H), 7.40-7.35 (m, 2 H), 7.16-7.14 (m, 1 H), 7.08-7.04 (m, 1 H), 4.10 (q, 2 H), 4.02 (q, 2 H), 3.92- 3.88 (m, 2 H), 2.48-2.44 (m, 2 H), 2.27 (s, 3 H), 2.06-1.98 (m, 2 H), 1.30 (t, 3 H), 1.16 (t, 3 H); ES- MS m/z 487.3 [M+H]+, LCMS RT (min) 3.03. [286] Example 317
Preparation of 4-{r2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-vπamino)butanoic acid
Figure imgf000132_0001
[287] A mixture of ethyl 4-{[2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-yl]amino} butanoate (Example 316, 62.5 mg, 0.13 mmol) and lithium hydroxide (15.4 mg, 0.64 mmol) in water (1.0 mL) and THF (5.0 ml_) was stirred at rt for 16 h. The solvents were evaporated under reduced pressure and the residue was suspended in water (10 mL). The pH was adjusted to 4 using 2N hydrochloric acid, and the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC using a gradient of 20 - 90% acetonitrile in water over 8 min to yield 31.3 mg (53%) of desired product. 1H NMR (400 MHz, DMSO-Qf6) δ 13.84 (bs, 1 H), 8.38-8.36 (m, 1 H), 8.09 (bs, 1 H), 8.03-7.99 (m, 1 H), 7.89-7.86 (m, 1 H), 7.79-7.77 (m, 2 H), 7.70-7.68 (m, 2 H), 7.40-7.35 (m, 2 H), 7.16-7.14 (m, 1 H), 7.06-7.04 (m, 1 H), 4.10 (q, 2 H), 3.90- 3.89 (m, 2 H), 2.39-2.36 (m, 2 H), 2.27 (s, 3 H), 2.02-1.95 (m, 2 H), 1.30 (t, 3 H); ES-MS m/z 459.4 [M+H]+, LCMS RT (min) 3.03.
[288] The following compound was prepared using the procedures of Example 313-317 and substituting the appropriate starting materials.
[289] Table 23
Figure imgf000132_0002
[290] Example 319
Preparation of 6-fluoro-4-hvdroxy-2-(4-prøpylphenvπαuinoline-3-carbonitrile
Figure imgf000133_0001
[291] To a cooled (O0C) solution of 4-n-propylbenzoylacetonitrile (2.30 g, 12.3 mmol) in THF (25 ml_) was added sodium hydride (0.59 g, 14.7 mmol) in one portion. After the gaseous evolution ceased, the ice bath was removed and 5-fluoroisatoic anhydride (2.45 g, 13.5 mmol) was added. The reaction was heated to reflux for 16 h and then cooled to rt. The reaction was quenched and adjusted to pH 5 by slow addition of 1 N hydrochloric acid. The resulting light yellow solid was collected by filtration and triturated with diethyl ether/acetone (3:1 ) to afford 750 mg (20%) of desired product. 1H NMR (400 MHz, DMSOd6) δ 12.75 (s, 1 H), 7.77-7.79 (m, 2 H), 7.72 (d, 2 H), 7.46 (d, 2 H), 7.29 (d, 1 H), 2.68 (t, 2 H), 1.62-1.68 (m, 2 H), 0.93 (t, 3 H), ES-MS m/z 307.3 [MH-H]+, HPLC RT (min) 3.21.
[292] Example 320
Preparation of 4-chloro-6-fluoro-2-(4-propylphenyl)quinoline-3-carbonitrile
Figure imgf000133_0002
[293] A mixture of 6-fluoro-4-hydroxy-2-(4-propylphenyl)quinoline-3-carbonitrile (Example 319, 730 mg, 2.38 mmol) and phosphorus oxychloride (5.0 mL, 53.6 mmol) was heated to reflux for 5 h and then cooled to rt. The resulting yellow precipitate was collected by filtration and rinsed with acetone and diethyl ether to afford 750 mg (97%) of crude product. This material was taken to the next step without further purification or analysis. [294] Example 321
Preparation of N-r3-cvano-6-fluoro-2-(4-propylphenyl)quinolin-4-vllalanine
Figure imgf000134_0001
[295] A mixture of 4-chloro-6-fluoro-2-(4-propylphenyl)quinoline-3-carbonitrile (Example 320, 165 mg, 0.51 mmol), DL-alanine (136 mg, 1.52 mmol) and triethylamine (308 mg, 3.05 mmol) in DMF (3 mL) was heated to 1000C for 3 h. After cooling to rt, the mixture was purified by preparative HPLC using a gradient elution from 25-85% acetonitrile in water to afford 5.0 mg (3%) of desired product. 1H NMR (400 MHz, DMSOd6) 8.25-8.27 (m, 1 H), 7.85-7.89 (m, 1 H), 7.77- 7.79 (m, 1 H), 7.62-7.69 (m, 3 H), 7.29 (d, 2 H), 4.47-4.50 (m, 1 H), 2.64 (t, 2 H), 1.62-1.68 (m, 2 H), 1.46 (d, 3 H), 1.23 (t, 3 H), ES-MS m/z 378.2 [M+H]+, HPLC RT (min) 2.99.
[296] The following compounds were prepared using the procedures of Example 319-321 and substituting the appropriate starting materials.
[297] Table 24
Figure imgf000134_0002
[298] Example 324 Preparation of 2,4-dihvdroxyquinoline-3-carbonitrile
Figure imgf000135_0001
[299] To a solution of 2H-3,1-benzoxazine-2,4(1 H)-dione (5 g, 30 mmol) and ethyl cyanoacetate (3.5 g, 30 mmol) in DMF (50 ml_) was added f-BuOK (9 g, 90 mmol). The resulting mixture was stirred at 950C for 8 h, cooled to rt, and then poured into ice-water. The precipitate was collected by filtration to afford the desired product (4 g, 70%) that was used in next step without purification. 1H NMR (300 MHz, DMSO-de) δ 11.80 (s, 2H) 8.0 (dd, 1 H), 7.60 (dd, 1 H), 7.20 (m, 2 H); ES-MS m/z 187.2 [M+H]+, LCMS RT (min) 1.50.
[300] The following compound was prepared using the procedure of Example 324 and substituting the appropriate starting materials.
[301] Table 25
Figure imgf000135_0003
[302] Example 326 Preparation of 2, 4-dichloroquinoline-3-carbonitrile
Figure imgf000135_0002
[303] POCI3 (5 mL) was added drop-wise into a mixture of 2, 4-dihydroxyquinoiine-3-carbonitrile (Example 324, 4 g, 21 mmol) and DMA (2 mL), and the mixture was heated to 6O0C for 1 h. The resulting mixture was poured into ice-water and the resulting precipitate (3 g, 70%) was collected, dried, and used in next step without further separation. ES-MS m/z 223.2 [M+H]+, LCMS RT (min) 3.45.
[304] The following compound was prepared using the procedure of Example 326 and substituting the appropriate starting materials.
[305] Table 26
Figure imgf000136_0002
[306] Example 328
Preparation of ethyl N-(2-chloro-3-cyanoquinolin-4-vπqlvcinate
Figure imgf000136_0001
[307] To a solution of 2, 4,-dichloroquinoline-3-carbonitrile (Example 326, 600 mg, 2.6 mmol) and ethyl glycinate (200 mg) in DMF (5 mL) was added Et3N (5 ml_). The mixture was stirred for 4 h at 90° C, cooled to rt, and then poured into ice-water. The product was extracted from the aqueous solution using ethyl acetate. The combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column to yield desired product (600 mg, 70%). 1H NMR (300 MHz, CD3CN) 58.00 (dd, 1 H), 7.80 (m, 2 H), 7.60 (dd 1 H), 7.00 (br, 1 H), 4.70 (d, 2H), 4.25 (q, 2H), 1.20 (t, 3H); ES-MS m/z 290.1 [M+H]+, LCMS RT (min) 2.77.
[308] The following compounds were prepared using the procedure of Example 328 and substituting the appropriate starting materials.
[309] Table 27
Figure imgf000137_0002
[310] Example 331 Preparation of N-r2-(4-butylphenyl)-3-cvanoquinolin-4-vπqlvcine
Figure imgf000137_0001
[311] To a solution of ethyl N-(2-chloro-3-cyanoquinolin-4-yl)glycinate (Example 328, 300 mg 1.0 mmol) and π-butylphenyl boronic acid (165 mg, 1.2 mmol) in a 4:1 mixture of toluene and dioxane (15 mL), were added sodium carbonate (15 mL, 2 M aqueous solution) and 40 mg PdCI2(dppf). The resulting mixture was degassed (15 min) and then stirred for 4 h at 850C. The organic layer was separated, dried (Na2SO4), filtered, and concentrated. The residue was passed though a silica gel pad, and the desired fractions were collected and concentrated. The residue was dissolved into methanol (3 mL), and KOH (5 mL, 3 M aqueous solution) was added into the mixture, which was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was then purified by preparative HPLC to yield Example 331 (100 mg, 35%). 1H NMR (400 MHz, DMSO-CZ6) δ 8.60 (d, 1H), 8.00 (dd, 2H), 7.80 (m, 2 H), 7.70 (d, 2 H), 7.40 (d, 2 H), 4.70
(d, 2H), 2.70 (t, 2H), 1.60 (m, 2H), 1.40 (m, 2H), 0.90 (t, 3H); ES-MS m/z 360.2 [M+H]+, LCMS RT (min) 2.47.
[312] The following compounds were prepared using the procedure of Example 331 and substituting the appropriate starting materials.
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
[314] Example 344
Preparation of 2-(4-brømophenyl)-3-cvano-6-fluoroquinoline-4-carboxylic acid
Figure imgf000141_0001
[315] To a suspension of 5-fluoroisatin (7.37 g, 44.6 mmol) in water (50 ml_) was added 1 N aqueous potassium hydroxide solution (45 ml_). The reaction was warmed (400C) for 2 h and then cooled to rt. The mixture was filtered, and then the volume of filtrate was reduced under reduced pressure to 25 ml_. The remaining filtrate was added to a solution of 4-bromophenyl-cyanoketone (10.0 g, 44.6 mmol) in ethanol (50 mL). The solution was heated to reflux for 16 h and cooled to rt. The resulting solid was collected by filtration and triturated with diethyl ether/acetone (3:1) to afford 6.5 g (39%) of desired product. 1H NMR (400 MHz, DMSO-c/6) δ 8.17 (dd, 1 H), 7.88 (ddd, 1 H), 7.76-7.82 (m, 5 H); ES-MS m/z 372.8 [M+H]+, HPLC RT (min) 3.55.
[316] Example 345
Preparation of 3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinoline-4-carboxylic acid
Figure imgf000141_0002
[317] A mixture of 2-(4-bromophenyl)-3-cyano-6-fluoroquinoline-4-carboxylic acid (Example 344, 850 mg, 2.08 mmol), 2-ethoxybenzeneboronic acid (414 mg, 2.49 mmol), sodium carbonate (440 mg, 4.15 mmol), and [1 ,4-bis(diphenylphosphino)-butane]palladium(ll) dichloride (105 mg, 0.10 mmol) in DMF (10 mL) and water (3 mL) was heated (1200C) for 16 h. The mixture was cooled to rt, and filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography using a gradient elution from 10 - 20% methanol in dichloromethane to afford 520 mg (61%) of desired product. 1H NMR (400 MHz, DMSO-cfe) δ 8.13 (dd, 1 H), 7.87-7.90 (m, 2 H), 7.76-7.85 (m, 2 H), 7.68-7.71 (m, 2 H), 7.33-7.40 (m, 2 H), 7.13 (d, 1 H), 7.05 (ddd, 1 H), 4.09 (q, 2 H), 1.31 (t, 3H); ES-MS m/z 413.1 [M+Hf , HPLC RT (min) 3.57.
[318] The following compounds were prepared using the procedures of Example 344-345 and substituting the appropriate starting materials. [319] Table 29
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0002
[320] Example 357
Preparation of ethyl N-{F2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4- vncarbonvDglycinate
Figure imgf000144_0001
[321] To a solution of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxylic acid (Example 345, 500 mg, 1.25 mmol) in DMF (8 mL) was added glycine ethyl ester hydrochloride (208 mg, 1.49 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (286 mg, 1.49 mmol), 1 -hydroxybenzotriazole hydrate (202 mg, 1.49 mmol), and triethylamine (0.61 mL, 4.36 mmol). The reaction was stirred at rt and then diluted with water (80 mL). The product was extracted with ethyl acetate (3 x 20 mL) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 25% ethyl acetate/hexanes to afford 273 mg (45%) of desired product. 1H NMR (300 MHz, DMSO-d6) δ 9.31 (t, 1 H), 8.10 (dd, 1 H), 7.78 (dd, 1 H), 7.71- 7.59 (m, 5 H), 7.40-7.30 (m, 2 H), 7.12 (d, 1 H), 7.03 (ddd, 1 H), 4.25-4.05 (m, 6 H), 2.44 (s, 3 H), 1.34-1.24 (m, 6 H); ES-MS m/z 487.4 [M+H]+, LCMS RT (min) 3.63. [322] Example 358
Preparation of N-fr2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-
4-yllcarbonvl>qlycine
Figure imgf000145_0001
[323] To a solution of ethyl N-{[2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoIin-4- yl]carbonyl}glycinate (Example 357, 250 mg, 0.51 mmol) in THF (6 ml_) was added a solution of lithium hydroxide (61 mg, 2.57 mmol) in water (2 ml_). The reaction was stirred at rt for 1 h. The THF was evaporated under reduced pressure, and then the remaining aqueous solution was adjusted to pH 7 with acetic acid and diluted with water (20 imL). The product was extracted with ethyl acetate (3 x 10 ml_) and the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure to afford 123 mg (52%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 12.85 (br s, 1 H), 9.20 (t, 1 H), 8.09 (dd, 1 H), 7.85 (dd, 1 H), 7.70-7.59 (m, 5 H)1 7.40-7.30 (m, 2 H), 7.12 (d, 1 H), 7.04 (t, 1 H), 4.10-4.03 (m, 4 H), 2.43 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 459.3 [M+H]+, LCMS RT (min) 3.18.
[324] Example 359
Preparation of 2-(4-bromophenvO-4-hvdroxyquinoline-3-carbonitrile
Figure imgf000145_0002
[325] To a cooled (O0C) and stirred solution of 3-(4-bromophenyl)-3-oxopropanenitrile (Example 230, 4.00 g, 17.85 mmol) in THF (20 mL) was added sodium hydride (60% in oil dispersion, 857 mg, 21.4 mmol). After gas evolution ceased, the mixture was warmed to rt, and isatoic anhydride (3.49 g, 17.85 mmol) was added. The reaction was heated to reflux for 16 h and then cooled to rt. The reaction was quenched and adjusted to pH 5 by slow addition of hydrochloric acid (1 N aqueous solution). The resulting white solid was collected by filtration and triturated with diethyl ether/acetone (3:1 ) to afford 3.5 g (60%) of desired product. 1H NMR (400 MHz, DMSOd6) δ 12.73 (br s, 1 H), 8.13 (dd, 1 H), 7.70-7.87 (m, 6 H), 7.49 (dddd, 1 H); ES-MS m/z 326.8 [M+H]+, HPLC RT (min) 2.95 [326] Example 360 Preparation of 2-(2'-ethoxybiphenyl-4-yl)-4-hvdroxyquinoline-3-carbonitrile
Figure imgf000146_0001
[327] A mixture of 2-(4-bromophenyl)-4-hydroxyquinoline-3-carbonitrile (Example 359, 1.0 mg, 3.08 mmol), 2-ethoxybenzeneboronic acid (562 mg, 3.38), sodium carbonate (652 mg, 6.15 mmol), and [1 ,4-bis(diphenylphosphino)butane]-palladium(ll) dichloride (93 mg, 0.15 mmol) in DMF (10 mL) and water (3 mL) was heated (1200C) for 16 h. The mixture was cooled to rt, filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was poured into water (20 mL). The resulting white precipitate was collected by filtration and triturated with diethyl ether/acetone (3:1) to afford 730 mg (65%) of the desired product. 1H NMR (400 MHz, DMSOd6) δ 12.70 (br s, 1 H), 8.13 (dd, 1 H), 7.73-7.83 (m, 6 H), 7.48 (dddd, 1 H), 7.34-7.39 (m, 2 H), 7.14 (d, 1 H), 7.05 (dddd, 1 H), 4.09 (q, 2 H), 1.30 (t, 3 H); ES-MS m/z 370.0 [M+H]+, HPLC RT (min) 3.50
[328] Example 361
Preparation of 4-chloro-2-(2'-ethoxybiprienyl-4-yl)quinoline-3-carbonitrile
Figure imgf000146_0002
[329] A mixture of 2-(2'-ethoxybiphenyl-4-yl)-4-hydroxyquinoline-3-carbonitrile (Example 360, 650 mg, 1.77 mmol) and phosphorus oxychloride (5 mL, 53.64 mmol) was heated to reflux for 5 h. The reaction was cooled to rt, and the resulting yellow precipitate was collected by filtration and was rinsed with acetone and diethyl ether to afford 730 mg (99%) of the desired product. 1H NMR (400 MHz, DMSO-CZ6) δ 8.33 (dd, 1 H), 8.20 (d, 1 H), 8.07 (dddd, 1 H), 7.96-7.99 (m, 2 H), 7.90 (dddd, 1 H), 7.72-7.74 (m, 2 H), 7.34-7.41 (m, 2 H), 7.13 (d, 1 H), 7.05 (dddd, 1 H), 4.09 (q, 2H), 1.31 (t, 3 H); ES-MS m/z 385.1 [M+H]+, HPLC RT (min) 4.23 [330] Example 362
Preparation of S-cvano-Σ-te'-ethoxybiphenyl-ΦvQquinoline-'l-carboxylic acid
Figure imgf000147_0001
[331] A mixture of 4-chloro-2-(2'-ethoxybiphenyl-4-yI)quinoline-3-carbonitrile (Example 361 , 300 mg, 0.78 mmol), palladium (II) acetate (18 mg, 0.08 mmol), 1 ,3-bis(diphenylphosphino) propane (35 mg, 0.09 mmol) and potassium carbonate (162 mg, 1.17 mmol) in 1-butanol (3 mL) and DMF (3 mL) was heated (8O0C) under a carbon monoxide atmosphere (1 atm) for 16 h. After cooling to rt, solids were removed by filtration through a pad of Celite® using ethyl acetate to rinse. The filtrate was concentrated to dryness affording crude butyl 3-cyano-2-(2'- ethoxybiphenyl-4-yl)quinoline-4-carboxylate. This material was dissolved in aqueous sodium hydroxide (5 mL) and acetone (5 mL), and was stirred for 2 h at rt. The reaction was diluted with dichloromethane (20 mL), washed with water (20 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 30 - 95% acetonitrile in water (with 0.1% TFA) to afford 15 mg (9%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, 1 H), 8.02-8.06 (m, 2 H), 7.95-7.97 (m, 2 H), 7.84 (dddd, 1 H), 7.71- 7.74 (m, 2 H), 7.33-7.41 (m, 2 H), 7.13 (d, 1 H), 7.05 (dddd, 1 H), 4.09 (q, 2 H), 1.31 (t, 3 H); ES- MS m/z 395.2 [M+H]+, HPLC RT (min) 3.52.
[332] The following compounds were prepared using the procedures of Examples 359-362 and substituting the appropriate starting materials.
[333] Table 30
Figure imgf000147_0002
Figure imgf000148_0002
[334] Example 366
Preparation of methyl 2-f2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxylate
Figure imgf000148_0001
[335] To a solution of 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxylic acid (Example 308, 100 mg, 0.25 mmol) in DMF (5 ml_) was added iodomethane (0.08 mL, 1.25 mmol) and sodium bicarbonate (41.9 mg, 0.50 mmol). The reaction was stirred at rt for 16 h and then quenched with water (50 mL). The product was extracted with ethyl acetate (3 X 15 mL) and then the combined organic extracts were dried with sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography using 25% ethyl acetate in hexanes as eluent to obtain 91 mg (88%) of desired product. 1H NMR (300 MHz, DMSO-c/6) δ 8.13 (dd, 1 H), 7.72 (ddd, 1 H), 7.64 (s, 4 H), 7.55 (dd, 1 H), 7.41-7.29 (m, 2 H), 7.14-7.09 (m, 1 H), 7.04 (ddd, 1 H), 4.09 (q, 2 H), 4.06 (s, 3 H), 2.43 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 416.3 [M+H]+, LCMS RT (min) 4.11. [336] Example 367
Preparation of r2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4- vlimethanol
Figure imgf000149_0001
[337] To a cooled (O0C) solution of methyl 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline- 4-carboxylate (Example 366, 475 mg, 1.14 mmoi) in THF (10 mL) was added diisobutylaluminum hydride (1 M in THF, 2.86 mL, 2.86 mmol) over 5 min. The reaction was warmed to rt and stirred for 3 h. The reaction was cooled (O0C) and slowly quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 15 mL) and then the combined organic extracts were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to afford 370 mg (84%) of crude product. This material was used without further purification. 1H NMR (300 MHz DMSO- dβ) δ 8.03 (dd, 1 H), 7.97 (dd, 1 H), 7.67-7.53 (m, 5 H), 7.41-7.29 (m, 2 H), 7.12 (dd, 1 H), 7.04 (ddd, 1 H), 5.38 (t, 1 H), 4.97 (d, 2 H), 4.09 (q, 2 H), 2.52 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 388.3[M+H]+, LCMS RT (min) 2.90.
[338] Example 368
Preparation of 4-(bromomethyl)-2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-
3-methylquinoline
Figure imgf000149_0002
[339] To a cooled (O0C) suspension of [2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4- yl]methanol (Example 367, 371 mg, 0.96 mmol) in dichloromethane (15 mL) was added triphenylphosphine (502 mg, 1.92 mmol) and carbon tetrabromide (635 mg, 1.92 mmol). The reaction was stirred for 10 min, warmed to rt, and stirred an additional hour. The reaction was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography using 5% ethyl acetate in hexanes to afford 361 mg (84%) of desired product. 1H NMR (300 MHz, DMSO-Cf6) δ 8.11-8.01 (m, 2 H), 7.69-7.56 (m, 5 H), 7.41-7.30 (m, 2 H), 7.12 (dd, 1 H), 7.04 (ddd, 1 H), 5.22 (s, 2 H), 4.09 (q, 2 H), 2.51 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 450.3 [MH-H]+, LCMS RT (min) 4.00.
[340] Example 369
Preparation of dimethyl fr2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoIin-
4-yllmethyl)malonate
Figure imgf000150_0001
[341] To a suspension of sodium hydride (31.97 mg, 60% in oil, 0.80 mmol) in DMF (4 mL) was added dimethyl malonate (0.09 mL, 0.80 mmol) dropwise (10 min). The reaction was stirred for 30 min and then a solution of 4-(bromomethyl)-2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3- methylquinoline (Example 368, 360 mg, 0.80 mmol) in DMF (4 mL) was added dropwise (10 min). The reaction was heated to reflux for 1 h, cooled to rt and then quenched by slow addition of water 40 mL). The product was extracted with dichloromethane (3 X 15 mL) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 10% ethyl acetate in hexanes to give 70 mg (18%) of desired product. 1H NMR (300 MHz, DMSOd6) δ 8.02 (d, 1 H), 7.87 (dd, 1 H), 7.65-7.50 (m, 5 H), 7.39-7.29 (m, 2 H), 7.11 (d, 1 H), 7.03 (dd, 1 H), 4.09 (q, 2 H), 3.93 (t, 1 H), 3.70 (d, 2 H), 3.57 (s, 6 H), 2.41 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 502.4 [M+H]+, LCMS RT (min) 3.54.
[342] Example 370
Preparation of 3-r2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-vnpropanoic acid
Figure imgf000150_0002
[343] To a solution of dimethyl {[2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-yl]methyl} malonate (Example 369, 70 mg, 0.14 mmol) in ethanol (5 mL) was added a solution of potassium hydroxide (78 mg, 1.40 mmol) in water (5 mL). The reaction was refluxed for 1 h and then cooled to rt. The reaction was extracted with ethyl acetate (3 x 10 mL) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated to dryness. The crude intermediate was dissolved in 2N hydrochloric acid (5 mL) and refluxed for 16 h. The reaction was then cooled to rt and the resulting precipitate was collected by filtration to afford 13 mg (22%) of desired product. 1H NMR (300 MHz, DMSO- dβ) δ 8.16-8.04 (m, 2 H), 7.80-7.60 (m, 5 H), 7.41- 7.31 (m, 2 H), 7.13 (d, 1 H), 7.04 (dd, 1 H), 4.09 (q, 2 H), 3.43 (t, 2 H), 2.58 (t, 2 H), 2.47 (s, 3 H), 1.30 (t, 3 H); ES-MS m/z 430.3 [M+H]+, LCMS RT (min) 2.82.
[344] Example 371
Preparation of r2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinolin-4-vnacetic acid
Figure imgf000151_0001
[345] A solution of 4-(bromomethyl)-2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-3-methylquinoline (Example 368, 50 mg, 0.11 mmol), chloro(1 ,5-cyclooctadiene)rhodium(l) dimer (27 mg, 0.06 mmol), and potassium iodide (9.2 mg, 0.06 mmol) in formic acid (5 mL) was heated (600C) under a carbon monoxide atmosphere (1 atm) for 18 h. The reaction was then cooled to rt and then evaporated under reduced pressure. The residue was purified by silica gel chromatography using 10% ethyl acetate in hexanes to afford 22 mg (48%) of desired product. 1H NMR (300 MHz, DMSO-Cf6) δ 8.33 (s, 1 H), 8.09 (dd, 1 H), 7.98 (dd, 1 H), 7.72-7.56 (m, 5 H), 7.41-7.30 (m, 2 H), 7.12 (d, 1 H), 7.03 (ddd, 1 H), 5.72 (s, 2 H), 4.08 (q, 2 H), 2.53 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 416.2 [M+H]+, LCMS RT (min) 3.71.
[346] Example 372
Preparation of methyl f2E)-3-r3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4- yliacrylate
Figure imgf000151_0002
[347] To an oven-dried flask equipped with a stir bar was added 4-chloro-2-(2'-ethoxybiphenyl-4- yl)-6-fluoroquinoline-3-carbonitrϋe (Example 233, 403 mg, 1 mmol), methyl acrylate (94 mg, 1.1mmol), Pd2(dba)3 (14 mg, 0.015 mmol), Cy2Nme (215 mg, 1.1 mmol), P(t-Bu)3 (6 mg, 0.03 mmol), followed by dioxane (2 ml_). The reaction mixture was stirred at 700C for 16 h and then cooled to it The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (100% hexanes to 10% EtOAc in hexanes) to obtain 150 mg (33%) of the desired product. 1H NMR (400 MHz, acetone- d6) δ 8.37-8.22 (m, 2 H), 8.15-7.92 (m, 2 H), 7.82 (d, 1 H), 8.15-7.72 (m, 2 H), 7.38 (m, 1 H), 7.18 (d, 2 H), 7.12 (m, 2 H) 6.83 (d, 1 H), 4.19 (q, 2 H), 3.92 (s, 3 H), 1.34 (t, 3 H); ES-MS m/z 453.2 [M+H]+, LCMS RT (min) 3.38.
[348] Example 373
Preparation of 3-r3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-vnpropanoic acid
Figure imgf000152_0001
[349] To a solution of methyl (2£)-3-[3-cyano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4- yl]acrylate (Example 372, 75 mg, 0.165 mmol) dissolved in EtOH was added 10% Pd/C (10 mg), under an atmosphere of hydrogen (1 atm) and the reaction mixture was stirred for 12 h at rt. Upon completion, the reaction mixture was filtered through Celite®, and the Celite® washed with ethanol. The solvent was evaporated and the product was used in the next step without further purification.
[350] The product from the reduction step (64 mg, 0.141 mmol) was dissolved in a MeOH/THF/water (1 :2:2, 5 mL) mixture. Lithium hydroxide (13.5 mg, 0.563 mmol) was added to the reaction mixture that was then stirred for 16 h. The organic phase was evaporated under reduced pressure, and the aqueous phase diluted with water (5 mL). The pH was lowered to 5 using HCI (1 N aqueous solution), and the product extracted with EtOAc (2 x 50 mL). The organic fractions were combined, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield Example 373 (36 mg, 58 %) as a solid. 1H NMR (400 MHz, acetone-αfe) δ 8.16- 8.32 (m, 4 H), 7.95-7.72 (m, 3 H), 7.51-7.32 (m, 2 H), 7.02-7.18 (m, 2 H), 4.21 (q, 2 H), 3.82 (t, 2 H), 2.82 (t, 2 H), 1.41 (t, 3 H); ES-MS m/z 441.3 [M+H]+, LCMS RT (min) 3.11.
[351] The following compounds were prepared using the procedures of Examples 372-373 and substituting the appropriate starting materials. [352] Table 31
Figure imgf000153_0003
[353] Example 375 Preparation of 2-(4-bromophenyl)-6-f luoroquinoline-4-carboxylic acid
Figure imgf000153_0001
[354] A mixture of 5-fluoroisatin (2.0 g, 12.1 mmol), 4'-bromoacetophenone (2.89 g, 14.5 mmol), and potassium hydroxide (2.04 g, 36.3 mmol) in ethanol (60 mL) was heated (80°C) for 16 h. The reaction was allowed to cool to rt and was concentrated to dryness. The residue was dissolved in water (200 mL), and the mixture was washed with diethyl ether (2 x 200 mL). The aqueous layer was cooled (00C) and then adjusted to pH 1 using concentrated hydrochloric acid. The resulting red-orange precipitate was collected by filtration and then recrystallized from ethanol to afford 2.00 g (48%) of the desired product. 1H NMR (300 MHz, DMSO-e/6) δ 8.53 (s, 1 H), 8.43 (dd, 1 H), 8.19-8.25 (m, 3 H), 7.72-7.82 (m, 3 H); ES-MS m/z 346.3 [M+H]+, HPLC RT (min) 3.93.
[355] Example 376 Preparation of methyl 2-(4-bromophenyl)-6-fluoroquinoline-4-carboxylate
Figure imgf000153_0002
[356] A mixture of 2-(4-bromophenyl)-6-fluoroquinoline-4-carboxylic acid (Example 375, 1.00 g, 2.89 mmol), iodomethane (0.90 mL, 14.4 mmol), and sodium bicarbonate (490 mg, 5.78 mmol) in DMF (20 mL) was stirred at rt for 3 h. The reaction was diluted with ethyl acetate (25 mL), washed with water (3 x 25 ml_) and brine (1 x 25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1.01 g (97%) of the desired product. 1H NMR (300 MHz, DMSO- Cf6) δ 8.53 (s, 1 H), 8.32 (dd, 1 H), 8.19-8.25 (m, 3 H), 7.23-7.83 (m, 3 H), 4.02 (s, 3 H); ES-MS m/z 360.2 [M+H]+, HPLC RT (min) 4.14.
[357] Example 377
Preparation of r2-(4-bromophenyl)-6-fluoroquinolin-4-vπmethanol
Figure imgf000154_0001
[358] To a cooled (0°C) solution of methyl 2-(4-bromophenyl)-6-fluoroquinoline-4-carboxylate (Example 376, 480 mg, 1.33 mmol) in THF (7 mL) was added DIBAL in THF (1 M, 3.33 mL, 3.33 mmol) dropwise over 5 min. The reaction was allowed to slowly warm to rt. After 3 h, the reaction was cooled (O0C) and additional DIBAL (3.33 mL, 3.33 mmol) was added dropwise. The reaction was allowed to warm slowly to rt. A third aliquot of DIBAL was added as described above, and then the reaction was stirred for an additional 16 h at which time TLC indicated that the reaction had gone to completion. The mixture was cooled (00C) and the reaction was quenched by the very slow addition of saturated aqueous ammonium chloride solution (3 mL). The mixture was allowed to warm to rt and was filtered through a pad of Celite® using ethyl acetate to rinse. The filtrate was washed with water (2 X 10 mL), dried over sodium sulfate, and concentrated to dryness to afford 442 mg (100%) of the desired product. 1H NMR (300 MHz, DMSO-cfe) δ 8.11- 8.21 (m, 4 H), 7.81 (dd, 1 H), 7.74 (ddd, 2 H), 7.68 (ddd, 1 H), 5.69 (t, 1 H), 5.03 (d, 2 H); ES-MS m/z 332.2 [MH-H]+, HPLC RT (min) 3.05.
[359] Example 378
Preparation of methyl fr2-(4-bromophenyl)-6-fluoroquinolin-4-vπmethoxy)acetate
Figure imgf000154_0002
[360] To a cooled (O0C) solution of [2-(4-bromophenyl)-6-fluoroquinolin-4-yl]methanol (Example 377, 750 mg, 2.26 mmol) in DMF (10 mL) was added sodium hydride (68 mg, 2.71 mmol). After 5 min, methyl chloroacetate (0.24 mL, 2.71 mmol) was added. The mixture was allowed to warm to rt and stirred for 3 h. The reaction was quenched with water (20 mL) and then extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with water (2 x 25 mL) and brine (1 x 25 ml_), dried over sodium sulfate, and concentrated to dryness to afford 910 mg of the desired crude product as a yellow oil that was used without purification. ES-MS m/z 404.4 [M+H]+, HPLC RT (min) 3.69.
[361] Example 379
Preparation of methyl fr2-(2'-ethoxybiphenvI-4-vO-6-fluoroquinolin- 4-vπmethoxy)acetate
Figure imgf000155_0001
[362] To a stirred solution of methyl {[2-(4-bromophenyl)-6-fluoroquinolin-4-yl]methoxy}acetate (Example 378, 450 mg, 1.11 mmol), 2-ethoxybenzeneboronic acid (554 mg, 3.34 mmol), and sodium carbonate (354 mg, 3.34 mmol) in DME (7.5 ml_) and water (1.5 ml_) was added [1 ,1'- bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (91 mg, 0.11 mmol). The reaction was heated (50°C) for 16 h and then cooled to rt. The mixture was diluted with ethyl acetate (50 ml_) and then successively washed with water (50 ml_) and 1 N aqueous sodium hydroxide solution (30 ml_), dried over sodium sulfate, and concentrated to dryness. The residue was purified by HPLC using a gradient of 25-75% acetonitrile in water to afford 167 mg (34%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, 2 H), 8.23 (s, 1 H), 8.16 (dd, 1 H), 8.00 (dd, 1 H), 7.67-7.75 (m, 3 H), 7.31-7.41 (m, 2 H), 7.12 (d, 1 H), 7.04 (t, 1 H), 5.09 (s, 2 H), 4.39 (s, 2 H), 4.08 (q, 2 H), 3.71 (s, 3 H), 1.31 (t, 3 H); ES-MS m/z 446.4 [M+Hf, HPLC RT (min) 3.86.
[363] The following compound was prepared using the procedures of Examples 375-379 and substituting the appropriate starting materials.
[364] Table 32
Figure imgf000156_0001
[365] Example 381
Preparation of fr2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-vπ methoxyjacetic acid
Figure imgf000156_0002
[366] A mixture of methyl {[2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl]methoxy}acetate (Example 379,167 mg, 0.37 mmol) and lithium hydroxide (180 mg, 7.50 mmol) in THF (1 ml.) and water (1 ml_) was heated (700C) for 16 h. The solution was cooled to rt, and adjusted to pH 7 using 1N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (3 x 5 mL), and then the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated to dryness to afford 19 mg (12%) of the desired product. 1H NMR (300 MHz, DMSO-CZ6) δ 8.26-8.32 (m, 3 H), 8.22 (s, 1 H), 8.13 (dd, 1 H), 7.65-7.73 (m, 3 H), 7.31-7.41 (m, 2 H), 7.12 (d, 1 H), 7.04 (t, 1 H), 5.04 (s, 2 H), 4.08 (q, 2 H), 4.03 (br s, 2H), 1.31 (t, 3 H); ES- MS m/z 432.3 [M+H]+, HPLC RT (min) 3.86.
[367] The following compound was prepared using the procedure of Example 381 and substituting the appropriate starting materials. [368] Table 33
Figure imgf000157_0001
[369] Example 383
Preparation of 2-(4-bromophenyl)-4-(chloromethyl)-6-fluoroquinoline hydrochloride
Figure imgf000157_0002
[370] A mixture of [2-(4-bromophenyl)-6-fluoroquinolin-4-yl]methanol (Example 377, 1.00 g, 3.01 mmol) and thionyl chloride (3.73 ml_, 51.2 mmol) in dichloromethane (15 ml.) was stirred at rt for 16 h. The reaction was concentrated under reduced pressure to afford 1.17 g of the desired product as a yellow solid that was used without further purification or analysis.
[371] Example 384
Preparation of methyl ΛHr2-(4-bromophertyl)-6-fluoroquinolin-4-yl1 methvDqlvcinate
Figure imgf000157_0003
[372] A mixture of 2-(4-bromophenyl)-4-(chloromethyl)-6-fluoroquinoline hydrochloride (Example 383, 500 mg, 1.29 mmol), glycine methyl ester hydrochloride (162 mg, 1.29 mmol), triethylamine (0.56 mL, 4.00 mmol), and sodium iodide (39 mg, 0.26 mmol) in DMF (8 mL) was heated (400C) overnight. The reaction was cooled to rt and diluted with ethyl acetate (30 mL). This solution was washed with water (3 x 30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated to dryness to afford 459 mg of the desired crude product that was used without purification. ES-MS m/z403 [M+H]+, HPLC RT (min) 2.60. [373] The following compound was prepared using the procedures of Example 384 and substituting the appropriate starting materials.
[374] Table 34
Figure imgf000158_0001
[375] Example 386
Preparation of methyl ΛHr2-(2'-ethoxybiphenyl-4-vO-6-fluoroquinolin-4- yllmethvlTqlycinate
Figure imgf000158_0002
[376] To a stirred solution of methyl Λ/-{[2-(4-bromophenyl)-6-fluoroquinolin-4-yl]methyl} glycinate (Example 384, 225 mg, 0.56 mmol), 2-ethoxybenzeneboronic acid (278 mg, 1.67 mmol), and sodium carbonate (177 mg, 1.67 mmol) in DME (2.5 ml.) and water (0.5 mL) was added [1 ,1 '- bis(diphenylphosphino)-ferrocene]dichloro palladium(ll) (46 mg, 0.06 mmol). The reaction was heated (5O0C) for 16 h and then cooled to rt. The mixture was diluted with ethyl acetate (50 mL), and then washed with water (50 mL), sodium hydroxide (30 mL, 1N aqueous solution), and brine (30 mL). The organic phase was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of 25-75% acetonitrile in water to afford 47 mg (19%) of the desired product. 1H NMR (300 MHz, DMSO-CZ6) δ 8.28 (d, 2 H), 8.18 (s, 1 H), 8.12 (dd, 1 H), 7.99 (dd, 1 H), 7.62-7.73 (m, 3 H), 7.30-7.41 (m, 2 H), 7.11 (d, 1 H), 7.03 (dd, 1 H), 4.22 (s, 2 H), 4.01 (q, 2 H), 3.64 (s, 3 H), 3.50 (br s, 2H), 1.17 (t, 3 H); ES-MS m/z 445.2 [MH-H]+, HPLC RT (min) 3.32.
[377] The following compounds were prepared using the procedure of Example 386 and substituting the appropriate starting materials. [378] Table 35
Figure imgf000159_0002
[379] Example 390
Preparation of ΛHr2-(2'-ethoxybiphenyl-4-vD-6-fluoroquinolin-4-vπ methvDqlycine
Figure imgf000159_0001
[380] A mixture of methyl Λ/-{[2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl]methyl}glycinate (Example 386, 45 mg, 0.10 mmol) and lithium hydroxide (12 mg, 0.51 mmol) in water (0.5 mL) and THF (0.5 mL) was heated (500C) for 6 h. The reaction was cooled to rt, and was diluted with water (5 mL). The solution was washed with ethyl acetate (5 mL) and then adjusted to pH 6 using hydrochloric acid (1 N aqueous solution). The resulting solid was collected by filtration, rinsed with water, and dried to afford 13 mg (31%) of the desired product. 1H NMR (300 MHz, DMSO-Qf6) δ 8.22 (d, 2 H), 8.16 (S, 1 H), 8.07 (dd, 1 H), 7.97 (dd, 1 H), 7.60-7.68 (m, 3 H), 7.24-7.35 (m, 2 H), 7.05 (d, 1 H), 6.97 (dd, 1 H), 4.24 (s, 2 H), 4.01 (q, 2 H), 3.32 (br s, 2H), 1.24 (t, 3 H); ES-MS m/z 431.2 [MH-H]+, HPLC RT (min) 3.23.
[381] The following compound was prepared using the procedures of Example 390 and substituting the appropriate starting materials.
[382] Table 36
Figure imgf000160_0001
[383] Example 394
Preparation of 3-(2'-ethoxybiphenyl-4-yl)-3-oxopropanenitrile
Figure imgf000161_0001
[384] A mixture of 3-(4-bromophenyl)-3-oxopropanenitrile (Example 230, 1.25 g, 5.58 mmol), 2- ethoxyphenylboronic acid (1.39 g, 8.37 mmol), PdCI2(dppf)»CH2CI2 (0.17 g, 0.28 mmol), and 2M aqueous sodium carbonate (8.4 ml_, 16.8 mmol) in DMF (24 ml_) was heated (12O0C) under nitrogen for 16 h. The reaction mixture was cooled to rt and diluted with water (200 mL). The mixture was extracted dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified on by silica gel flash chromatography using 10% ethyl acetate/hexanes to yield 1.1 g (74%) of desired product. 1H NMR (400 MHz, CDCI3) δ 7.95-7.93 (m, 2 H), 7.72-7.70 (m, 2 H), 7.38-7.25 (m, 2 H), 7.06-6.98 (m, 2 H), 4.12 (s, 2 H), 4.07 (q, 2 H), 1.37 (t, 3 H); EI-MS m/z 265 [M]+, GCMS RT (min) 17.0.
[385] Example 395
Preparation of 4-(chloromethvO-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinoline-
3-carbonitrile
Figure imgf000161_0002
[386] A mixture of 1-(2-amino-5-fluorophenyl)-2-chloroethanone (0.50 g, 2.67 mmol), 3-(2'- ethoxybiphenyl-4-yl)-3-oxopropanenitrile (Example 394, 0.71 g, 2.67 mmol), and 4-toluenesulfonic acid dihydrate (27.8 mg, 0.13 mmol) in toluene (13 mL) was refluxed under nitrogen for 12 h and cooled to rt. The reaction mixture was subjected to silica gel chromatography using 5% ethyl acetate/hexanes. The resulting solid was washed with 5% ethyl acetate/hexanes to yield 0.27 g (24%) of desired product. 1H NMR (400 MHz, CDCI3) δ 8.39-8.35 (m, 1 H), 8.02-8.00 (m, 2 H), 7.83-7.67 (m, 4 H), 7.41-7.29 (m, 2 H), 7.06-6.99 (m, 2 H), 5.22 (bs, 2 H), 4.08 (q, 2 H), 1.39 (t, 3 H); ES-MS m/z 417.2 [M+H]+, LCMS RT (min) 4.68. [387] Example 396
Preparation of ethyl N-{r3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin- 4-vπmethvl)-N-methvlglycinate
Figure imgf000162_0001
[388] A mixture of 4-(chIoromethyl)-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinoline-3-carbonitrile (Example 395, 70 mg, 0.17 mmol), sarcosine ethyl ester hydrochloride (38.7 mg, 0.25 mmol), and potassium carbonate (58.0 mg, 0.42 mmol) in THF (3 ml_) was refluxed for 16 h and then cooled to rt. The reaction was diluted with water (15 ml_) and extracted with ethyl acetate (3 x 15 ml_). The combined organic extracts were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by HPLC using a gradient of 60 - 95% acetonitrile in water over 8 min to yield 50.0 mg (60%) of desired product. 1H NMR (400 MHz, DMSO-CZ6) δ 8.52-8.49 (m, 1 H), 8.22-8.18 (m, 1 H), 7.94-7.89 (m, 3 H), 7.72-7.67 (m, 2 H), 7.40- 7.33 (m, 2 H), 7.14-7.03 (m, 2 H), 4.39 (bs, 2 H), 4.16-4.05 (m, 4 H), 3.57 (bs, 2 H), 2.33 (bs, 3 H), 1.31 (t, 3 H), 1.23 (t, 3 H); ES-MS m/z 498.3 [M+H]+, LCMS RT (min) 4.20.
[389] Example 397
Preparation of N-fr3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl1methyl>-N- methylqlvcine
Figure imgf000162_0002
[390] A mixture of ethyl N-{[3-cyano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-4-yl]methyl}-N- methylglycine (Example 396, 50 mg, 0.10 mmol) and lithium hydroxide (12.0 mg, 0.50 mmol) in water (0.7 mL) and THF (2.0 mL) was stirred at rt for 16 h. THF was evaporated under reduced pressure and additional water (10 mL) was added. The pH was adjusted to 3 using 1 N hydrochloric acid and then the aqueous solution was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by HPLC using a gradient of 20 - 95% acetonitrile in water over 8 min to yield 3.2 mg (7%) of desired product. 1H NMR (400 MHz, DMSO-Qf6) δ 8.61-8.58 (m, 1 H), 8.22-8.19 (m, 1 H), 7.93-7.87 (m, 3 H), 7.73-7.70 (m, 2 H), 7.41-7.33 (m, 2 H), 7.14-7.12 (m, 1 H), 7.07-7.03 (m, 1 H), 4.40 (bs, 2 H), 4.09 (q, 2 H), 3.52 (bs, 2 H), 2.33 (bs, 3 H), 1.31 (t, 3 H); ES-MS m/z 470.2 [MH-H]+, LCMS RT (min) 3.64.
[391] The following compound was prepared using the procedures of Example 394-397 and substituting the appropriate starting materials.
[392] T able 37
Figure imgf000163_0001
[393] Example 401
Preparation of ethyl ir3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-
4-vπoxvlacetate
Figure imgf000164_0001
[394] A mixture 2-(2'-ethoxybiphenyl-4-yI)-6-fluoro-4-hydroxyquinoline-3-carbonitrile (Example 232, 250 mg, 0.65 mmol), ethyl bromoacetate (0.36 ml_, 3.25 mmol), and potassium carbonate (269 mg, 1.95 mmol) in DMF (5 ml.) was heated to reflux for 1 h. The mixture was cooled to rt, and excess ethyl bromoacetate was evaporated off. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, then concentrated in vacuo. The crude residue was purified by silica gel flash chromatography using a 3:1 hexanes/ethyl acetate eluent to afford 217 mg (71%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.96 (m, 2 H), 7.76-7.82 (m, 3 H), 7.34-7.47 (m, 4 H), 7.13 (d, 1 H), 7.05 (dddd, 1 H), 4.05-4.15 (m, 4 H), 1.28 (t, 3 H), 1.13 (t, 3 H); ES-MS m/z 471.4 [M+H]+, HPLC RT (min) 3.87.
[395] Example 402
Preparation of fr3-cvano-2-(2'-ethoxybiphenyl-4-v0-6-fluoroquinolin-4- vlloxvlacetic acid
Figure imgf000164_0002
[396] To a solution of ethyl {[3-cyano-2-(2'-ethoxybipheny!-4-yl)-6-fluoroquinolin-4-yl]oxy}acetate (Example 401, 200 mg, 0.43 mmol) in THF (6 mL) was added a solution of lithium hydroxide (51 mg, 2.13 mmol) in water (2 mL) and stirred at rt for 16 hr. The reaction mixture was washed with ethyl acetate, and the combined aqueous fractions were acidified with acetic acid. Product was extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, then concentrated under reduced pressure. The residue was triturated with diethyl ether to afford 18 mg (10%) of the desired product. 1H NMR (300 MHz, DMSO- de) δ 7.88-7.95 (m, 2 H), 7.76-7.82 (m, 3 H), 7.34-7.42 (m, 4 H), 7.12-7.14 (d, 1 H), 7.05 (dddd, 1 H), 4.07 (q, 2 H), 2.64 (t, 2 H), 1.28 (t, 3 H); ES-MS m/z 443.3 [M+H]+, LCMS RT (min) 3.11.
[397] Example 403
Preparation of ethyl 4-fr3-cvano-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinolin-
4-vnoxy)butanoate
Figure imgf000165_0001
[398] A mixture 2-(2'-ethoxybiphenyl-4-yl)-6-fluoro-4-hydroxyquinoline-3-carbonitrile (Example 232, 250 mg, 0.65 mmol), ethyl bromoacetate (0.36 ml_, 3.25 mmol), and potassium carbonate (269 mg, 1.95 mmol) in DMF (5 mL) was heated to reflux for 5 h and then at rt for 72 hr. The mixture was cooled to rt, and excess ethyl bromoacetate was evaporated off. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, then concentrated in vacuo. The crude residue was purified by silica gel flash chromatography using a 3:1 hexanes/ethyl acetate eluent to afford 45 mg (14%) of the desired product. 1H NMR (400 MHz, DMSOd6) δ 8.14 (br s, 1 H), 7.71-7.95 (m, 5 H), 7.58-7.62 (m, 2 H), 7.32-7.40 (m, 2H), 7.01-7.14 (m, 2 H), 4.07-4.08 (m, 4 H), 3.86-3.90 (m, 2 H), 2.21 (m, 2 H), 1.86-1.88 (m, 2 H), 1.24-1.29 (m, 3 H), 1.02-1.06 (m, 3 H); ES-MS m/z 499.4 [M+H]+, HPLC RT (min) 3.93.
[399] Example 404
Preparation 4-(r3-cvano-2-(2'-ethoxybiphenvI-4-yl)-6-fluoroquinolin- 4-vπoxy)butanoic acid
Figure imgf000166_0001
[400] To a solution of ethyl 4-{[3-cyano-2-(2'-ethoxybiphenyl-4-yl)-6-fIuoroquinolin-4- yl]oxy}butanoate (Example 403, 40 mg, 0.08 mmol) in THF (3 mL) was added a solution of lithium hydroxide (10 mg, 0.40 mmol) in water (1 mL) and stirred at rt for 1 hr. The THF was evaporated off, and the aqueous layer was acidified with acetic acid. Product was extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, then concentrated under reduced pressure. The residue was triturated with diethyl ether to afford 18 mg (48%) of the desired product. 1H NMR (400 MHz, DMSOd6) δ 8.18-8.21 (m, 1 H), 7.92-7.95 (dd, 1 H), 7.75-7.85 (m, 3 H), 7.62-7.64 (m, 2 H), 7.34-7.44 (m, 2 H), 7.04-7.14 (m, 2 H), 4.04-4.09 (q, 4 H), 2.12 (t, 2 H), 1.87 (t, 2 H), 1.28 (t, 3 H); ES-MS m/z 471.3 [M+H]+, LCMS RT (min) 3.49.
Methods of Treatment
[401] As used herein, various terms are defined below.
[402] 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.
[403] The term "subject" as used herein includes mammals (e.g., humans and animals).
[404] 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.
[405] The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a disease, condition, and/or disorder. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.
[406] The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in a disease, condition, and/or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
[407] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product.
[408] Compounds of the present invention may be used to treat diseases, such as diabetes, including both type 1 and type 2 diabetes. Such compounds may also delay the onset of diabetes and diabetic complications. Other diseases and conditions that may be treated or prevented using compounds of the present invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40, 1994), Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11 :299, 1994), impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999), impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796, 1991), gestational diabetes (Metzger, Diabetes, 40:197, 1991), and metabolic Syndrome X.
[409] Compounds of the present invention may also be used to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1 ):S5, 1999). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, β-adrenergic agents, α-interferon, and drugs used to treat HIV infection.
[410] cAMP-mediated release of insulin is also dependent on the presence of stimulatory glucose concentrations. A method of the invention further relates to stimulating insulin release from islet cells by the administration of compounds of the present invention. Glucose-dependent stimulation of insulin secretion with non-peptide compounds therefore, lowers blood glucose concentrations without causing hypoglycemia.
[411] 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, a compound of the present invention may be used partially or completely, in combination therapy.
[412] For example, compounds of the present invention may 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, α-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-1 B) inhibitors; dipeptidyl peptidase IV (DPP-IV) inhibitors; and 11beta-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 antagonists 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 , GIP, 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.
[413] 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 adrenergic receptor agonists; CB-1 (cannabinoid) receptor antagonists; neuropeptide Y antagonists; appetite suppressants, such as, for example, sibutramine (Meridia); and lipase inhibitors, such as, for example, orlistat (Xenical). Compounds of the present invention may be administered in combination with other pharmaceutical agents, such as apo-B/MTP inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, dopamine agonists, melanocyte- stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptins, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, ciliary neurotrophic factors, AGRPs (human agouti-related proteins), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, and the like.
[414] In addition, compounds of the present invention may also be administered 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., acipimox); 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.
[415] Furthermore, compounds of the present invention may also be administered 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.
[416] Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the present 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 below.
[417] Other methods of the invention relate to administration of a compound of the present invention for the treatment of dementia (Shimamoto, et al., Mechanisms of Aging Development 5 (4):241-250, 1976; Nicholson, et a!., Trend Pharmacol. Sd. 12 (1): 19-27, 1991).
[418] In a further aspect, methods of the invention relate to treatment of urogenital tract disorders by the administration of a compound of the present invention. Such urogenital tract disorders include, but are not limited to, incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction (including female sexual arousal disorder), and hypertrophy of prostate (Ballard, et al., J. Urology 159 (6):2164-2171 , 1998).
[419] Other methods of the invention relate to administration of a compound of the present invention to treat cardiovascular disorders, such as hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke. Pharmaceutical Compositions
[420] 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 the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient 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.
[421] The compounds of the present invention may be administered as compound perse. Alternatively, the compounds of the present invention may be administered with an acceptable carrier in the form of a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the composition and must not be intolerably deleterious to the recipient. The carrier can be a solid or a liquid, or both, and preferably is formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from about 0.05% to about 95% by weight of the active compound(s) based on a total weight of the dosage form. Other pharmacologically active substances can also be present, including other compounds useful in the treatment of a diabetic condition.
[422] Compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a therapeutically effective dose for the treatment intended. The compounds of the present invention may, for example, be administered orally, sublingually, nasally, pulmonary, mucosally, parenterally, intravascularly, intraperitoneal^, subcutaneously, intramuscularly or topically. Unit dose formulations, particularly orally administrable unit dose formulations such as tablets or capsules, generally contain, for example, from about 0.001 to about 500 mg, preferably from about 0.005 mg to about 100 mg, and more preferably from about 0.01 to about 50 mg, of the active ingredient. In the case of pharmaceutically acceptable salts, the weights indicated above for the active ingredient refer to the weight of the pharmaceutically active ion derived from the salt.
[423] Of course, the specific initial and continuing dosage regimen to prevent, treat, give relief from, or ameliorate a diabetic condition or disorder, or to otherwise protect against or treat a diabetic condition 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, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered with other active ingredients, and the like. The desired mode of treatment and number of doses of a compound may be ascertained by those skilled in the art using conventional treatment tests. [424] The compounds of the present invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. The compounds of the present invention 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.
[425] For oral administration, the compounds of the present invention may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, pastes, syrups, 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. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
[426] The compounds of the present invention may be tableted with conventional tablet bases in combination with binders; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration; 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; 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, 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.
[427] 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. Additional excipients, for example, sweetening, flavoring and coloring agents may also be present.
[428] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The emulsions may also contain sweetening and flavoring agents. Oily suspensions may be formulated by suspending the active ingredient in, for example, a vegetable oil. The oily suspensions may contain a thickening agent; one or more preservatives; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents.
[429] Syrups and elixirs may be formulated with sweetening agents. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
[430] Oral delivery of the compounds of the present invention can include formulations well known in the art to provide immediate delivery or prolonged or sustained delivery of a drug to the gastrointestinal tract by any number of mechanisms. Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, fast-dissolving tablets or capsules, sublingual tablets, disintegrating tablets and the like. Prolonged or sustained delivery formulations include, but are not limited to, pH sensitive release of the active ingredient from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which an active drug molecule is delivered to the site of action by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations may be used in methods of the present invention.
[431] Pharmaceutical compositions can be prepared by any suitable method of pharmacy, which includes the step of bringing into association, the compounds of the present invention and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the compounds of the present invention with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the inhibitors, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made, for example, by molding the powdered compound in a suitable machine.
[432] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
[433] Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a base, and pastilles comprising the compound in an inert base.
[434] The compounds of the present invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids; an alcohol; glycols; glycerol ketals; ethers; 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, suspending agent, or emulsifying agent and other pharmaceutical adjuvants.
[435] 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.
[436] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed. In addition, fatty acids may be used in the preparation of injectables.
[437] 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 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.
[438] Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[439] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011 ,472, incorporated herein by reference.
[440] 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. [441] The total daily dose of a compound can be administered to the patient in a single dose, or in multiple subdoses. Typically, subdoses can be administered two to six times per day, preferably two to four times per day, and even more preferably two to three times per day. Doses can be in immediate release form or sustained release form sufficiently effective to obtain the desired control over the diabetic condition.
[442] The compounds of the present invention may also be utilized 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 a compound of the present invention. An inert carrier is any material which does not interact with a 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.
[443] A compound of the present invention may also be administered as the pharmaceutically acceptable salt, protected acid, conjugate acid, tautomer, prodrug or stereoisomer. Tautomers include, for example, hydroxy tautomers. Protected acids include, but are not limited to, protected acids such as esters, hydroxyamino derivatives, amides and sulfonamides. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see, e.g., Pharmaceutical Dosage Form and Drug Delivery Systems (Sixth Edition), ed. Ansel, et al., Williams & Wilkins (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 Λ/-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, /V-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see, e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), ed. Molinoff, et al., McGraw-Hill (1996), which is hereby incorporated by reference).
[444] Besides being useful for human treatment, administration of a compound of the present invention may also be useful for veterinary treatments of companion animals (e.g., horses, dogs, cats, etc.), exotic animals and farm animals. Even though the invention is described in terms of human biology, it is understood by those of ordinary skill in the art that the present invention is applicable to other mammals as well.
[445] 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).
[446] 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
[447] In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.
[448] 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 activity of the compounds of the present invention, the following assays may be used.
PDEIOA inhibition assay
[449] Test compounds and PDE1 OA enzyme in assay buffer are added to 96-well whitewall/clear bottom isoplates (Wallac). The reaction is initiated by the addition of 3H-CAMP (Amersham). Following a 45-minute incubation at room temperature, the reaction is stopped by the addition of SPA yttrium silicate beads (Amersham). The samples are incubated for an additional 30 minutes, and the plates are read in the Microbeta (Wallac) for 30 seconds in the SPA mode. Data may be expressed as a percentage of control. To measure PDE2, PDE3A, PDE4B, and PDE10A activity, 3H-CAMP may be used as a substrate; and to measure PDE5 activity, 3H- cGMP may be used as a substrate. The activity of several test compounds is shown in Table A.
Dispersed islet assay
[450] Dispersed pancreatic islet isolation. Lean rats (male Sprague-Dawley, 200-250 g) are anesthetized with nembutal (60 mg/kg, i.p.) and the abdomen opened to expose the liver and pancreas. The pancreas is distended by injection of Hank's solution into the bile duct, and then the pancreas is excised and minced with scissors while in Hank's solution. After rinsing the tissue with buffer, the pancreas is digested for 10 minutes with collagenase, rinsed, and the islets separated from debris on a Ficoll gradient. The isolated islet fraction is then rinsed with buffer, incubated with EDTA for 8 minutes, followed by incubation with trypsin and DNAase I for an additional 10 minutes. The dispersed islets are transferred to culture media containing 8 mM glucose, seeded in "V-bottom" 96-well plates (2,500 cells per well), and cultured overnight.
[451] For assaying insulinotropic compounds, the dispersed islets are pre-incubated in 3 mM glucose for 30 minutes. The islets are then transferred to media containing 8 mM glucose, test compounds, and 0.3 uM forskolin; and incubated for an additional 30 minutes. The media is then assayed for insulin content using, for example, a SPA assay. Activity is reported as fold over control (FOC). The activity of several test compounds is shown in Table A. [452] Table A
Figure imgf000176_0001
In vivo assay
[453] Lean rats (male Wistar, 250 - 300 g) are fasted overnight and divided into two groups: vehicle and compound treatment (8 rats per group). Vehicle or compound is administrated via oral gavage (1.5 mL/rat). Three hours later, a glucose solution (30%, 2 g/kg body weight) is injected intraperitoneal^. Tail blood samples are collected at 0, 15, 30, and 60-minute time points after the glucose injection to measure blood glucose using Glucometer (Bayer Diagnostics, Mishawaka, IN).
[454] All publications and patents mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the described methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the field of diabetes or related fields are intended to be within the scope of the following claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

Claims We claim:
1. A method of treating a disease or disorder comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I)
Figure imgf000177_0001
(I)
wherein
X is a group selected from
Figure imgf000177_0002
Y is CR7 or N;
R1 is:
• H,
• (Ci-C6)alkyl,
• (C3-C6)cycloalkyl,
• (Ci-C6)alkoxy,
• (C3-C6)cycloalkoxy,
• (CrC6)thioalkyl,
• halo,
• (CrC6)haloalkyl,
• (CrC6)haloalkoxy, CN, or
• NR6R6;
R2 is:
• H,
• (CrC6)alkyl optionally substituted with (C3-C6)cycloalkyl,
• (C3-C6)cycloalkyl,
• (CrC6)alkoxy optionally substituted with (C3-C6)cycloalkyl,
• (C3-C6)cycloalkoxy,
• (CrC6)thioalkyI,
• halo,
• (C1-C6)haloalkyl,
• (CrC6)haloalkoxy,
• NR6R6,
• (C1-C6)HCyI, or
• (C3-C6)cycloalkyl;
R3 is:
• H,
• (d-C6)alkyl, or
• (C3-C6)cycloalkyl;
R4 and R4 , which may be the same or different, are:
• H,
• (CrC6)haloalkyl,
• (C3-C6)cycloalkyl,
• (CrC6)alkoxy,
• (C3-C6)cycloalkoxy,
• (C1-C6)haloalkoxy, or
• (CrC6)alkyl optionally substituted with aryl, heteroaryl, OH, CN, or NR6R6, or, when taken together, R4 and R4' can join to form a saturated (C3-C6)-cycloalkyl or a (C3- C6)heterocyclyl ring optionally substituted with:
• (CrC6)haloalkyI,
• (C3-C6)cycloalkyl,
• (CrC6)alkoxy,
• (C3-C6)cycloalkoxy,
• (CrC^haloalkoxy, or
• (CVCβJalkyl optionally substituted with aryl, heteroaryl, OH, CN, or NR6R6;
R5 is:
• H,
• aryl,
• heteroaryl, or
• (CrC6)alkyl optionally substituted with an aryl or heteroaryl group;
R6 is:
• H,
• (d-QOalkyl,
• (C3-C6)cycloalkyl, or
• (CrC6)haloalkyl;
R7 is:
• H,
• (C3-C6)alkyl,
• (CrC6)cycloalkyl,
• (CrCe)thioakyl,
• halo, or
• CN; Z is:
H1
(d-CβJalkyl, (C3-C6)cycloalkyl, (CrC6)alkoxy,
• (CrC6)thioaIkyl,
• halo,
• (CrC6)haloalkyi,
• (C3-C6)cycloalkoxy,
• CN,
• thioaryl,
• (C2-C6)alkenyl optionally substituted with aryl, heteroaryl, heterocyclyl, (C3- C6)cycloalkyl, (Ci-C6)haloalkyl, or halo,
• aryl,
• heteroaryl, or
• heterocyclyl,
wherein said aryl, heteroaryl, and heterocyclyl being optionally substituted at any available position by up to 3 independently selected R8 groups, and optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl or heteroaryl ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein said fused ring may be optionally substituted at any available position by up to 3 independently selected R8 groups;
R is selected from
• hydroxy,
• SH,
• formyl,
• halo,
• CN,
• NO2,
• SiMe3,
• C(=O)OH,
• C(=O)-O(CrC6)alkyl, • C(=O)-O-(C3-C6)cycloalkyl,
• (C1-Ce)BCyI1
• C(=O)-(C3-C6)cycloalkyl,
• C(=O)-aryl,
• C(=O)-heteroaryl,
• NR6R6,
• C(=O)NR6R6,
• C(=S)NR6R6,
• (CrC6)alkyl optionally substituted with halo, OH, NR6R6, (C1-C6JaIkOXy, cycloalkyl, CN,
or
Figure imgf000181_0001
wherein Q is CH2, O, S, NR ,60ιR->6, or aryl,
(C1-C6)haloalkyl,
(CrCβJalkoxy optionally substituted with (C3-C6)cycloalkyl, heteroaryl, or aryl,
(C1-C6)thioalkyl,
(C2-C6)alkenyl,
(C1-C6)haloalkoxy,
(C3-C8)cycloalkyl,
(C3-C8)cycloalkoxy, phenoxy optionally substituted on the phenyl ring with halo, (Ci-C6)alkyl, or (C1-
C6)alkoxy, or a mono or bicyclic ring radical selected from the group consisting of: d) a phenyl optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, e) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and f) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R9 groups;
R9 is:
• halo,
• hydroxy,
• 0X0,
• CN, • (d-C6)alkyl optionally substituted with halo, OH, NR6R6, or (CrC6)alkoxy,
• (CrC6)haloalkyl,
• (CrC6)alkoxy,
• (CrC6)thioalkyl,
• (Ci-C6)haloaikoxy,
• (C3-C8)cycloalkyl,
• (C3-C8)cycloalkoxy,
• (C1-Ce)SiCyI1
• C(=O)OH,
• CH2C(=O)OH,
• NR6R6,
• C(=O)NR6R6,
• C(=O)O(CrC6)alkyl, and
• C(=0)0(C3-C6)cyc!oalkyl;
m is 0, 1 , 2, or 3; n is 1 , 2, 3, or 4; p is 0, 1 , or 2;
or pharmaceutically acceptable salts and esters thereof;
with the proviso that when X is An 2 and m _ Oj then Y is C-R7 and R7 is CN or
SO2(CrC6)alkyl.
Figure imgf000182_0001
2. The method of claim 1 , wherein said disease or disorder is diabetes or a diabetes-related disorder.
3. The method of claim 2, wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes.
4. The method of claim 1 , wherein said disease or disorder is Syndrome X .
5. The method of claim 2, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.
6. The method of claim 2, further comprising the step of administering the compound of Formula (I) in combination with one or more pharmaceutical agents.
7. The method of claim 6, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, biguanides, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors, dipeptidyl peptidase IV (DPP-I V) inhibitors, 11 beta- HSD inhibitors, hepatic glucose output lowering compounds, insulin, and anti-obesity agents.
8. The method of claim 7, wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes.
9. The method of claim 4, further comprising the step of administering the compound of Formula (I) in combination with one or more pharmaceutical agents.
10. The method of claim 9, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, biguanides, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, 11 beta- HSD inhibitors, hepatic glucose output lowering compounds, insulin, and anti-obesity agents.
11. The method of claim 6, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.
12. The method of claim 11 , wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, biguanides, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, 11beta- HSD inhibitors, hepatic glucose output lowering compounds, insulin, and anti-obesity agents.
13. The method of claim 6, wherein said pharmaceutical agent is selected from the group consisting of 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.
14. The method of claim 13, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.
15. The method of claim 9, wherein said pharmaceutical agent is selected from the group consisting of 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.
16. The method of claim 1 , wherein said disease or disorder is cardiovascular disease.
17. The method of claim 16, wherein said cardiovascular disease is selected from hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke.
18. The method of claim 1 , wherein said disease or disorder is obesity.
19. The method of claim 18, further comprising the step of administering the compound of Formula (I) in combination with one or more pharmaceutical agents.
20. The method of claim 19, wherein said pharmaceutical agent is selected from the group consisting of β-3 adrenergic receptor agonists, CB-1 receptor antagonists, neuropeptide Y antagonists, appetite suppressants, lipase inhibitors, apo-B/MTP inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptins, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, ciliary neurotrophic factors, AGRPs, ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, and neuromedin U receptor agonists.
21. The method of claim 7, wherein said pharmaceutical agent is selected from the group consisting of β-3 adrenergic receptor agonists, CB-1 receptor antagonists, neuropeptide Y antagonists, appetite suppressants, lipase inhibitors, apo-B/MTP inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptins, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, ciliary neurotrophic factors, AGRPs, ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, and neuromedin U receptor agonists.
22. The method of claim 1 , wherein said disease or disorder is dementia.
23. The method of claim 1 , wherein said disease or disorder is a urogenital tract disorder.
24. The method of claim 23, wherein said urogenital tract disorder is selected from incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction, female sexual arousal disorder, and hypertrophy of prostate
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